key: cord-262135-oic7uvs0 authors: gautier, jean‐françois; ravussin, yann title: a new symptom of covid‐19: loss of taste and smell date: 2020-04-01 journal: obesity (silver spring) doi: 10.1002/oby.22809 sha: doc_id: 262135 cord_uid: oic7uvs0 nan to the editor: as the ongoing covid-19 pandemic rapidly progresses across the globe, quickly obtaining accurate information on symptoms and their progression is vital. since most affected patients have mild to no symptoms, it remains crucial to quickly relate any commonly observed symptoms and to do so widely. cough, fever, and/or trouble breathing are the major symptoms that have been publicly communicated in a consistent manner. meanwhile, the people with the greatest knowledge of current symptoms are the healthcare workers in the countries being most affected (e.g. italy, france, iran), yet they also have the least time to transmit this important information to the greater public. one of the authors (jean-françois gautier), an endocrinologist in paris, has transformed his diabetes and endocrinology inpatient beds at l'hopital lariboisiere, as have other specialized units, into an inpatient unit totally dedicated to covid-19-positive patients. his recent interactions with patients and other doctors have rapidly led to the realization that sudden loss of smell (anosmia) and/or taste (ageusia) may be experienced in the infected, symptoms not commonly reported in china. the other author (yann ravussin), an obesity researcher currently living in geneva, has recently experienced a rapid onset of anosmia following 2 to 3 days of strong fatigue and headache. having presented no fever, coughing, or breathing problems, he initially decided that covid-19 was unlikely based on readily available news outlets and official governmental websites (cdc, swiss government health) yet was subsequently told he likely had the virus but did not reach the criteria for testing based on age and/or symptoms. yet it is slowly emerging that these symptoms are quite common. anosmia has been reported to be found in upwards of 2/3 of patients in germany by epidemiologist hendrik streek (1) while italian and swiss doctors are reporting similar findings with many also displaying ageusia. numbers from south korea suggest that 30% of positive patients had anosmia as the primary presenting symptom. dr. ravussin's frustration on the paucity of information related to the anosmia found online and in normal media outlets pushed him to contact various medical doctors directly working with infected patients on three continents and all confirmed that this presenting symptom is common knowledge within the medical professional communities directly fighting the covid-19 virus. we are writing to the editors to make sure this information is more widely circulated among readers of the journal and hope/suggest that people who present with anosmia and/or ageusia without other symptoms are admitted for testing and realize that they may be affected by the current pandemic. this moment in our lives will be complicated, stressful, and full of unknowns but with better knowledge transfer should come better decision-making to keep us and our loved ones safe.o there's an unexpected loss of smell and taste in coronavirus patients key: cord-264543-b4zwinh2 authors: daher, valéria barcelos; soares oliveira, daniela silva; daher júnior, mauro freitas; júnior de melo fernandes, edson; de castro guimarães, valeriana; bomtempo de castro, joão victor; moya, marcela ibanhes title: anosmia: a marker of infection by the new corona virus date: 2020-06-12 journal: respir med case rep doi: 10.1016/j.rmcr.2020.101129 sha: doc_id: 264543 cord_uid: b4zwinh2 the diagnosis of coronavirus disease 2019 (covid-19) is based on the identification of common symptoms such as fever, tiredness and dry cough. anosmia and ageusia are also in fact symptoms of the infection with the new coronavirus and recently were considered as symptoms by the world health organization. in this case report we present the new onset anosmia during the covid-19 pandemic. the patient, 31-year-old, reported olfactory and gustatory dysfunctions as initial symptoms of mild-to-moderate form of the covid-19. therefore, chemosensory dysfunctions should serve as a warning to health professionals as a possible marker of infection with the new corona virus. in otorhinolaryngology, the post-viral anosmia is a prevalent symptom (40%). although the anosmia and the ageusia are also in fact symptoms of the infection with the new coronavirus and recently were considered as symptoms by the world health organization (who). [1] the new coronavirus, the third human coronavirus, presents a high pathogenicity and transmissibility potential. [2] most infected patients with the coronavirus is asymptomatic or with unrecognised manifestations of the disease. [3] this population is also pointed as the virus main transmission source. [4] the objective of this case report is to describe anosmia and ageusia as emergent initial symptoms of covid-19 (coronavirus disease 2019). patient mfdj, 31-year-old, brown, single, previously healthy, from goiânia, brazil, works as an orthopedics resident physician at são paulo school hospital, brazil, attending patients of the specialty in different sectors, including the intensive care unit, where several patients were under treatment because of infection laboratorialy confirmed of the new corona virus (sars-cov-2). the patient started a sudden symptom of anosmia and ageusia. he denied previous olfactory changes, use of medications and encephalic-skull trauma. denies alcoholism, smoking and use of illegal drugs. after three days, he had corysa, odynophagia, headache, myalgia and asthenia. on the fourth day, there was clinical worsening with an armpit temperature of 37,8°c, dry cough and light thoracic pain. when looking for the emergency, the patient was with fall of the general state, cutaneous pallor, 4 profused sweating and afebrile, oxygen saturation of 94% breathing room air. the examination of the respiratory system reveled respiratory frequency of 20 incursions per minute and pulmonary auscultation showed crackling rales predominating in the right hemithorax and bilateral pulmonary bases. in the otorhinolaryngological clinical evaluation, the oropharynx and anterior rhinopharynx showed no changes. neurological physical examination without changes. in that occasion, the laboratorial examinations showed: vhs -10mm (slightly increased) and blood count, coagulogram, kidney function, hepatic profile (tgo/tgp) and reactive c protein in the normality. the radiographic examination of the chest evidenced the presence of predominant bilateral interstitial infiltrate in the right hemithorax, sparing the pulmonary apex with a slight cephalization of pulmonary vascularization. the computed tomography of paranasal sinuses was unchanged ( figure 1 ). a nasopharyngeal swab was collected with a positive result for the rt-pcr exam for sars-cov2. after clinical diagnosis, it was instituted home treatment with oseltamivir 75 mg an oral tablet every 12 hours for five days, azithromycin 500mg, one oral tablet per day for five days, acetylcysteine syrup 40mg /ml 15 ml orally at night for 5 days and dipyrone if pain or fever, resulting in marked improvement of the signals and symptoms presented by the patient in five days, however, with persistence of anosmia and ageusia. the recovery of smell and taste occurred on the fourteenth day after symptom onset. during this treatment, the patient did not show signs of seriousness that would justify hospitalization. home isolation was maintained for 14 days after the end of respiratory symptoms, with complete recovery of the patient and return to activities without functional impairment. according to the who, the diagnosis of covid-19 is based on the identification of common symptoms such as fever, tiredness and dry cough and severe symptoms such as high fever, pneumonia and dyspnoea. in the case described, the patient presented as initial symptoms anosmia (absence of smell) and ageusia (change in taste) followed by odynophagia, cough, low fever, chest pain and mild respiratory distress, so it was considered suggestive of covid-19 and confirmed, later, by the laboratory examination (rt-pcr) of the patient. [1] the american college of radiology currently considers chest radiography to be the first-line imaging exam in a suspected or confirmed case of covid-19. the examination allows the identification of the presence of consolidation translating to a pneumonia process, which is considered a criterion of severity of the disease according to the degree of involvement. the patient's examination of this case report showed the presence of bilateral interstitial infiltrate and an impairment of less than 50% of the lungs. this is not a specific finding of the covid-19 infection, but it is the one that was most frequently found in published studies, contributing to the clinical diagnosis. [5] the tomography of the paranasal sinuses in association with the ent physical examination are the most sensitive means for the diagnosis of pathologies derived from the nasal cavity and paranasal sinuses. [6] this examination was performed on the patient of the case at the time of the diagnosis and during the anosmia period and showed no structural changes. in the present case, nasofibroscopy was not performed due to the high transmissibility potential of the virus. it is important to perform imaging tests to elucidate the pathophysiology of an emerging disease such as covid-19. anosmia and hyposmia are terms that refer to complete and partial loss of smell, respectively. the sense of smell is strongly associated with gustatory perception, so that patients with anosmia have great difficulty in perceiving the taste of food, thus losing their appetite and pleasure with food. smelling is also associated with the limbic system and some olfactory stimuli can trigger diverse emotional responses and create cortical association with other senses, such as the individual's memory and the perception of the emotional quality of the stimulus. this way, anosmia can have a significant impact on the quality of life of patients, with difficulty in daily activities, mood disorders, decreased appetite. [7] the pathophysiology of olfactory and gustatory changes has not been fully elucidated yest and has been studied. angiotensin-converting enzyme 2 (ace2) is expressed in the nasal mucosa, where it participates in inflammatory processes of respiratory diseases by regulating the levels of inflammatory peptides, such as bradykinin. the most important protein on the surface of the corona virus is protein s (spike), which binds to eca2 to invade the host cell. however, in patients with covid-19, the inflammatory component does not seem to be present as important and, for this reason, the change in smell is generally not accompanied by allergic symptoms as in allergic rhinitis, as was seen in the case patient. therefore, a hypothesis could be that the changes are due to damage caused by the virus to the olfactory pathways, such as an olfactory nerve neuropathy. anosmia was once a symptom described in other coronavirus infections. [8] exposure to an intensive care unit with hospitalized patients diagnosed with covid-19 was mentioned by the patient, and it is found in the literature that the disease is airborne by droplets and aerosols and transmission by contact, directly with the body surface of the patient or indirectly through contact with contaminated objects and surfaces. [6] considering the disease process and severity, the prescription of azithromycin and oseltamivir was used for 5 days with monitoring of respiratory functions and surveillance of signs of severity throughout treatment. measures such as 8 drug maintenance as well as follow-up until complete clinical improvement of the condition and social isolation for 14 days after the disappearance of pulmonary symptoms were followed. [9] the brazilian association of otorhinolaryngology guides the treatment of anosmia to avoid the use of systemic corticosteroids while the covid-19 pandemic is in force. in relation to the use of topical nasal corticosteroids for chronic use, it can be maintained, and the initiation of medication for acute conditions such as that of the patient in the case should be avoided. nasal washing with saline solution can be indicated, however, it can get the entry of the virus into the lower airway and the spread of the virus through the environment easy, and the patient should be well oriented in case of prescription. [10] throughout the treatment, the patient was monitored by the institution's otorhinolaryngology and infectious disease teams until health was completely restored. disregarding the disease evolution process and neglecting early, subclinical or atypical symptoms, such as anosmia and ageusia presented by the patient, can worsen the case leading to death. chemosensory dysfunctions should serve as a warning to health professionals as a possible marker of infection with the new corona virus and its identification aims to interrupt the chain of viral transmission by identifying possible carriers of the virus in order to stimulate early diagnosis and isolation. folha informativa covid-19 (doença causada pelo novo corona vírus) the novel coronavirus (sars-cov-2) emergency and the role of timely and effective national health surveillance. cadernos de saúde pública covid-19: four fifths of cases are asymptomatic, china figures indicate presumed asymptomatic carrier transmission of covid-19 american college of radiology. acr recommendations for the use of chest radiography and computed tomography (ct) for suspected covid-19 infection comparison of diagnostic findings using different olfactory test methods. the laryngoscope anormalidades sensoriais: olfato e paladar potential pathogenesis of ageusia and anosmia in covid 19 patients ministério da saúde do brasil. diretrizes para diagnóstico e tratamento da covid -19. brasília (df) anosmia e tratamentos clínicos/cirúrgicos nasais this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. we know of no conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome.we hope you find our manuscript suitable for publication and look forward to hearing from you in due course. key: cord-272200-wkifto2o authors: rubin, g james; smith, louise e; melendez-torres, gj; yardley, lucy title: improving adherence to ‘test, trace and isolate’ date: 2020-09-10 journal: j r soc med doi: 10.1177/0141076820956824 sha: doc_id: 272200 cord_uid: wkifto2o nan the initial trigger for any test, trace and isolate system begins with a member of the public developing symptoms. unfortunately, the main symptoms of covid-19 (new continuous cough or a high temperature) are non-specific: most people with these symptoms will not have covid-19 (see box 1) . over the course of any major public health incident, symptoms that arise or are exacerbated as a result of heightened anxiety or media reporting are also likely. in other major incidents, the number of patients reporting possible exposure to a hazardous substance or infection and who are eventually found to be unaffected has dwarfed the number of genuine cases by as much as 100 to 1. even if only 1% or 2% of the uk population experience new continuous dry cough or fever, that will still represent an enormous workload for any test, trace and isolate system to cope with. many patients testing negative will have their own, varied health needs and will require targeted reassurance, guidance and, occasionally, onward referral to other health services. 3 patients suffering from health anxiety may prove difficult to reassure and may take up a disproportionate amount of staff time. patients with cough and fever will only make contact with services if they recognise that these may be indicators of covid-19. media reports have spotlighted newsworthy but peripheral symptoms (e.g. 'covid toe', delirium). surveys of the uk population suggest only 59% identify cough, fever and anosmia as 'red flag' symptoms. 4 basic factual education regarding the symptoms of covid-19 will be a pre-requisite for the success of any service. even where patients recognised relevant symptoms, the range of other, more likely explanations will likely delay or dissuade reporting, 5 especially for mild symptoms. during the early stages of the h1n1v pandemic, willingness to report symptoms was linked to severity. 3 media campaigns urging patients not to self-diagnose and not to 'wait and see' whether mild symptoms resolve by themselves will be needed to encourage speedy reporting, particularly as waiting to see if mild symptoms resolve before reporting them is a frequent message to patients in other contexts. other factors are also likely to stand in the way of timely reporting. for example, worry is associated with symptom perception and use of medical services, 6 but worry about covid-19 is showing a slow but steady decline in the uk. 7 concern about using a service properly, being perceived as a 'time waster', and practical aspects such as ease of access and competing demands on your time will also put people off reporting their symptoms. 5 conversely, pressure from friends, family or employers to 'get checked out' may provide motivation to report, 3 as will the offer of a test to resolve uncertainty. isolation is unpleasant and distressing 8 and can lead to severe financial and social costs. it results in no immediate benefit for the index case and is largely an act of altruism. unless people are convinced that they will be fully and quickly recompensed for any financial cost and that their use of the test, trace and isolate system is both expected and respected by their community, then, particularly where symptoms are mild, it may be tempting for some to accept their first assumption that their symptoms are probably unrelated to covid-19. reducing the costs associated with use of the service will be essential to improving its uptake; this could include an early release from isolation if a negative test result is obtained. prioritising rapid testing, especially as some households may develop symptoms multiple times, is therefore essential to the success of the service. among those who test positive, the challenges of maintaining isolation for the full duration, even among those motivated to try, should not be ignored. 9 we used our polling to compare people who reported cough or fever in their household with those who did not. there was no difference in the total number of times people in each group had left their homes in the past 24 hours. only 25% of those in the symptomatic group had followed government guidelines to not leave their home at all. identifying ways to promote adherence to isolation must therefore be a priority. in our polling, receiving help from others from outside the home was linked to people being less likely to break isolation. ensuring that a test, trace and isolate system links people up with community support mechanisms may help promote adherence. when the period of isolation is over, people who have tested positive will need to be warned that we still do not know if people can develop covid-19 more than once and that they must still be careful to avoid spreading infection. in the absence of guidance, social distancing can decrease in those who believe (rightly or wrongly) they have had covid-19. 10 contact tracing only works if the index case is both able and willing to identify their contacts. app-based approaches, which record contacts between app-users automatically and facilitate alerting, are one solution, but come with their own drawbacks 11 and are limited by uptake rates. more traditional methods of contact tracing require the index case to recall information about who they have been close to, know their contact details and volunteer that information. willingness to volunteer this information is not necessarily straightforward. people may be disinclined to cause disruption for some of their contacts, particularly if the cause of that disruption can be we calculated the proportion of participants who reported having either cough or fever themselves as 6.5% (n ¼ 146). the best estimate of covid-19 prevalence in england for the same period is 0.25%. 2 we used a chi-squared test to look for an association between the presence of symptoms in either the respondent themselves or a household member (symptoms present n ¼ 217, symptoms not present n ¼ 1945), and whether the respondent had left their home at least once in the past 24 hours. this showed no significant association ( 2 (1, 2147) ¼ 0.54, p ¼ 0.46). linked back to them. for example, one voluntary group's attempt at a small covid-19 contact-tracing service in sheffield reported that employers dissuaded some of their staff from reporting contacts from within the organisation. 12 guaranteeing that people may use the service confidentially, and that their details will be well-guarded against accidental disclosure, is essential if people are to trust the system. 11 giving people the option to notify contacts themselves rather than having someone else, or an app, undertake this task may increase cooperation and decrease the perception of intrusiveness. relatedly, some evidence from contact tracing for sexually transmitted infections via geosocial networking apps suggests automatic notification may be preferred for casual partners, whereas contact notification for proximal relationships is still preferred. 13 alerting contacts that they may have been in touch with an index case can occur in a variety of ways, including a message on a mobile phone app, an sms, an email or a phone call. bogus contract tracing messages are already known to be circulating, which will reduce engagement with genuine messages. an electronic alerting system will therefore require a mechanism for people to verify a message. contact tracing is also viewed as more acceptable against a background of high levels of trust in an individualised provider. personalising that provider as, for example, a health visitor or other public health clinician can increase acceptability of contact tracing, even where contact tracing is undertaken using a technological solution. the anonymity of the test, trace and isolate system and quarantine's financial and social impact may also work against the likelihood of a contact's compliance. if employers or neighbours are unaware that the individual is meant to be in quarantine, there will be limited social support or pressure to remain at home. altruism will therefore be a key motivator. contact tracing is viewed as more acceptable when framed in terms of an appeal to duty and being 'the right thing to do'. 14 the large volume of symptoms in the community mean that some people, particularly those with many contacts, might be asked to quarantine multiple times. some proposed systems therefore only isolate contacts based on a positive test result in the index case. however, for some people, particularly those with regular contact with people who are clinically vulnerable, a very early warning that they may be at risk may be valuable. this may allow them to avoid or reduce contact with vulnerable people while the index case awaits results. implementing the test, trace and isolate system poses a complex set of behavioural challenges for the individual, involving self-diagnosis, self-referral and selfmanagement. as with other contexts, 15 adherence to these steps will be improved if we ensure that people understand exactly when and how to act, are motivated by perceived personal and sociocultural benefits, and are helped to overcome the many practical and social barriers to adherence. ethical approval: not applicable. guarantor: gjr. contributorship: all authors are currently providing advice to the uk government about the covid-19 pandemic. rubin had the idea for the article. smith led on the survey. rubin wrote the first draft. all authors contributed to developing the idea and revising manuscript drafts. the corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. factors associated with adherence to self-isolation and lockdown measures in the uk; a cross-sectional survey reassuring and managing patients with concerns about swine flu: qualitative interviews with callers to nhs direct what are the symptoms of covid-19? only 59% of britons know all three the andersen model of total patient delay: a systematic review of its application in cancer diagnosis do health people worry? modern health worries, subjective health complaints, perceived health, and healthcare utilization the psychological impact of quarantine and how to reduce it: rapid evidence review how to improve adherence with quarantine: rapid review of the evidence the impact of believing you have had covid-19 on behaviour: cross-sectional survey exit through the app store? uk's first coronavirus contact-tracing group warns of difficulties. the guardian attitudes about the use of geosocial networking applications for hiv/std partner notification: a qualitative study the right thing to do: patients' views and experiences of telling partners about chlamydia improving patient adherence: a three-factor model to guide practice we are grateful to the helpful comments from cathy rice and jennifer bostock, who acted as lay advisors and reviewed this manuscript for concept and clarity. key: cord-300550-l28tadhn authors: luers, jan c; rokohl, alexander c; loreck, niklas; wawer matos, philomena a; augustin, max; dewald, felix; klein, florian; lehmann, clara; heindl, ludwig m title: olfactory and gustatory dysfunction in coronavirus disease 19 (covid-19) date: 2020-05-01 journal: clin infect dis doi: 10.1093/cid/ciaa525 sha: doc_id: 300550 cord_uid: l28tadhn coronavirus-disease-2019 (covid-19) caused by the severe-acute-respiratory-syndrome-coronavirus-2 (sars-cov-2) shows a rapid spread over-the-world. given scarce resources, non-laboratory diagnostics is crucial. in this cross-sectional study, two-thirds of european patients with polymerase chain reaction confirmed covid-19 reported olfactory and gustatory dysfunction, indicating the significance of this history in the early diagnostics. m a n u s c r i p t the rapid spread of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) urges clinicians and researchers to analyze the virus, characterize the disease, and find suitable treatment strategies. currently, fever, (dry) cough and fatigue are regarded as the main and most common symptoms in the early disease stage of especially with the transfer of the pandemic to europe, olfactory dysfunction has emerged as a new symptom of 3 interestingly, this symptom was not reported by most of the early studies from china 4,5 and still seems rather uncommon in chinese covid-19 patients, 1 accounting for only up to 5% of the patients. 6 herein, we show for the first time the high prevalence of reduced olfaction and decreased sense of taste in european covid-19 patients. this study was conducted by the university hospital of cologne, cologne, germany in adherence to the tenets of the declaration of helsinki and its later amendments. outpatients who had polymerase chain reaction (pcr) confirmed covid-19 in a deep throat-swab between 22 th and 28 th march 2020 were retrospectively identified by the records of the university hospital of cologne, cologne, germany. beside a covid-19 confirmed by polymerase chain reaction (pcr) in a deep throat-swab (which is the institutional screening standard for diagnosis of sars-cov-2), inclusion criteria were age ≥ 18 years and adequate command of the german language. exclusion criteria were hospitalization in the past or at the current time point caused by covid-19 or at the current time point due to other reasons. all included patients were asked using a standardized twosection questionnaire. section 1 requested demographic data and general information, including the date of positive pcr confirmed test and date of contact to confirmed covid-19 patients. section 2 assessed the detailed history of symptoms potentially associated with covid-19. first of all, patients were asked for the onset of fever, cough, sore throat, rhinitis, muscle aches, headache, diarrhea, reduced olfaction, and a reduced sense of taste during covid-19. if yes, date of the beginning of each symptom was recorded. furthermore, total nasal symptom score (tnss) was evaluated as the sum of scores for each of nasal congestion, sneezing, a c c e p t e d m a n u s c r i p t nasal itching, and rhinorrhea during covid-19 using a four-point scale (0-3). 7 a score of 0 indicated no symptoms, 1 documented mild symptoms that were easily tolerated, 2 described the awareness of symptoms which were bothersome but tolerable, and 3 matched severe symptoms that were hard to tolerate and interfered with daily activities or sleep. tnss was then calculated by adding the score for each of the symptoms to a total score between 0-12. all statistical analyses were performed using commercial software (spss version 26.0 for windows; spss, inc., chicago, il.). to investigate factors related to reduced olfaction as well as to a reduced sense of taste two general linear models were used with explanatory variables of age, gender, tnss, fever, cough, sore throat, rhinitis, and headache, respectively. furthermore, the associations between reduced olfaction and the sense of taste were investigated. the threshold for statistical significance was set at p < 0.05. 72 patients with polymerase chain reaction confirmed covid-19 agreed to participate and were enrolled in this study. none declined. out of these 72 participants, 41 were males and 31 females with a mean age of 38 ± 13 years (range, 21 -87 years; table 1 ). 44 of the 72 included patients (61%) had known contact with individuals with confirmed covid-19. the mean potential incubation time of these 44 patients was 3 ± 2 days. patients were asked 13 ± 3 days (range, 6 -22 days) after the first symptom occurred and 7 ± 1 days (range, 3 -9 days) after a positive covid-19 test. the most common general symptoms included headache (78%), cough (75%), and muscle aches (71%) while diarrhea was relatively rare (31%; table 1 ). reduced olfaction occurred in 53 covid-19 patients (74%) while reduced a sense of taste was present in 50 covid-19 patients (69%). 49 patients (68%) reported both symptoms, while one patient (1%) had only reduced sense of taste and four patients (6%) only reduced olfaction. both symptoms occurred on average at the fourth day after the first symptoms had been noted. however, nine patients (13%) noticed that reduced olfaction and loss of sense occurred together on the first day they realized any symptoms. one patient had reduced sense of taste alone at the first day he realized any symptoms. regarding nasal symptoms, mean tnss was 2.71 ± 2.50 (range, 0 -9; table 2 ). while a lot of patients had nasal congestion (54%), nasal sneezing (50%), and rhinorrhea (53%), nasal itching was rare (11%). none of the included participants reported new medical treatment potentially influencing the sense of smell and taste. a c c e p t e d m a n u s c r i p t the regression model for reduced olfaction was not significant (anova: = 0.610) while the model for reduced sense of taste was highly significant (anova: < 0.001). none of the investigated demographic factors including age and gender were associated with reduced olfaction or reduced sense of taste (p ≥ 0.05, respectively). in addition, fever, cough, sore throat, rhinitis, headache, and tnss were also not associated with reduced olfaction or reduced sense of taste (p ≥ 0.05, respectively). however, there was significance between the presence of reduced olfaction and a reduced sense of taste (p < 0.001). our study shows for the first time that both olfactory and gustatory dysfunction is very common in covid-19 patients, with olfactory dysfunction even leveling the symptom 'cough' at > 70%. we also demonstrate that rhinitis and many of its associated symptoms (nasal congestions, sneezing, and rhinorrhea) regularly occur in these patients, a finding that has not been reported before. others often see olfactory dysfunction as a standalone nasal symptom in covid-19 patients. 7 surprisingly, in participants of our study rhinitis was not associated with reduced olfaction. future studies must show whether there is really no pathophysiological link between the two but just a co-existence. in addition, patients were not tested for other respiratory tract pathogens and therefore other infections were not excluded. this fact and the missing matched control group are significant limitations of this study and have to be evaluated in further studies. according to the results of the tnss the measured nasal symptoms (not the olfactory dysfunction) are mostly mild in nature and not particularly bothersome to these patients. both, olfactory and gustatory dysfunction seem to develop in the early to mid-phase (average 4th day after the onset of symptoms) of the disease. there was only one participant of our study showing olfactory/gustatory dysfunction as the first symptom at all, but we would still regard it as a possible early-warning symptom, especially if it comes along without rhinitis. whether or not gustatory problems in covid-19 patients really target the sense of taste is unclear. the gustatory system (transmitted via the glossopharyngeal, facial and vagal nerve) only recognizes the basic tastes (sweet, sour, salty, bitter and umami (glutamate)), but most of the culinary experiences are recognized by the olfactory nerve. the fact that one of our patients experienced gustatory dysfunction alone with no smelling problems, indicates that more than one pathophysiological pathway might exist. many viruses affecting the upper aerodigestive tract (e.g. rhinovirus, parainfluenza epstein-barr virus, and some coronavirus) can lead to olfactory dysfunction, mostly through an inflammatory reaction of the nasal a c c e p t e d m a n u s c r i p t mucosa. the pathophysiology through which sars-cov-2 affects the olfactory system is unclear. a key receptor for the entry of sars-cov-2 into the host cells is angiotensin-converting-enzyme-2 (ace2). 8 this receptor is expressed in multiple organs (heart, lungs, kidney, intestines, buccal cavity, brain, etc.). a recent preprint study from india reported that inside the olfactory mucosa, the expression of ace2 is restricted to a subset of sustentacular and horizontal basal cells and not the olfactory sensory neurons. 8 thus, sustentacular and horizontal basal cells are thought to be highly susceptible to viral entry. nonetheless, although these cells play a role in the maintenance of the olfactory organ (i.e., metabolic and physical support to the olfactory mucosa as well as regeneration) they are not sensory in function. still little is known about which cells of the olfactory mucosa are affected by sars-cov-2 and whether the virus can directly attack sensory cells or the olfactory bulb directly. detailed clinical evaluation and functional tests regarding olfactory and gustatory dysfunctions including exact grading and duration of the complaints are now a high priority. a c c e p t e d m a n u s c r i p t notes: acknowledgment: all procedures performed in this were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. formal approval to conduct this study was obtained from the ethics committee of the university of cologne (no. 20-1161) . informed consent was obtained from all study participants. none of the authors has a conflict of interest. all authors have no financial or proprietary interest in any material or method mentioned in the manuscript. all authors have control of all primary data and they agree to allow to review the data upon request. nasal sneezing, mean ± sd (range) none, n (%) mild, n (%) total nasal symptom score, mean ± sd (range) 2.71 ± 2.50 (range 13.38 ± 3.20 (range, 6 -22) a c c e p t e d m a n u s c r i p t key: cord-020846-mfh1ope6 authors: zlabinger, markus; hofstätter, sebastian; rekabsaz, navid; hanbury, allan title: dsr: a collection for the evaluation of graded disease-symptom relations date: 2020-03-24 journal: advances in information retrieval doi: 10.1007/978-3-030-45442-5_54 sha: doc_id: 20846 cord_uid: mfh1ope6 the effective extraction of ranked disease-symptom relationships is a critical component in various medical tasks, including computer-assisted medical diagnosis or the discovery of unexpected associations between diseases. while existing disease-symptom relationship extraction methods are used as the foundation in the various medical tasks, no collection is available to systematically evaluate the performance of such methods. in this paper, we introduce the disease-symptom relation collection (dsr-collection), created by five physicians as expert annotators. we provide graded symptom judgments for diseases by differentiating between relevant symptoms and primary symptoms. further, we provide several strong baselines, based on the methods used in previous studies. the first method is based on word embeddings, and the second on co-occurrences of mesh-keywords of medical articles. for the co-occurrence method, we propose an adaption in which not only keywords are considered, but also the full text of medical articles. the evaluation on the dsr-collection shows the effectiveness of the proposed adaption in terms of ndcg, precision, and recall. disease-symptom knowledge bases are the foundation for many medical tasks -including medical diagnosis [9] or the discovery of unexpected associations between diseases [12, 14] . most knowledge bases only capture a binary relationship between diseases and symptoms, neglecting the degree of the importance between a symptoms and a disease. for example, abdominal pain and nausea are both symptoms of an appendicitis, but while abdominal pain is a key differentiating factor, nausea does only little to distinguish appendicitis from other diseases of the digestive system. while several disease-symptom extraction methods have been proposed that retrieve a ranked list of symptoms for a disease [7, 10, 13, 14] , no collection is available to systematically evaluate the performance of such methods [11] . while these method are extensively used in downstream tasks, e.g., to increase the accuracy of computer-assisted medical diagnosis [9] , their effectiveness for disease-symptom extraction remains unclear. in this paper, we introduce the disease-s ymptom relation collection (dsrcollection) for the evaluation of graded disease-symptom relations. the collection is annotated by five physicians and contains 235 symptoms for 20 diseases. we label the symptoms using graded judgments [5] , where we differentiate between: relevant symptoms (graded as 1) and primary symptoms (graded as 2). primary symptoms-also called cardinal symptoms-are the leading symptoms that guide physicians in the process of disease diagnosis. the graded judgments allow us for the first time to measure the importance of different symptoms with grade-based metrics, such as ndcg [4] . as baselines, we implement two methods from previous studies to compute graded disease-symptom relations: in the first method [10] , the relation is the cosine similarity between the word vectors of a disease and a symptom, taken from a word embedding model. in the second method [14] , the relation between a disease and symptom is calculated based on their co-occurrence in the meshkeywords 1 of medical articles. we describe limitations of the keyword-based method [14] and propose an adaption in which we calculate the relations not only on keywords of medical articles, but also on the full text and the title. we evaluate the baselines on the dsr-collection to compare their effectiveness in the extraction of graded disease-symptom relations. as evaluation metrics, we consider precision, recall, and ndcg. for all three metrics, our proposed adapted version of the keyword-based method outperforms the other methods, providing a strong baseline for the dsr-collection. the contributions of this paper are the following: -we introduce the dsr-collection for the evaluation of graded disease-symptom relations. we make the collection freely available to the research community. 2 -we compare various baselines on the dsr-collection to give insights on their effectiveness in the extraction of disease-symptom relations. in this section, we describe the new disease-s ymptom relation collection (dsr-collection) for the evaluation of disease-symptom relations. we create the collection in two steps: in the first step, relevant disease-symptom pairs (e.g. appendicitis-nausea) are collected by two physicians. they collect the pairs in a collaborative effort from high-quality sources, including medical textbooks and an online information service 3 that is curated by medical experts. in the second step, the primary symptoms of the collected disease-symptom pairs are annotated. the annotation of primary symptoms is conducted to incorporate a graded relevance information into the collection. for the annotation procedure, we develop guidelines that briefly describe the task and an online annotation tool. then, the annotation of primary symptoms is conducted by three physicians. the final label is obtained by a majority voting. based on the labels obtained from the majority voting, we assign the relevance score 2 to primary symptoms and 1 to the other symptoms, which we call relevant symptoms. in total, the dsr-collection contains relevant symptoms and primary symptoms for 20 diseases. we give an overview of the collection in table 1 . for the 20 diseases, the collection contains a total of 235 symptoms, of which 55 are labeled as primary symptom (about 25%). the top-3 most occurring symptoms are: fatigue which appears for 15 of the 20 diseases, fever which appears for 10, and coughing which appears for 7. notice that the diseases are selected from different medical disciplines: mental (e.g. depression), dental (e.g. periodontitis), digestive (e.g. appendicitis), and respiration (e.g. asthma). we calculate the inter-annotator agreement using fleiss' kappa [2] , a statistical measure to compute the agreement for three or more annotators. for the annotation of the primary symptoms, we measure a kappa value of κ = 0.61, which indicates a substantial agreement between the three annotators [6] . individual κ-values per disease are reported in table 1 . by analyzing the disagreements, we found that the annotators labeled primary symptoms with varying frequencies: the first annotator annotated on average 2.1 primary symptoms per disease, the second 2.8, and the third 3.8. vocabulary compatibility: we map each disease and symptom of the collection to the unified medical language system (umls) vocabulary. the umls is a compendium of over 100 vocabularies (e.g. icd-10, mesh, snomed-ct) that are cross-linked with each other. this makes the collection compatible with the umls vocabulary and also with each of the over 100 cross-linked vocabularies. although the different vocabularies are compatible with the collection, a fair comparison of methods is only possible when the methods utilize the same vocabulary since the vocabulary impacts the evaluation outcome. for instance, the symptom loss of appetite is categorized as a symptom in mesh; whereas, in the cross-linked umls vocabulary, it is categorized as a disease. therefore, the symptom loss of appetite can be identified when using the mesh vocabulary, but it cannot be identified when using the umls vocabulary. evaluation: we consider following evaluation metrics for the collection: recall@k, precision@k, and ndcg@k at the cutoff k = 5 and k = 10. recall measures how many of the relevant symptoms are retrieved, precision measures how many of the retrieved symptoms are relevant, and finally, ndcg is a standard metric to evaluate graded relevance [5] . in this section, we discuss disease-symptom extraction methods used in previous studies. a commonly used resource for the extraction of disease-symptom relations are the articles of the pubmed database. pubmed contains more than 30 million biomedical articles, including the abstract, title, and various metadata. previous work [3, 7] uses the abstracts of the pubmed articles together with rule-based approaches. in particular, hassan et al. [3] derive patterns of disease-symptom relations from dependency graphs, followed by the automatic selection of the best patterns based on proposed selection criteria. martin et al. [7] generate extraction rules automatically, which are then inspected for their viability by medical experts. xia et al. [13] design special queries that include the name and synonyms of each disease and symptom. they use these queries to return the relevant articles, and use the number of retrieved results to perform a ranking via pointwise mutual information (pmi). the mentioned studies use resources that are not publicly available, i.e., rules in [3, 7] and special queries in [13] . to enable reproducibility in future studies, we define our baselines based on the methods that only utilize publicly available resources, described in the next section. here, we first describe two recently proposed methods [10, 14] for the extraction of disease-symptom relations as our baselines. afterwards, we describe limitations of the method described in [14] and propose an adapted version in which the limitations are addressed. we apply the methods on the open-access subset of the pubmed central (pmc) database, containing 1,542,847 medical articles. to have a common representation for diseases/symptoms across methods (including an unique name and identifier), we consider the 382 symptoms and 4,787 diseases from the medical subject headings (mesh) vocabulary [14] . given the set of diseases (x) and symptoms (s), each method aims to compute a relation scoring function λ(x, s) ∈ r between a disease x ∈ x and a symptom s ∈ s. in the following, we explain each method in detail. embedding: proposed by shah et al. [10] , the method is based on the cosine similarity of the vector representations of a disease and a symptom. we first apply metamap [1] , a tool for the identification of medical concepts within a given text, to the full text of all pmc articles to substitute the identified diseases/symptoms by their unique names. then, we train a word2vec model [8] with 300 dimensions and a window size of 15, following the parameter setting in [10] . using the word embedding, the disease-symptom relation is defined as λ(x, s) = cos(e x , e s ), where e refers to the vector representation of a word. cooccur: this method, proposed by zhou et al. [14] , calculates the relation of a disease and a symptom, by measuring the degree of their co-occurrences in the mesh-keywords of medical articles. the raw co-occurrence of the disease x and symptom s, is denoted by co(x, s). the raw co-occurrence does not consider the overall appearance of each symptom across diseases. for instance, symptoms like pain or obesity tend to co-occur with many diseases, and are therefore less informative. hence, the raw co-occurrence is normalized by an inverse symptom frequency (isf) measure, defined as isf(s) = |x| ns , where |x| is the total number of diseases and n s is the number of diseases that co-occur with s at least in one of the articles. finally, the disease-symptom relation is defined as λ(x, s) = co(x, s) × isf(s). we compute three variants of the cooccur method: -kwd: the disease-symptom relations are computed using the mesh-keywords of the ≈1.5 million pmc articles. -kwdlarge: while kwd uses the 1.5 million pmc articles, zhou et al. [14] apply the exact same method on the ≈30 million articles of the pubmed database. while they did not evaluate the effectiveness of their diseasesymptom relation extraction method, they published their relation scores which we will evaluate in this paper. -fulltext: applying the cooccur method only on mesh-keywords has two disadvantages: first, keywords are not available for all articles (e.g. only 30% of the ≈1.5 million pmc articles have keywords) and second, usually only the core topics of an article occur as keywords. we address these limitations by proposing an adaption of the cooccur method, in which we use the full text, the title, and the keywords of the ≈1.5 million pmc articles. specifically, we adapt the computation of the co-occurrence co(x, s), as follows: we first retrieve a set of relevant articles to a disease x, where an article is relevant if the disease exists in either the keyword, or the title section of the article. given these relevant articles and a symptom s, we compute the adapted co-occurrence co(x, s), which is the number of relevant articles in that the symptom occurs in the full text. the identification of the diseases in the title and symptoms in the full text is done using the metamap tool [1] . we now compare the disease-symptom extraction baselines on the proposed dsrcollection. the results for various evaluation metrics are shown in table 2 . the fulltext-variant of the cooccur method outperforms the other baselines on all evaluation metrics. this demonstrates the high effectiveness of our proposed adaption to the cooccur method. further, we see a clear advantage of the cooccur-method with meshkeywords from ≈30 million pubmed articles as the resource (kwdlarge) -in comparison to the same method with keywords from approximately 1.5 million pmc articles (kwd). this highlights the importance of the number of input samples to the method. error analysis: a common error source is a result of the fine granularity of the symptoms in the medical vocabularies. for example, the utilized mesh vocabulary contains the symptoms abdominal pain and abdomen, acute 4 . both symptoms can be found in the top ranks of the evaluated methods for the disease appendicitis (see table 3 ). however, since the corpus is not labeled on such a fine-grained level, the symptom abdomen, acute is counted as a false positive. another error source is a result of the bias in medical articles towards specific disease-symptom relationships. for instance, between the symptom obesity and periodontitis 5 a special relationship exists, which is the topic of various publications. despite obesity not being a characteristic symptom of a periodontitis, all methods return the symptom in the top-3 ranks. a promising research direction is the selective extraction of symptoms from biomedical literature by also considering the context (e.g. in a sentence) in that a disease/symptom appears. effective mapping of biomedical text to the umls metathesaurus: the metamap program measuring nominal scale agreement among many raters extracting disease-symptom relationships by learning syntactic patterns from dependency graphs cumulated gain-based evaluation of ir techniques binary and graded relevance in ir evaluations -comparison of the effects on ranking of ir systems the measurement of observer agreement for categorical data symptom extraction issue distributed representations of words and phrases and their compositionality automated medical diagnosis by ranking clusters across the symptom-disease network neural networks for mining the associations between diseases and symptoms in clinical notes enhancing ontology-driven diagnostic reasoning with a symptom-dependency-aware naïve bayes classifier evaluating wikipedia as a source of information for disease understanding mining disease-symptom relation from massive biomedical literature and its application in severe disease diagnosis human symptoms-disease network we introduced the disease-s ymptom relation collection (dsr-collection) for the evaluation of graded disease-symptom relations. we provided baseline results for two recent methods, one based on word embeddings and the second on the cooccurrence of mesh-keywords of medical articles. we proposed an adaption to the co-occurrence method to make it applicable to the full text of medical articles and showed significant improvement of effectiveness over the other methods. key: cord-275391-dmfacaua authors: liu, yuan; chen, hongguang; zhang, nan; wang, xing; fan, qinyi; zhang, yuling; huang, liping; hu, bo; li, mengqian title: anxiety and depression symptoms of medical staff under covid-19 epidemic in china date: 2020-09-07 journal: j affect disord doi: 10.1016/j.jad.2020.09.004 sha: doc_id: 275391 cord_uid: dmfacaua background: : it is well known that unexpected pandemic has led to an increase in mental health problems among a variety of populations. methods: in this study, an online non-probability sample survey was used to anonymously investigate the anxiety and depression symptoms among medical staff under the covid-19 outbreak. the questionnaire included perceived stress scale-10 (pss-10), generalized anxiety disorder 7-item scale (gad-7) and patient health questionnaire-9 (phq-9). factors associated with anxiety and depression symptoms were estimated by logistic regression analysis. results: a total of 1090 medical staff were investigated in this study. the estimated self-reported rates of anxiety symptoms, depression symptoms and both of the two were 13.3%, 18.4% and 23.9% respectively. factors associated with self-reported anxiety symptoms include married status (or=2.3, 95%ci: 1.2, 4.4), not living alone (or=0.4, 95%ci: 0.2, 0.7), never confiding their troubles to others (or=2.2, 95%ci: 1.4, 3.5) and higher stress (or=14.4, 95%ci: 7.8, 26.4). factors associated with self-reported depression symptoms include not living alone (or=0.4, 95%ci: 0.3, 0.7), sometimes/often getting care from neighbours (or=0.6, 95%ci: 0.4, 0.9), never confiding their troubles to others (or=2.0, 95%ci: 1.3, 3.0) and higher stress (or=9.7, 95%ci: 6.2, 15.2). limitations: the study was a non-probability sample survey. besides, scales used in this study can only identify mental health states. conclusions: under outbreak of covid-19, self-reported rates of anxiety symptoms and depression symptoms were high in investigated medical staff. psychological interventions for those at high risk with common mental problems should be integrated into the work plan to fight against the epidemic. an outbreak of pneumonia was reported in central china's wuhan city in december 2019. the disease, which has spread across china and beyond, is caused by a novel coronavirus, officially named as covid-19. it has gained intense attention both nationwide and globally (xiang et al., 2020) . at 3:32 a.m., on january 31, 2020, the world health organization declared that the outbreak constituted a public health emergency of international concern (pheic) (who, 2020) . pheic was defined as "unusual events that pose public health risks to other countries through the international spread of disease and may require a coordinated international response." as of 11 february, a total of 1716 medical staff were confirmed to have covid-19 infections in mainland china, accounting for 3.8% of all confirmed cases (the novel coronavirus pneumonia emergency response epidemiology team, 2020). as of feb. 23, there have been more than 330 medical teams composed of more than 41600 medical staff to support hubei province. as of 9:03 p.m., on april 16, 2020, covid-19 has spread rapidly worldwide, particularly in the united states of america (total confirmed cases: 639,733), spain (total confirmed cases: 182,816), italy (total confirmed cases: 165,155), germany (total confirmed cases: 134,753), and france (total confirmed cases: 134,598) (johns hopkins university, 2020). whether in wuhan or elsewhere, all medical staff were under tremendous pressure, resulting from overwork, a high risk of infection, uncertainty about medical technology and personal capabilities, a lack of contact with their families, and isolation during covid-19 (kang et al., 2020) . the severe situation might cause mental health problems such as stress, anxiety, depressive symptoms, insomnia, denial, anger, and fear (kang et al., 2020) . several studies have reported mental health problems among medical staff (zhang et al., 2020; lu et al., 2020; guo et al., 2020) , however, the results vary depending on the measurement tools, survey time and location. this survey, based on non-probability sampling design, was conducted from 24 february to 9 march, 2020. we surveyed medical staff who had been working in the hospitals during the outbreak, using an online questionnaire administered via a web-based survey platform. during the survey, the quick response code (qr code) linked the online questionnaire was sent to the wechat group of eight hospitals located in seven provinces. among the respondents, there were also a small number of participants who were contacted through the help of medical staff working in hospitals. only clinical healthcare workers were included, and non-clinical were excluded, such as administrative personnel, logisticians and ambulance drivers. those who have come into contact with fever patients or patients with covid-19 are defined as the front-line medical staff. each individual could complete the questionnaire only once. electronic informed written consent was obtained from all respondents before the data collection. besides, the research was approved by the research ethics board at the first affiliated hospital of nanchang university (ethical number: 2020-048). the measurements contained the following four parts: sociodemographic data and others, perceived stress scale-10, generalized anxiety disorder 7-item scale and patient health questionnaire-9. sociodemographic data and others: sociodemographic data included gender, age, qualification, marital status, the nature of work, job type, professional title, and work experience. besides, other questions included "whether living alone", "the frequency of caring from the neighbours (never/almost never or sometimes/often)", "the frequency of helping from friends (never/almost never or sometimes/often)", "whether confiding their troubles to others", "do you need to contact fever patients or patients diagnosed with covid-19?" perceived stress scale-10 (pss-10): this questionnaire had a professional appearance, and was formatted in such a way as to make it easy to fill in (lee, 2012) . each of the 10 items was divided into a five-point frequency scale (0=never; 1=almost never; 2=sometimes; 3=fairly often; 4=very often) in relation to the past month. the pss-10 consisted of six negative items and four positive items. the positive items were reversely coded when calculating the total score of the pss-10 (cohen et al., 1983) . scores for 10 items were summed to obtain a pss-10 total score, ranging from 0 to 40. higher scores indicated a higher level of perceived stress. in this study, higher stress was defined as a total score of pss-10 ≥15. generalized anxiety disorder 7-item (gad-7) scale: this was a self-rating measure used to assess general anxiety disorder, consisting of 7 items (kertz et al., 2013) . each item was rated on a four-point degrees of the scale (0=not at all; 1=some of the time; 2=more than half the time; 3=nearly every day) in relation to the past two weeks. the scale had demonstrated good reliability and validity as established measures of anxiety (spitzer et al., 2006; kertz et al., 2013) . the gad-7 severity score ranged from 0 to 21. the study reported that it was of more clinical significance to use 10 as the cut-off points for anxiety symptoms (löwe et al., 2008) . therefore, 10 points was taken as the cut-off point in this study. patient health questionnaire-9 (phq-9): this was a self-rating measure used to assess depression and depression severity (brooke et al., 2019) . each of the 9 items was divided into a four-point degrees of the scale (0=not at all; 1=some of the time; 2=more than half the time; 3=nearly every day) in the past two weeks. phq-9 was the most widely used instrument for screening depression in primary health care (brooke et al., 2019; spitzer et al., 1999) . the total score ranged from 0 to 27. the study reported that it was of more clinical significance to use 10 as the cut-off points for depression symptoms (manea et al., 2015) . therefore, 10 points was taken as the cut-off point in this study. chi-square test was used to compare the distribution characteristics of cases with selfreported anxiety symptoms and depression symptoms. binary logistic regression analysis was performed to screen factors associated with self-reported anxiety symptoms, self-reported depression symptoms, calculate ors (odds ratios) and its 95% ci (confidence interval). statistical tests were two-tailed with p<0.05 and the database was constructed by using epidate3.1 and analyzed by spss 25.0. 59.8% of the participants worked in jiangxi province, 18.5% worked in heilongjiang province; 80.2% were women and 19.8% were men; 40.6% were doctors and 59.4% were nurses; 34.0% were front-line medical staff and 66.0% were the non-front-line medical staff. 39.2% were aged <30 years, 32.7% were aged 26 to 40 years; the range of work experience varied from less than 2 years to more than 20 years. the self-reported rates of anxiety symptoms and self-reported depression symptoms were 13.3% and 18.4% respectively; self-reported anxiety or depression symptoms was 23.9%; self-reported anxiety and depression symptoms was 7.8%. significantly higher proportions of self-reported anxiety symptoms were found in investigated medical staff with the following characteristics: married status, living alone, never/almost never getting help from friends and never/almost never getting care from neighbours and higher stress (see table 1). significantly higher proportions of self-reported depression symptoms were found in investigated medical staff with the following characteristics: ＜30 years old, living alone, never/almost never getting help from friends, never/almost never getting care from neighbours, never confiding their troubles to others and higher stress. significantly higher proportions of self-reported anxiety or depression symptoms were found in investigated medical staff with the following characteristics: nurse, junior college or below, living alone, never/almost never getting help from friends, never/almost never getting care from neighbours, never confiding their troubles to others and higher stress. binary logistic regression analysis showed that correlators associated with self-reported anxiety symptoms included married status (or=2.3, 95%ci: 1.2, 4.4), never confiding their troubles to others (or=2.2, 95%ci: 1.4, 3.5), higher stress (or=14.4, 95%ci: 7.8, 26.4) and not living alone (or=0.4, 95%ci: 0.2, 0.7) (see table 2 ). the analysis showed that correlators associated with self-reported depression symptoms included higher stress (or=9.7, 95%ci: 6.2, 15.2), never confiding their troubles to others (or=2.0, 95%ci: 1.3, 3.0), not living alone (or=0.4, 95%ci: 0.3, 0.7) and sometimes/often getting care from neighbours (or= 0.6, 95%ci: 0.4, 0.9). the analysis showed that correlators associated with any of the two self-reported symptoms included higher stress (or=9.8, 95%ci: 6.6, 14.5), never confiding their troubles to others (or=2.0, 95%ci: 1.3, 2.9), master degree or above (or=0.5, 95%ci: 0.2, 0.9), not living alone (or=0.4, 95%ci: 0.2, 0.6) and sometimes/often getting care from neighbours (or=0.6, 95%ci: 0.4, 0.9). during the covid-19 epidemic, medical staff had to work in the hospital and some even were involved in the treatment of patients with covid-19 (xiang et al., 2020) . they might suffer from great mental health problems. in this study, up to one-fifth of medical staff had anxiety or depression symptoms. anxiety and depression were the most common mental health problems in the general population. the estimated self-reported rate of anxiety and depression symptoms among medical staff during the covid-19 epidemic was higher than that from the general population (huang et al., 2019) and similar to those reported in medical staff using the same measurement (pappa et al., 2020) . working in the hospital during the epidemic, medical staff suffered great psychological pressure, not only worried about their high risk of being infected, but also about their patients being treated (kang et al., 2020; bao et al., 2020) . therefore, it was important to provide psychological interventions for this population to reduce their depression symptoms and anxiety symptoms. the results of this study showed that medical staff who perceived a higher level of stress tend to develop anxiety and depression symptoms. under the effect of a long-term negative event, people were more vulnerable and stressful, and more likely to be involved in serious psychological problems such as depression and anxiety (schneiderman et al., 2005) . similar to findings from other studies (sun et al., 2019) , those lacked care from their neighbours and never told troubles to others were at high risk for depression symptoms. in terms of qualification, medical staff with relatively low educational background had a higher risk for anxiety or depression symptoms. this population might lack knowledge of the disease and easily feel helpless in the face of the epidemic, thus easily causing adverse psychological reactions (guo et al., 2020) . similar to findings from other studies (zhang et al., 2020; chen et al., 2019) , married medical staff had a high risk of anxiety symptoms. the main reason might be related to their higher family burdens. not only did the level of perceived stress significantly affect the occurrence of mental problems, but it also affected its severity (schneiderman et al., 2006) . this study found the average score of pss-10 for medical staff was 13.97±5.83, which was higher than the standard level (line et al., 2017) . under the epidemic of covid-19, perceived stress of medical staff significantly increased, which had been shown to be related to psychological problems in our study. during the epidemic, the medical worker had high prevalence of self-reported anxiety symptoms, depression symptoms and suffered from great stress. psychological interventions should be offered to the medical staff, especially for those living alone, being married, with relatively low educational background, lacking of care from the neighbours, never confiding their troubles to others, and having higher perceived stress. the limitations of this study were as follows: firstly, the study used a non-probability sample survey instead of a random sample survey due to the limitation during the covid-19 epidemic. in addition, the difference between the online survey and the traditional face-toface survey should also be considered. therefore, extrapolation of the results should be cautious. secondly, all the diagnoses in this study were mental health states, not mental disorders. we found that the self-reported rates of anxiety symptoms and depression symptoms were high in investigated medical staff. factors associated with anxiety symptoms and depression symptoms varied. bearing in mind the importance of precision prevention, our findings suggest that targeted psychological interventions for medical staff should be integrated into the work plan to fight against the covid-19 epidemic. this research did not receive any specific grant from funding agencies from the public, commercial, or not-for-profit sectors. mengqian li and hongguang chen planned the study. mengqian li, hongguang chen, yuan liu, nan zhang, bo hu, xing wang, qinyi fan, yuling zhang, and liping huang took none. 2019-ncov epidemic: address mental health care to empower society accuracy of patient health questionnaire-9 (phq-9) for screening to detect major depression: individual participant data meta-analysis health anxiety in medical employees: a multicentre study a global measure of perceived stress analytical report of anxiety and depression of 130 firstline medical staff against covid-19 prevalence of mental disorders in china: a crosssectional epidemiological study covid-19 dashboard by the the mental health of medical workers in wuhan, china dealing with the 2019 novel coronavirus validity of the gad-7 in an acute psychiatric setting review of the psychometric evidence of the perceived stress scale cross-cultural adaptation and validation of the danish 10-item connor-davidson resilience scale among hospital staff psychological status of medical workforce during the covid-19 pandemic: a cross-sectional study validation and standardization of the generalized anxiety disorder screener (gad-7) in the general population mcmillan d. a diagnostic meta-analysis of the patient health questionnaire-9 (phq-9) algorithm scoring method as a screen for depression prevalence of depression, anxiety, and insomnia among healthcare workers during the covid-19 pandemic: a systematic review and meta-analysis stress and health: psychological, behavioral, and biological determinants validation and utility of a self-report version of primemd: the phq primary care study a brief measure for assessing generalized anxiety disorder:the gad-7 mental health sataus and influencing factors of medical staff after blood-borne occupational exposure the novel coronavirus pneumonia emergency response epidemiology team, 2020. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) -china statement on the second meeting of the international health regulations(2005) emergency committee regarding the outbreak of novel coronavirus timely mental health care for the 2019 novel coronavirus outbreak is urgently needed mental health and psychosocial problems of medical health workers during the covid-19 epidemic in china ＂ ‡ ＂higher perceived stress, defined as a total score of pss-10≥15 we would like to acknowledge all medical staff who participated in the study. besides, for comprehensive support in the english-language polishing we would like to thank ewolo kana adji salomon didier who is an international student of nanchang university and can be reached at his email pacifiquesalomon@yahoo.fr. key: cord-189256-72eumkal authors: santosh, roshan; schwartz, h. andrew; eichstaedt, johannes c.; ungar, lyle h.; guntuku, sharath c. title: detecting emerging symptoms of covid-19 using context-based twitter embeddings date: 2020-11-08 journal: nan doi: nan sha: doc_id: 189256 cord_uid: 72eumkal in this paper, we present an iterative graph-based approach for the detection of symptoms of covid-19, the pathology of which seems to be evolving. more generally, the method can be applied to finding context-specific words and texts (e.g. symptom mentions) in large imbalanced corpora (e.g. all tweets mentioning #covid-19). given the novelty of covid-19, we also test if the proposed approach generalizes to the problem of detecting adverse drug reaction (adr). we find that the approach applied to twitter data can detect symptom mentions substantially before being reported by the centers for disease control (cdc). the covid-19 pandemic has interrupted many everyday behaviors. sars-cov-2 is a relatively new virus and gaps in knowledge persist about how it affects the body, and consequently, its symptoms and symptom severity. in the early phases of the pandemic, patients and providers in affected areas used social media to exchange information about symptoms and clinical treatment (iacobucci, 2020; . during covid-19, the use of social media has increased dramatically (>20%) as individuals shelter in place (venkatraman, 2020) . while social media is non-representative and contains misinformation (singh et al., 2020) , it provides an open forum for individuals to share their perceptions, concerns (giorgi et al., 2020) , understanding of health and science (yang et al., 2018) , and mental health status during emergencies when wide spread polling may not be available . social media could enable early symptom discovery for diseases such as covid-19 where the pathology is not completely known and our knowledge of it is evolving (del rio and malani, 2020) . the most prominent symptoms such as fever, cough, and shortness of breath were known early on during the covid-19 pandemic. however, others such as changes in smell/taste, body aches, and diarrhea were added later to the symptom list by the cdc (grant et al., 2020) . using social media to gather information on public health is a growing focus of research, with a special emphasis on discovering side effects of drugs (pharmacovigilance) (o'connor et al., 2014) , often using labeled datasets to build supervised machine learning models (luo et al., 2017) . we propose a graph-based natural language processing framework to automatically detect emerging symptoms using twitter data. our approach is built on the hypothesis that by identifying token embeddings that capture the context of symptom mentions, new tokens used in a similar context can be identified through embedding similarity (devlin et al., 2018) . our approach shares similarities with the idea of lexicon development (bontcheva et al., 2013) , which uses an unsupervised graph-based approach for labeling new words given a few labeled words. however, the graph is initiated with words of interest that have already been identified. our method's focus on a specific context allows it to search through large imbalanced corpora to identify context-specific (e.g. symptoms) tweets. this differentiates it from previous works by (wu et al., 2019; mpouli et al., 2020) that identify domain specific lexicon. further, the approach by (wu et al., 2019) relies on a domain specific corpus and topic modeling to build a lexicon, which would require the construction of a symptom-specific covid-19 corpus. as is the case with several applications involving creating word lists associated with a construct arxiv:2011.03983v1 [cs.cl] 8 nov 2020 figure 1 : comparative timeline of symptom detection by our approach against cdc reporting or topic (das and smith, 2012) , symptom mentions associated with covid-19 come in different forms and shapes -often difficult to curate in advance (rúa, 2007) . the approach we propose assumes that we know at least one word of interest (i.e., a seed word) along with few corresponding seed texts where the seed word has been used in the desired context. for the case of emerging symptom detection, cough, a seed text could be 'i have a dry cough, chest pain and feeling lethargic as hell plus a headache'. given the seed word and corresponding seed texts, bert (bert-base) embeddings (devlin et al., 2018) for the seed word are extracted from each of the texts. the bert embedding for each token was computed by summing the hidden states of the last 4 layers of bert. individual embeddings from each of the seed texts are then averaged to generate a representative embedding for the seed word. we use 5 seed texts that capture part of the considerable variance associated with the symptom context. using the representative embedding for the seed word, an exhaustive search is performed across the dataset at a token level to identify tokens that are most similar to the seed word, where similarity is measured using cosine similarity (one minus cosine distance). all tokens with a similarity value less than a minimum threshold (set empirically at 0.3) are excluded. similarity scores of all occurrences of a given word are averaged. training details we fine-tuned a bert-baseuncased model using the masked language modeling protocol with the following parameters: num. epochs: 5, learing rate: 1e-5, batch size: 8, max sequence length: 128. embeddings were extracted from the model by summing the hid-den states of the last 4 bert layers, resulting in 768-dim embeddings. huggingface library (wolf et al., 2019) was used for loading pre-trained model weights as well as language model training. the previous model required text for every new seed word and did not allow multiple runs with different seeds to learn from each other. to address this, we propose an iterative search model to develop a similarity-based word graph, retaining the search methodology of the earlier approach, but including a graph element and a trainable search parameter that improves the detection of contextspecific words with increased iterations. the directed and weighted word graph of the model represents connections between tokens. each node in the graph corresponds to a word and is characterized by the representative embedding of the word. the edges have weights corresponding to the similarity score between the connected words (nodes). the second component of the model is the so-called 'context embedding', cemb. the context embedding is conceptualized to be an embedding vector that represents the specific context that we are interested in. initialized by the representative embedding of the seed word, the context embedding incorporates embeddings from other words over iterations, to develop into a more robust representation of the specified context. 1 initialization initialize graph g by setting the root node with the representative embedding of the seed word. initialize a queue q by adding the seed 1 code available at https://github.com/ rsk2327/covid-symptoms-nlp. word to it. the context embedding cemb is also initialized to the representative embedding of the seed word. cemb ← emb{seed word}, where emb{x} denotes the representative embedding of token x. procedure the specific steps used in the algorithm are as follows: 1. pop next word from q, denoted by t. initialise a new node in g corresponding to t and set the node embedding to emb{t}. 2. initialise the query embedding q as q ← k * cemb + (1 − k) * emb{t}. 3. iterate through all tokens in the data, comparing their embeddings against the query embedding q. all tokens with similarity less than the minimum similarity threshold minsimt hresh are dropped. 4. select the top n words based on their similarity to q. add these words to q. instantiate new nodes (if one does not already exist) for these words in g and add outgoing edges from t to these new nodes. 5. if all words for given depth are explored, the top m words corresponding to that depth are selected based on similarity to cemb. the context embedding is then updated by averaging cemb with the representative embeddings of the selected words (eq 1). 6. stop iterations when either q is empty or when the maximum depth maxdepth of g is achieved. otherwise, repeat from step 1. we tested our approach on a twitter dataset containing tweets related to covid-19, collected between march 12 to april 23. our experiments were run on a random subset of this dataset containing 1 million tweets. our objective for this dataset is to identify new symptoms of covid-19 mentioned in tweets. we ran tests with cough, an established symptom, as the seed word. seed texts (tweets) were selected where cough was used as a symptom to ensure that the correct context is captured. top 10 results are shown in table 1 . the scores represent the cosine similarity scores of the context embedding of cough with the averaged embeddings of we evaluate our graph-based approach on 2 different datasets, with each dataset having a different context -1) covid-19 symptom detection; and 2) adverse drug reaction identification. with the 1 million covid-19 tweet dataset, we use cough as the seed word, k = 0.3, maxdepth = 3 and n = 5 to test our approach. the resulting graph from our model is shown in figure 2 . the size of the nodes represent the number of occurrences of a token as a symptom while the color intensity of the nodes represent the similarity values computed for the node during the graph building process (shown in appendix). we observe that the model identified a wide range of symptoms ranging from common symptoms like fever, fatigue to less common ones like headache, vomiting, (chest) congestion, nausea, mig-##raine. evaluation though a quantitative evaluation of our approach is not straightforward as there is no definitive 'ground truth', we evaluate our approach by computing the precision in detecting correct words that fit the specified context. for the problem of symptom detection, precision is calculated as the percentage of the actual symptoms detected by our model. given that our model outputs a ranked list of words, precision is computed by looking at the top p results, where p through a manual inspection of the top 100 results, rare to-be-confirmed symptoms like lack of appetite, skin/eye irritation, vertigo, anemia were detected. this marks a key utility of our approach as it helps generate potential symptom candidates which can guide further evaluation. for the second task, we use an annotated adr dataset (sarker and gonzalez, 2015) , where 13% of the tweets are labeled as adr. the objective of this task is the identification of words denoting adverse drug reactions. therefore, the specific context of interest is different from the previous dataset where it was identification of symptoms of a disease. by testing our model on this dataset, we also test the ability of our approach to generalize to new tasks. for the experiment, the seed word used is pain. k = 0.2, maxdepth = 3, and n = 5. the resulting graph from our model is shown in figure 3 . some of the key adr identified include inflammation, bleeding, muscle (pain), (skin) lesions, tremors, discomfort, and (calcium) deposits. evaluation similar to covid-19 symptom detection evaluation, we evaluate the model's performance for adr detection, where a positive word represents an adverse reaction to a drug (table 3) . the covid-19 pandemic evolved in a global climate of confusion and uncertainty. the professional and lay public alike speculated on disease course, severity, and symptoms. the covid-19 symptoms first observed appeared to be largely nonspecific to covid-19 (e.g., cough, fever). finding covid-specific symptoms (such as the sudden loss of the sense of smell) is important and potentially of clinical significance as large populations are being risk-assessed (wu and mcgoogan, 2020) . the "digital exhaust" of social media encodes in-formal case reports of symptoms and discussions of media content about the virus alike. in principle, it could allow for the generation of a "master list" of covid-19 symptom candidates, which the public health and medical community can, in turn, consider for further evaluation as covid-specific markers (chan et al., 2020) . in this study, we present an iterative learning approach to generate such a "master" list of covid-19 symptoms, using the identification of words matching a specific symptom context. our approach is intended to work at the intersection of human-machine interaction and provide a ranked list of most important keywords for a user to explore and validate. a typical workflow would involve users from the medical/ pharmacovigilance domain inputting a small number of known keywords of interest, detecting the emerging signals (symptoms/adr) output by the model, and validating them using the corresponding text. this allows for very early detection of symptoms/adr from social media platforms without the need to manually scavenge large corpora. our initial experiments with word2vec (mikolov et al., 2017) , glove (pennington et al., 2014) , and latent dirichlet allocation (blei et al., 2003) for the same task, did not perform well since the similarity between tokens was the same irrespective of the context in which the word was being used. so with 'cough' as the seed word, highly correlated words like 'fever' were detected by these approaches, while words like 'congestion', 'nausea', 'diarrhea' were not. consequently, we developed an iterative graph-based training approach using bert embeddings that are able to take into account the context in which words are used. through a preliminary evaluation, our approach shows high sensitivity in detected words. the approach detected headache, chills, sore throat, diarrhea, and other symptoms around a month before the cdc reported them (figure 1) . given the novelty of covid-19, the current method is hard to evaluate. recall and other metrics that depend on false negatives are not useful as there is no definitive 'ground truth'. this is even more true for covid-19 as the symptoms are evolving and newer symptoms are being observed even after several months from the first case. we, therefore, considered the approach in the more studied context of detecting adverse drug reactions and show that the approach generalizes to this domain. the annotations in adr vary from very specific entities like 'pain', 'headache' to very broad phrases like 'a tingling sensation' (nikfarjam et al., 2019) . though our approach does not extract multi-word terms, given that the typical workflow is expected to focus on the validation of symptoms using their corresponding full-length texts, the utility of multiword terms is minimal. the approach relies on the context embedding contribution parameter (k). by varying k, we observe a phenomenon analogous to 'exploration vs exploitation' (coggan, 2004) , which, in principle, means that this method can be calibrated for different use cases. in the early phase of the disease, for example, a low k parameter may be chosen to aid in the generation of symptom candidates to be considered in light of the emerging clinical literature on covid-19 and known physiological and biological interactions in the human body. a high k may be chosen to yield the subset of covid-19 symptoms that are more robustly associated with the disease, at the cost of missing infrequent (albeit potentially specific) disease markers. in summary, this study demonstrates that the digital traces of social media can be mined effectively to detect emerging symptoms in the population during a public health emergency. latent dirichlet allocation twitie: an open-source information extraction pipeline for microblog text social media for rapid knowledge dissemination: early experience from the covid-19 pandemic exploration and exploitation in reinforcement learning graph-based lexicon expansion with sparsity-inducing penalties covid-19-new insights on a rapidly changing epidemic bert: pre-training of deep bidirectional transformers for language understanding twitter corpus of the# blacklivesmatter movement and counter protests the prevalence of symptoms in 24,410 adults infected by the novel coronavirus (sars-cov-2; covid-19): a systematic review and meta-analysis of 148 studies from 9 countries tracking mental health and symptom mentions on twitter during covid-19 covid-19: diabetes clinicians set up social media account to help alleviate patients' fears natural language processing for ehrbased pharmacovigilance: a structured review advances in pre-training distributed word representations lexifield: a system for the automatic building of lexicons by semantic expansion of short word lists. knowledge and information systems early detection of adverse drug reactions in social health networks: a natural language processing pipeline for signal detection. jmir public health and surveillance pharmacovigilance on twitter? mining tweets for adverse drug reactions glove: global vectors for word representation keeping up with the times: lexical creativity in electronic communication portable automatic text classification for adverse drug reaction detection via multi-corpus training a first look at covid-19 information and misinformation sharing on twitter public priorities and concerns regarding covid-19 in an online discussion forum: longitudinal topic modeling weekly time spent in apps grows 20% year over year as people hunker down at home huggingface's transformers: stateof-the-art natural language processing automatic construction of target-specific sentiment lexicon characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention to retweet or not to retweet: understanding what features of cardiovascular tweets influence their retransmission appendix covid-19 keywords used to pull tweets from the streaming twitter api: coronavirus, covid, 2019ncov, covd, outbreak, pandemic, corona, corono, washyourhand, handwashing, stayhome, stayathome, and sarscov. key: cord-012898-1jl6zcwa authors: schäfer, sarah k.; sopp, m. roxanne; schanz, christian g.; staginnus, marlene; göritz, anja s.; michael, tanja title: impact of covid-19 on public mental health and the buffering effect of a sense of coherence date: 2020-08-18 journal: psychother psychosom doi: 10.1159/000510752 sha: doc_id: 12898 cord_uid: 1jl6zcwa introduction: it is claimed that the coronavirus disease 2019 (covid-19) pandemic has had a negative impact on mental health. however, to date, prospective studies are lacking. moreover, it is important to identify which factors modulate the stress response to the pandemic. previously, sense of coherence (soc) has emerged as a particularly important resistance factor. objective: this prospective study aimed to assess the impact of the covid-19 outbreak on mental health and to investigate the ability of pre-outbreak soc levels to predict changes in psychopathological symptoms. methods: this study assessed psychopathological symptoms and soc before and after the covid-19 outbreak as well as post-outbreak covid-19-related traumatic distress in a german-speaking sample (n =1,591). bivariate latent change score (blcs) modeling was used to analyze preto post-outbreak changes in psychopathological symptoms and the ability of soc to predict symptom changes. results: overall, there was no change in psychopathological symptoms. however, on an individual-respondent level, 10% experienced a clinically significant increase in psychopathological symptoms and 15% met cut-off criteria for covid-19-related traumatic distress. using blcs modeling, we identified a high-stress group experiencing an increase in psychopathological symptoms and a decrease in soc and a low-stress group showing the reversed pattern. changes in soc and psychopathological symptoms were predicted by pre-outbreak soc and psychopathological symptom levels. conclusions: although mental health was stable in most respondents, a small group of respondents characterized by low levels of soc experienced increased psychopathological symptoms from preto post-outbreak. thus, soc training might be a promising approach to enhance the resistance to stressors. in march 2020, the outbreak of the coronavirus disease 2019 reached all countries of the western world [1] . to reduce the speed of its spread, many countries slowed down their economies and enforced pro it is well known that pandemics pose a threat to mental health [2] [3] [4] . correspondingly, 2 recent reviews found a consistently negative impact of covid-19 on mental health, with 16-18% of participants showing symptoms of anxiety and depression [5, 6] . the first evidence indicates that women [7, 8] , younger people [9] , and those with a poor sleep quality [7, 9] are at an increased risk for mental health problems. however, so far, no study has assessed whether mental health in the general population has genuinely changed from pre-to post-outbreak. we had conducted a panel study in germany shortly before the outbreak (february [17] [18] [19] [20] [21] [22] [23] 2020 ) that investigated associations between mental health and health-promoting factors. we were able to contact respondents again in mid-march after the outbreak to gather data reflective of the pandemic's impact on mental health. furthermore, we assessed the resistance factor of sense of coherence (soc), which constitutes an important step towards developing interventions aimed at buffering the effects of global stressors [10] [11] [12] . such interventions may target resistance factors like soc, the key component of the salutogenesis framework [13, 14] . individuals with high levels of soc perceive life as comprehensible and manageable and believe that life challenges reflect a potential source of growth. in the salutogenesis framework, soc is conceptualized as a stable disposition that is particularly important in situations that are perceived as highly demanding [15] (see online suppl. material; for all online suppl. material, see www. karger.com/doi/10.1159/000510752). however, previous research has also found short-term stressor-related changes in soc, challenging its temporal stability [16] . soc shows a robust positive correlation with mental health [17] [18] [19] . moreover, it may also reflect an aspect of euthymia [20, 21] . the positive component of euthymia is characterized by resistance, flexibility, and a unifying outlook on life-guiding actions and feelings to shape one's future, the latter of which may be encompassed by soc. yet, little is known about the ability of soc to predict changes in mental health. only 2 studies -assessing women after pregnancy loss and patients with mental disorders in a psychosomatic rehabilitation clinic -found soc to be predictive of changes in mental health [22, 23] . however, these studies did not apply state-of-the-art methods for prospective data [24] . in the current study, we aimed to examine the number of respondents who experienced a clinically significant change in psychopathological symptom levels from preto post-outbreak assessment or significant levels of co-vid-19-related traumatic distress. based on previous studies on covid-19-related traumatic distress [5, 25] , we expected significant levels of traumatic distress in 10-20% of the sample and stronger stress responses in females, younger respondents, and those reporting a poor sleep quality. moreover, building on studies on the sars epidemic [26] , we hypothesized that some respondents would show an increase in psychopathological symptoms from pre-to post-outbreak. in line with previous research [16] , we expected soc to decrease over time in those experiencing high levels of stress. second, we aimed to examine the ability of soc to predict symptom changes, which should be particularly strong in those experiencing high covid-19-related stress. the current study is part of a larger project investigating the factorial structure of health-promoting factors. for sample recruitment, we used an online panel (wisopanel, https://www.wisopanel.net [27] ; see online suppl. material for details). data were collected via the platform sosci survey [28] and respondents gave written informed consent according to the declaration of helsinki [29] (fig. 1 ; online suppl. material). soc was assessed using a 9-item short version of the antonovsky scales [30] . psychopathological symptoms were measured using the mini-symptom checklist [31] . sleep quality during the last week was measured at the post-outbreak assessment using the single-item sleep quality scale [32] . covid-19-related rumination was evaluated at the post-outbreak assessment using a modified version of the perseverative thinking questionnaire (ptq) [33] . covid-19-related traumatic distress was measured using a modified version of the peritraumatic distress inventory (pdi) [34] . following bunnell et al. [35] , scores ≥23 indicate a greater risk for covid-19-related traumatic distress (see online suppl. material). to assess respondents' covid-19-related stress, we calculated a covid-19 stress index as the sum of the z-standardized scores of ptq and pdi (see online suppl. material). higher scores indicate more severe stress. scores > 0 reflect an above-average co-vid-19-related stress burden (high covid-19-related stress group, score > 0; low covid-19-related stress group, score ≤0). analyses were conducted using rstudio [28] and the lavaan package [29] . we calculated reliable change indices according to the mini symptom checklist (mini-scl) manual to quantify clinically significant changes in psychopathological symptoms. to further analyze pre-to post-changes in psychopathological symptoms and soc and the ability of soc to predict symptom changes, we applied bivariate latent change score (blcs) models [27, 36] (see online suppl. material). the mean age of the participants who completed the second assessment (n = 1,591) was 55.03 years (sd = 13.90, range: 20-95) and 53.6% were female. the majority lived in germany (96.2%), 2.3% lived in austria, 1.1% lived in switzerland, and 0.4% were german speaking but reported living in other countries (i.e., french-german border area). see the online supplementary material for a comparison with the german general public and results after excluding respondents not living in germany. we analyzed reliable change indices and found significant changes from pre-to post-outbreak in 18% of the respondents (n = 287), whereby 10% (n = 152) showed a significant increase and 8% (n = 135) a significant decrease in psychopathological symptom levels. moreover, 15% exceeded the pdi cut-off for traumatic distress. the separate blcs models for the total sample, the high-stress group (stress score > 0, n = 634) and the lowstress group (stress score ≤0, n = 862) showed a good fit (cfi = 1.00; srmr = 0.00). in the total sample, there was no change in psychopathological symptoms and soc levels from pre-to post-outbreak ( fig. 2; table 1 ). by contrast, in the high-stress group, symptom levels increased while soc levels decreased. changes in soc levels and psychopathological symptoms were negatively correlated. in the low-stress group, psychopathological symptoms decreased from pre-to post-outbreak assessment and soc levels increased. again, both changes were negatively correlated. analyses of group differences revealed that individuals in the high-stress group reported a poorer sleep quality in the total sample, individual changes in psychopathological symptoms were significantly predicted by pre-outbreak symptoms and pre-outbreak soc levels. the same pattern of results was found in the high-stress group and the low-stress group (table 1) . across all analyses, higher pre-outbreak soc levels were associated with smaller changes (i.e., increases and decreases) in symptom levels. in the total sample, individual changes in soc were significantly predicted by the pre-outbreak soc and preoutbreak symptoms. the findings were the same for the high-stress group and the low-stress group (table 1) . higher pre-outbreak symptom levels were related to smaller changes in soc levels. this is the first study to examine mental health before and after the covid-19 outbreak and potential modulatory effects of soc. despite the overall stability (82%), we identified clinically significant symptom changes in 18% of respondents (increased in 10% and decreased in 8%). moreover, 15% showed above-cut-off covid-19-related traumatic distress. taking covid-19-related stress into account, we identified a group that experienced aboveaverage stress levels and another group that experienced below-average stress levels. while symptoms increased in the high-stress group, the low-stress group showed reduced symptoms at the post-outbreak assessment. moreover, we consistently identified soc as a predictor of individual symptom change, with higher soc levels predicting smaller symptom changes. in line with previous research, we found stress to be higher in women [7, 8] and younger respondents [9] . one may assume that as-of-yet-unknown factors contributed to this observation (e.g., women may be more stressed during lockdown, as they may be overproportionately burdened by childcare duties). furthermore, corresponding to prior studies [7, 9] , stress levels were higher in respondents experiencing a poor sleep quality. interestingly, respondents living in high-risk regions were not more likely to report higher levels of covid-19-related stress. as such, factors that are associated with a greater psychological vulnerability seem to be more important than factors associated with the risk of infection in predicting mental health consequences of the pandemic. beyond insights on risk factors of covid-19 related psychopathology, the current study sheds further light on the impact of soc on psychopathology. our results firstly demonstrate that pre-stressor soc predicts symptom changes over a short pre-to post-assessment interval. higher levels of pre-outbreak soc were related to small-er symptom changes. soc may thus buffer the impact of stressors on mental health without necessarily resulting in lower symptom levels. moreover, we did not find differences between the high-stress group and low-stress group concerning the ability of soc ability to predict symptom changes. thereby, our findings challenge the assumption that soc is of particular importance in highstress situations and may thus suggest its universal relevance as a component of euthymia [20, 21] . additionally, our study provides important insights into the temporal stability of soc. consistent with the salutogenesis framework [13] , we did not find an overall change in soc levels. however, in line with previous studies challenging the concept of a stable disposition [16, 37] , we found soc to be reduced in respondents reporting above-average stress levels. by contrast, those experiencing below-average stress reported increased levels of soc and decreased symptom levels. no study to date has demonstrated such a steeling effect of stressful life events on soc [38] . these findings indicate that soc-targeting trainings [39, 40] may be useful to enhance resistance by enabling individuals to buffer negative mental health consequences of stressors. the current study has the following limitations. first, this study used a nonrepresentative sample (see online suppl. material for details) and was purely observational. we aimed to account for different responses to co-vid-19 by conducting subgroup analyses. however, changes in psychopathological symptoms also occur in a percentage of respondents when assessing cohorts over time without specific stressors [41, 42] , which may account for some of the findings. nevertheless, it is important to note that significant pre-to post-symptom increases were more likely in the high-stress group than in the low-covid-19-stress group (χ 2 [1] = 52.87, p < 0.001). this finding strengthens our interpretation. second, to assess covid-19-related stress we had to modify wellestablished instruments, thereby affecting cross-study comparability. third, the time of assessment may not capture the most stressful period of the covid-19 outbreak but rather a marked change in policymaking in germany. thus, we plan to conduct 2 further assessments in the sample, which will also explore the surprising finding of a potential steeling effect, its potential sources (e.g., successful use of coping resources), and why higher preoutbreak psychopathological symptom levels were related to smaller symptom changes. despite these limitations, the findings of the current study improve our understanding of the mental health consequences of covid-19. despite the majority of respondents showing no clinically significant symptom change, our results demonstrate that a group of respondents characterized by low levels of soc may be at risk for the development of clinically significant symptom change from pre-to post-outbreak. future studies should investigate the pandemic's impact on public mental health but also its influence on the mental health of health care professionals [43, 44] . our results may also support the development of resilience trainings [45] . furthermore, future research should address a broad range of psychosocial consequences of covid-19 [11] and their impact on treatment access for mental disorders [46, 47] . an interactive web-based dashboard to track covid-19 in real time risk factors for chronic post-traumatic stress disorder (ptsd) in sars survivors long-term psychiatric morbidities among sars survivors mental symptoms in different health professionals during the sars attack: a follow-up study covid-19 and mental health: a review of the existing literature covid-19 pandemic and mental health consequences: systematic review of the current evidence prevalence and predictors of ptss during covid-19 outbreak in china hardest-hit areas: gender differences matter immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china mental health burden for the public affected by the covid-19 outbreak in china: who will be the high-risk group? psychol health med multidisciplinary research priorities for the covid-19 pandemic: a call for action for mental health science impact of covid-19 on public mental health 7 using social and behavioural science to support covid-19 pandemic response the covid-19 pandemic: setting the mental health research agenda unraveling the mystery of health: how people manage stress and stay well the handbook of salutogenesis negative life events and stability of sense of coherence: a five-year follow-up study of finnish women and men antonovsky's sense of coherence scale and the relation with health: a systematic review the relationship between sense of coherence and post-traumatic stress: a metaanalysis sense of coherence, burden and mental health in caregiving: a systematic review and meta-analysis the concept of euthymia the pursuit of euthymia. world psychiatry the sense of coherence in early pregnancy and crisis support and posttraumatic stress after pregnancy loss: a prospective study pre-rehabilitation sense of coherence as a predictor of symptom change after rehabilitation. stress health developmental cognitive neuroscience using latent change score models: a tutorial and applications psychological health during the coronavirus disease 2019 pandemic outbreak psychological resilience and dysfunction among hospitalized survivors of the sars epidemic in hong kong: a latent class approach using attention testing to select crowdsourced workers and research participants sosci survey. version 2.5. 00-i1142 [software world medical association declaration of helsinki: ethical principles for medical research involving human subjects sense of coherence scale«: testhandbuch zur deutschen version. göttingen: vandenhoeck & ruprecht bscl-53 ® -s. brief symptom-checklist-standard -deutsches manual a new single-item sleep quality scale: results of psychometric evaluation in patients with chronic primary insomnia and depression the perseverative thinking questionnaire (ptq): validation of a content-independent measure of repetitive negative thinking der peri-trauma-belastungs-fragebogen -deutsche übersetzung the peritraumatic distress inventory: factor structure and predictive validity in traumatically injured patients admitted through a level i trauma center evaluating the fit of structural equation models: tests of significance and descriptive goodness-of-fit measures some conceptual considerations on the sense of coherence a salutogenic perspective on adverse experiences efficacy of mindfulness-based meditation therapy on the sense of coherence and mental health of nurses enhancing sense of coherence via early intervention among depressed occupational health care clients a longitudinal analysis of anxiety and depressive symptoms longitudinal trajectories of depression and anxiety in a prospective community study: the zurich cohort study mental health and psychosocial problems of medical health workers during the covid-19 epidemic in china. psychother psychosom covid-19 and working conditions in health care current psychosomatic practice remote treatment delivery in response to the covid-19 pandemic a call for addressing barriers to telemedicine: health disparities during the co-vid-19 pandemic we thank 2 anonymous reviewers for their insightful comments that helped to improve this paper. this study was conducted in accordance with the ethical standards of the ethics committee of saarland university and the 1964 helsinki declaration and its later amendments or comparable ethical standards. according to the ethics committee of saarland university, this study was exempt from ethical approval requirements. this article received no support from any funding agency, commercial business, or not-for-profit institution. in the last 3 years, the authors have had no commercial conflict of interests. none. key: cord-264412-2dwk06yd authors: dallavalle, gianfranco; pezzotti, elena; provenzi, livio; toni, federico; carpani, adriana; borgatti, renato title: migraine symptoms improvement during the covid-19 lockdown in a cohort of children and adolescents date: 2020-10-08 journal: front neurol doi: 10.3389/fneur.2020.579047 sha: doc_id: 264412 cord_uid: 2dwk06yd background: pediatric migraine is among the most common primary or comorbid neurologic disorders in children. psychological stressors are widely acknowledged as potential triggers involved in recurring episodes of pediatric migraine. as the covid-19 emergency may have affected the levels of stress perceived by children and adolescents with migraine, the present study was aimed to understand the effect of covid-19 emergency on symptoms intensity and frequency in pediatric patients. methods: a cohort of 142 child and adolescent patients with a diagnosis of migraine was enrolled at the child neurology and psychiatry unit of the irccs mondino foundation in pavia (italy). socio-demographic and clinical characteristics were obtained from medical records. an on-line survey was used to collect information on covid-19 exposure, stress response to the lockdown period, anxious symptoms during covid-19 emergency, as well as migraine symptoms intensity and frequency before and during the lockdown. results: the great majority were outpatients (n = 125, 88.0%), 52 (36.6%) had migraine with aura, whereas, 90 (63.4%) had migraine without aura. all the patients reporting worsening symptoms progression before covid-19, had reduced intensity during the lockdown (χ(2) = 31.05, p < 0.0001). symptoms frequency reduction was observed in 50% of patients presenting worsening symptoms before the lockdown, 45% of those who were stable, and 12% of those who were already improving. all patients who had resolved symptoms before covid-19 were stable during the lockdown (χ(2) = 38.66, p < 0.0001). anxious symptomatology was significantly associated with greater migraine symptoms frequency (χ(2) = 19.69, p < 0.001). repeating the analysis separately for individuals with and without aura did not affect the findings and significant associations were confirmed for both the patients' subgroups. discussion: a significant reduction of migraine symptoms intensity and frequency was observed in pediatric patients during the covid-19 lockdown phase in northern italy. the improvement in both intensity and frequency of the migraine symptoms was especially significant in patients who were stable or worsening before the lockdown. the reduction of symptoms severity during a period of reduced environmental challenges and pressures further highlights the need of providing effective training in stress regulation and coping for these patients. background: pediatric migraine is among the most common primary or comorbid neurologic disorders in children. psychological stressors are widely acknowledged as potential triggers involved in recurring episodes of pediatric migraine. as the covid-19 emergency may have affected the levels of stress perceived by children and adolescents with migraine, the present study was aimed to understand the effect of covid-19 emergency on symptoms intensity and frequency in pediatric patients. methods: a cohort of 142 child and adolescent patients with a diagnosis of migraine was enrolled at the child neurology and psychiatry unit of the irccs mondino foundation in pavia (italy). socio-demographic and clinical characteristics were obtained from medical records. an on-line survey was used to collect information on covid-19 exposure, stress response to the lockdown period, anxious symptoms during covid-19 emergency, as well as migraine symptoms intensity and frequency before and during the lockdown. results: the great majority were outpatients (n = 125, 88.0%), 52 (36.6%) had migraine with aura, whereas, 90 (63.4%) had migraine without aura. all the patients reporting worsening symptoms progression before covid-19, had reduced intensity during the lockdown (χ 2 = 31.05, p < 0.0001). symptoms frequency reduction was observed in 50% of patients presenting worsening symptoms before the lockdown, 45% of those who were stable, and 12% of those who were already improving. all patients who had resolved symptoms before covid-19 were stable during the lockdown (χ 2 = 38.66, p < 0.0001). anxious symptomatology was significantly associated with greater migraine symptoms frequency (χ 2 = 19.69, p < 0.001). repeating the analysis separately for individuals with and without aura did not affect the findings and significant associations were confirmed for both the patients' subgroups. discussion: a significant reduction of migraine symptoms intensity and frequency was observed in pediatric patients during the covid-19 lockdown phase in northern italy. the improvement in both intensity and frequency of the migraine symptoms was especially significant in patients who were stable or worsening before the lockdown. the reduction of symptoms severity during a period of reduced environmental challenges and pressures further highlights the need of providing effective training in stress regulation and coping for these patients. during the 1st months of 2020, northern italy has been the hotspot of the coronavirus disease of 2019 (covid-19) outbreak in europe (1). the adopted mitigation and containment actions included physical distancing strategies that indirectly resulted in the lockdown of schools and changes in daily habits. in this scenario, citizens may have been exposed to high levels of stress and anxiety (2) . the mental health impact of this unprecedented healthcare emergency might be especially significant for children who already were suffering from physical and/or psychosomatic conditions, as it is the case of pediatric population with migraine (3, 4) . pediatric patients with migraine have been previously reported to be especially vulnerable to stressful and anxious encounters (3, 4) . thus, these patients represent a specific atrisk population that should be monitored for covid-19-related effects on their health and symptoms progression. pediatric migraine is among the most common primary or comorbid neurologic disorders in children, with prevalence ranging from 3% in preschool children to 23% in adolescents (5, 6) . migraine may be generally considered as a disorder of psychobiology adaptation where genetic predisposition plays a critical role together with internal and external sources of environmental influence, including psycho-social and psychoemotional challenges, hormonal dysregulation, dietary and other factors (3) . a complex mix of factors is plausibly involved in setting the risk for pediatric migraine, including neurogenic inflammation, excitatory/inhibitory balance, genetic background and disturbed energy metabolism (7-9). psychosomatic contributions have recently supported by neuroimaging studies as the default mode network appears to play a critical role in mediating the effects of environmental stressors and coping strategies on the origin and emergence of migraine symptoms (7) . psychological stressors are widely acknowledged as potential triggers involved in recurring episodes of pediatric migraine (10, 11) . stressful, challenging and emotionally overwhelming experiences in school or educational environments may contribute to the overreaction of the central nervous system to environmental requests that are perceived as too intense by the individual, increasing the risk of headache and migraine (12) . in large cohort studies, children with frequent and more intense migraine symptoms also report higher levels of school, family and/or peer-relational stress compared to headache free counterparts (13) (14) (15) . there is evidence of covid-19 pandemic effects' on the psychological and physical well-being of children and adults in the general population (16) (17) (18) (19) . recent research conducted in italy reported that, during the covid-19 quarantine, subjects with migraine had fewer migraine attacks and lesser pain as well as moderate levels of depression (20) . nonetheless, no information is available for what pertains the health of at-risk children and adolescents with pediatric migraine. in the present study we report the results of a survey conducted at a tertiary level neurological hospital in northern italy. the survey was aimed to collect evidence on the impact of covid-19 lockdown phase on the frequency and intensity of migraine symptoms among children and adolescents. from march to april 2020, a cohort of 142 child and adolescent patients with a diagnosis of migraine was enrolled at the child neurology and psychiatry unit of the irccs mondino foundation in pavia (italy). this hospital receives families for inpatient and outpatient care from lombardy and other italian regions. patients were consecutively enrolled provided that parents could speak and understand italian language. patients were included if they did not present any comorbidity (e.g., psychomotor delay, neuromuscular diseases, epileptic disorders, cerebral palsy). the parents were asked to respond to an ad-hoc on-line survey targeting the exposure to covid-19, anxious symptoms during covid-19 emergency, as well as migraine symptoms intensity and frequency before and during the lockdown ( table 1) . participation was anonymous and voluntary. consent of parents was obtained according to local procedures. sociodemographic (sex, age, and ethnicity) and clinical variables (i.e., patient status, presence of aura) were obtained from medical charts. separate χ 2 tests were used to test changes in migraine symptoms intensity and frequency from before covid-19 to the lockdown period. a second set of χ 2 tests was used to test the association of anxious symptomatology with both intensity and frequency of migraine symptoms progression during the lockdown. statistic tests were considered significant if p < 0.05. all p-values were 2-tailed. the mean age of participants (78 females, 54.9%) was 15.04 years (range [5, 21] , sd = 3.23). the great majority were the intensity of migraine symptoms was changing before the lockdown 0, worsening; 1, stable; 2, improving; 3, resolution 8 the intensity of migraine symptoms changed during the lockdown 0, worsening; 1, stable; 2, improving; 3, resolution 9 the frequency of migraine symptoms was changing before the lockdown 0, worsening; 1, stable; 2, improving; 3, resolution 10 the frequency of migraine symptoms changed during the lockdown 0, worsening; 1, stable; 2, improving; 3, resolution figure 1 | association between migraine symptoms intensity (a) and frequency (b) before and during the lockdown. note. the symptoms severity before lockdown is reported on the x-axis, whereas the symptoms severity during the lockdown is reported using color gradients. the association between symptoms intensity and frequency before and during the lockdown is reported in figures 1a,b . migraine symptoms intensity worsened in four patients (2.8%) and improved in 13 cases (9.2%) during the lockdown. all the patients reporting worsening symptoms progression before covid-19, had reduced intensity during the lockdown (χ 2 = 31.05, p < 0.0001). frequency of migraine symptoms worsened in nine patients (6.3%) and improved in 40 cases (28.2%). symptoms frequency reduction was observed in 50% of patients presenting worsening symptoms before the lockdown, 45% of those who were stable, and 12% of those who were already improving. all patients who had resolved symptoms before covid-19 were stable during the lockdown (χ 2 = 38.66, p < 0.0001). during the lockdown, anxiety symptoms worsened in 37 patients (26.1%), were stable in 104 patients (73.2%), and improved only in one patient. anxious symptomatology was significantly associated with greater migraine symptoms frequency (χ 2 = 19.69, p < 0.001), but not intensity (χ 2 = 1.24, p = 0.54). repeating the analysis separately for individuals with and without aura did not affect the findings and significant associations were confirmed for both the patients' subgroups. this study highlighted a significant reduction of the intensity and frequency of migraine symptoms in the present cohort of children and adolescents during the covid-19 lockdown phase in northern italy. the improvement in both intensity and frequency of the migraine symptoms was especially significant in patients who were stable or worsening before the lockdown. additionally, patients who were already improving before the healthcare emergency, reported a stable clinical picture of migraine symptoms severity in terms of intensity and frequency during the lockdown. this finding is only apparently counterintuitive. for children and adolescents with recurring and worsening presentations of migraine, without any other comorbidity, the lockdown coincided with a dramatic reduction of potential stress-factors that may act as triggers for symptoms intensity and frequency. we hypothesized that the suspension of school and sport activities, the limitation of physical contacts with peers and the overall reduction of environmental requests may had potentially resulted in a fail-safe effect on the daily psychological stress usually lived by these patients before the lockdown. psychological stressors are widely acknowledged as potential triggers involved in recurring episodes of pediatric migraine (10, 11) . as such, the covid-19 lockdown may have produced unexpected, yet relevant relief from migraine symptoms for these patients. previous research suggested that stressful psychological experiences in school and/or family may widely affect pediatric migraine symptoms (12) . from this point of view, this finding further suggests that pediatric migraine may have a relevantyet partial -psychosomatic nature (10) , and dramatic situations such as a sudden change in daily habits can lead to unexpected improvements in the clinical picture. additionally, clinical worsening of migraine frequency was only observed in those patients reporting higher anxiety during the lockdown phase. the comorbidity of anxious symptomatology with migraine is well-documented in children and adolescents (21, 22) . additionally, previous research reported on the significant association between migraine frequency and mood disorders (23) . moreover, anxious symptomatology is one of the psychosocial and affective factors involved in pediatric migraine onset and chronicity (21, 24) and similar mechanisms have been theorized to be in place for both anxiety and chronic pain (25, 26) . this finding is of critical importance for at least two major reasons. first, the worsening of symptoms in patients who also reacted to the lockdown phase with increasing anxiety is reminiscent of the central involvement of psychological distress in the recurrence of headache symptoms in these children and adolescents. as anxiety symptoms were rated by parents, a careful exploration of anxious symptoms progression in daily life should be always considered by healthcare providers and may be conducted in partnership with the patient and the family. second, a relatively small -yet clinically compelling -percentage of patients (i.e., 37 out of 142; 26%) reported anxiety symptoms worsening during the lockdown phase. this means that approximately one out of four patients with pediatric migraine may have experienced a relevant reduction of their mental health and psychological well-being during the covid-19 emergency. as such, young patients with migraine should be considered as a specific vulnerable population that needs specialized and multi-professional attention during and after the epidemic, or major stressing events. although this study only included the enrollment of patients from a single hospital, it should be highlighted that the irccs mondino foundation receives patients and families from different regions of the italian territory. moreover, this survey only included parent-reported data and the indirect nature of this survey did not allow the collection of observational data on the quality of life experienced by patients and their parents during the lockdown. the lack of standardized and quantitative measures of pain intensity and/or frequency is another limitation to this study. similarly, internalizing behaviors may affect pain perception in children (27) and were not assessed in this study. finally, socio-demographic and socio-economic confounders have been previously associated with the incidence and severity of migraine (28, 29) and their role in affecting patients' symptoms cannot be completely ruled out in the present survey. taken together, these findings suggest that the covid-19 lockdown phase may had resulted in an unexpected relieving improvement of migraine symptoms' frequency and intensity in pediatric patients. it is well-known that daily sources of psychological stress may act as triggers of migraine symptoms in children and adolescents (30) . one can speculate that this unexpected improvements in migraine symptoms could be -at least partially -related to a reduction in external or internal demands for high performance in daily social settings, such as school and sport or leisure activities (10). on a theoretical level, these findings further confirms the role played by psychosocial factors in the onset, progression and stabilization of migraine symptoms in children and adolescents (10) . moreover, as psychological stress inherent to academic and social life can be a prominent factor linked with migraine symptoms severity, this study also underlines the need of promoting interventions aimed at improving stress resilience and coping in pediatric patients' with migraine (31) . for example, focusing on psychological and environmental aspects of child and adolescents' migraine in a multidisciplinary, continuous and integrated healthcare approach is warranted to improve patients' outcomes and quality of life (32, 33) . the raw data supporting the conclusions of this article will be made available by the authors, upon reasonable request. the study was reviewed and approved by ethics committee pavia. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. rb: has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. ep and gd: concept and design. ac, gd, ep, and ft: acquisition of data. lp: data analysis and drafting of the manuscript. rb: supervision. all authors interpretation of data and critical revision of the manuscript for important intellectual content. this study was supported by funds to rb from italian ministry of health (ricerca corrente 2020). covid-19 and italy: what next? psychological outcomes associated with stay-at-home orders and the perceived impact of covid-19 on daily life migraine in childhood: biobehavioural or psychosomatic disorder? perceived stress in patients with migraine: a casecontrol study frequency of pediatric migraine with aura in a clinic-based sample pediatric migraine equivalents: occurrence and clinical features in practice disrupted default mode network connectivity in migraine without aura trigger factors in childhood migraine: a clinic-based study from eastern india the diet factor in pediatric and adolescent migraine childhood and adolescent migraine: a neuropsychiatric disorder? med hypotheses an electronic daily diary process study of stress and health behavior triggers of primary headaches in children pathophysiology of tension-type headache school stressors, psychological complaints and psychosomatic pain stress and psychosomatic symptoms in chinese school children: cross-sectional survey behavioral management of migraine headache triggers: learning to cope with triggers burnout and somatic symptoms among frontline healthcare professionals at the peak of the italian covid-19 pandemic knowledge, attitudes, and practices towards covid-19 among chinese residents during the rapid rise period of the covid-19 outbreak: a quick online cross-sectional survey affective temperament, attachment style, and the psychological impact of the covid-19 outbreak: an early report on the italian general population evaluating covid-19 public health messaging in italy : self-reported compliance and growing mental health concerns. medrxiv impact of quarantine due to covid infection on migraine: a survey in genova comparative study of anxiety, depression, somatization, functional disability, and illness attribution in adolescents with chronic fatigue or migraine the medical costs of migraine and comorbid anxiety and depression migraine features in migraineurs with and without anxiety-depression symptoms: a hospital-based study psychosocial factors in recurrent pediatric headache chronic pain and the anxiety disorders: epidemiology, mechanisms and models of comorbidity, and treatment headache symptoms consistent with migraine and tension-type headaches in children with anxiety disorders parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months corrected age in children born very prematurely low socioeconomic status is associated with increased risk of frequent headache: a prospective study of 22718 adults in norway socio-economic factors, lifestyle, and headache disorders -a population-based study in sweden the prevalence of triggers in paediatric migraine: a questionnaire study in 102 children and adolescents behavioral therapies in headache: focus on mindfulness and cognitive behavioral therapy in children and adolescents a systematic review and metaanalysis of the efficacy of cognitive behavioral therapy for the management of pediatric migraine psychological interventions for headache in children and adolescents the authors are thankful to patients and their caregivers who took part in this study. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 dallavalle, pezzotti, provenzi, toni, carpani and borgatti. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-276831-1z27qsym authors: zhu, juhong; sun, lin; zhang, lan; wang, huan; fan, ajiao; yang, bin; li, wei; xiao, shifu title: prevalence and influencing factors of anxiety and depression symptoms in the first-line medical staff fighting against covid-19 in gansu date: 2020-04-29 journal: front psychiatry doi: 10.3389/fpsyt.2020.00386 sha: doc_id: 276831 cord_uid: 1z27qsym background: the outbreak of novel coronavirus pneumonia (covid-19) has brought enormous physical and psychological pressure on chinese medical staff. it is extremely important to understand the prevalence and influencing factors of anxiety and depression symptoms in first-line anti-epidemic medical staff and their coping styles for these negative emotions. methods: a cross-sectional survey was conducted in gansu (china), with a questionnaire packet which consisted of the self-rating anxiety scale (sas), self-rating depression scale (sds), and the simplified coping style questionnaire (scsq). a total of 79 doctors and 86 nurses participated in the survey. correlation analysis was performed to explore the relationship between sas, sds, and scsq score. a linear regression model was used to determine the influencing factors for anxiety or depression symptoms. results: the prevalence rates of anxiety and depression symptoms among doctors was 11.4% and 45.6%, respectively. history of depression or anxiety (t=-2.644, p= 0.010, 95%ci: -10.514~-1.481) was shown to be a risk factor for anxiety symptoms in doctors, while being male (t=2.970, p=0.004, 95%ci: 2.667~13.521) was a protective factor for depression. the prevalence rate of anxiety and depression symptoms among nurses was 27.9% and 43.0%, respectively. history of depression or anxiety was a common risk factor for anxiety symptoms (t=-3.635, p=0.000, 95%ci: -16.360~-4.789) and depression symptoms (t=-2.835, p=0.005, 95%ci:-18.238~-3.254) in nurses. the results of partial correlation analysis (controlled for gender and history of depression or anxiety) indicated that the total score of positive coping was negatively correlated with the total score of anxiety (r=-0.182, p=0.002) and depression (r=-0.253, p=0.001). conclusions: the first-line anti-epidemic medical staff have high anxiety and depression symptoms and adopting positive coping styles will help to improve their negative emotions. since mid-december of 2019, coronavirus disease 2019 (covid-19) has been spreading from china (wuhan) to 26 countries worldwide (1) . as of february 24 th , 41600 medical staff across the country have been fighting in the front line of the anti-epidemic campaign. of these medical staff, 3387 of them were infected with the novel coronavirus pneumonia, accounting for 4% of all confirmed cases, while 22 were killed and accounted for 0.8% of the deaths. the front-line medical staff will not only bear the work pressure of overload, but also face the huge risk of infection (2) . stress represents the main environmental risk factor for psychiatric illnesses, and in a long-term stress state, people can be more prone to depression or other mental disease (3) , which will also increase the risk of infection (4) (5) (6) . therefore, it is necessary to investigate the psychological state of the first-line anti-epidemic medical staff and give them necessary psychological interventions if they have anxiety or depression. this cross-sectional study was conducted between february 1, 2020 and february 29, 2020. the research objects were the first line medical staff in the designated hospitals and fever clinics of novel coronavirus pneumonia in gansu province. the inclusion criteria were as follows: 1) 18 years or older; 2) doctor or nurse; 3) first-line to covid-19; 4) without serious mental illness, such as schizophrenia or an intellectual disability; 5) without physical disease affecting anxiety or depression, such as hypothyroidism or coronary heart disease; and 6) willing to be investigated. exclusion criteria were as follows: 1) less than 18 years old, 2) non-frontline medical or administrative staff, 3) not in gansu, 4) serious mental illness or a combination of disorders that may affect anxiety or depression, and 5) refused to be investigated. finally, 165 front-line medical staff working in the wuhan isolation ward were enrolled in the study. ethical approval was issued by the ethics committee of the second clinical medical college of lanzhou university, and all the participants had signed an informed consent before the study was initiated. by using the self-designed questionnaire, we have obtained the general demographic information of the respondents, including gender, age, marriage, occupation, education level, specialty, level of worry, and level of expectation. the self-rating anxiety scale (sas) (7) and self-rating depression scale (sds) (8) were used to assess anxiety and depression symptoms of medical staff respectively. both sas and sds are 20-item likert and norm-referenced scales, in which items tap physiological and psychological symptoms and are rated by participants according to how each applied to them within the past week, using a 4-point scale ranging from 1 (none, or a little of the time) to 4 (most, or all of the time) (9) . the choice of sas items is based on diagnostic criteria listed in the major american psychiatry literature, whereas the sds taps depressive symptoms based on factor analytic studies of depression symptoms (9) . the zung self-rating anxiety/depression scale (sas/sds) has been widely applied in clinical institutions and scientific research, showing convincing results and a remarkable degree of consensus among clinicians (10) . according to the conclusion of other studies (11), we also utilized the standard score of 50 as the critical value to divide depression or anxiety in the present study. the simplified coping style questionnaire (scsq) (12) is a 20-item self-report scale that includes two dimensions. the first entry consists of 1-12 items and reflects the traits of passive coping and active coping (8-item). the second entry consists of 13-20 questions, reflecting the traits of passive coping. this instrument has been commonly used in china and has proven to be highly reliable and valid (13) . in the current study, we used the electronic "questionnaire star" questionnaire as the survey tool, and information was collected through friend circle forwarding and wechat group promotion. "questionnaire star" is a professional online survey platform, which can be used for questionnaire surveys, evaluation, voting, and other purposes. compared with traditional survey methods, "questionnaire star" has the obvious advantages of being fast, low cost, easy to learn, and easy to use (14) . the categorical variables were expressed as the frequency (%), while the continuous variables were presented as mean± sd. a single sample kolmogorov-smirnov test was used to test whether the data conform to normal distribution. chi square test was used to compare categorical variables, while independent sample t-test and mann-whitney u test were respectively used to compare the continuous variables with and without normal distribution. the prevalence of anxiety and depression symptoms was calculated by splitting the total number of cases diagnosed by the total number of participants. the influence factors of anxiety or depression were analyzed by linear regression analysis. partial correlation analysis was used to analyze the correlation between scsq and sds/sas. the statistical analysis was performed by using spss version 22.0 and a p-value < 0.05 was regarded as significant. through the online survey from questionnaire stars, we finally received 165 qualified questionnaires, and the recovery rate of the questionnaire was 100%. the average age of the respondents was 34.16 ± 8.06 (years), the average length of employment was 11.35 ± 8.60 (years), the average working day on the fever clinic or isolation ward was 15.65 ± 46.63 (days), the average anxiety score was 42.79 ± 8.50, and the average depression score was 46.94 ± 11.60. tables 1 and 2 show the results. with 50 points as the critical value (both for sas and sds), nine people were considered to have anxiety symptoms, with a prevalence of 11.4% (9/79), and 36 people were considered to have depression symptoms, with a prevalence of 45.6% (36/79). there were statistical differences (p < 0.05) in the total score of negative responses and a history of anxiety or depression between the anxiety group and non -anxiety group, while there were statistical differences (p < 0.05) in gender between the depression group and non -depression group. table 3 presents the results. then, by using linear regression analysis, we found that history of depression or anxiety (t=-2.644, p= 0.010, 95%ci: -10.514~-1.481) was a risk factor for anxiety symptoms in doctors, while being male (t=2.970, p=0.004, 95%ci: 2.667~13.521) was a protective factor for depression. table 4 lists the results. with 50 points as the critical value (both for sas and sds), 24 people were considered to have anxiety symptoms, with a prevalence of 27.9% (24/86), and 37 people were considered to objects of concern heavy workload, n(%) 12 ( have depression symptoms, with a prevalence of 43.0% (37/86). there were statistical differences (p < 0.05) in the history of anxiety or depression between the anxiety group and non -anxiety group, while there were statistical differences (p < 0.05) in the total scores of active response, history of anxiety or depression, and specialty between the depression group and non -depression group. table 5 presents the results. then, by using linear regression analysis, we found that a history of depression or anxiety was a common risk factor for anxiety symptoms (t=-3.635, p=0.000, 95%ci: -16.360~-4.789) and depression symptoms (t=-2.835, p=0.005, 95%ci:-18.238~-3.254) in nurses. table 6 lists the results. the results of partial correlation analysis (controlled for gender and history of depression or anxiety) indicated that the total score of positive coping was negatively correlated with the total score of anxiety (r=-0.182, p=0.002) and depression (r=-0.253, p=0.001) in the current study, we investigated the prevalence and influencing factors of anxiety and depression symptoms in the first-line medical staff fighting against novel coronavirus pneumonia in gansu, and came to some interesting conclusions: 1) the prevalence rate of anxiety and depression symptoms among doctors was 11.4% and 45.6%, respectively; 2) the prevalence rate of anxiety and depression symptoms among nurses was 27.9% and 43.0%, respectively; 3) a history of depression or anxiety (t=-2.644, p= 0.010, 95%ci: -10.514~-1.481) was a risk factor for anxiety symptoms in doctors, while being male (t=2.970, p=0.004, 95%ci: 2.667~13.521) was a protective factor for depression; 4) a history of depression or anxiety was a common risk factor for anxiety symptoms (t=-3.635, p=0.000, 95%ci: -16.360~-4.789) and depression symptoms (t=-2.835, p=0.005, 95%ci:-18.238~-3.254) in nurses; 5) the results of partial correlation (controlled for gender and history of depression or anxiety) indicated that the total score of positive coping was negatively correlated with the total score of anxiety (r=-0.182, p=0.002) and depression (r=-0.253, p=0.001). previous studies had suggested that the mental health status of medical staff was worse than in the general population (15, 16) . for example, kerrien m et al. (17) found that 27% of junior doctors were suffering from depression, while 28.7% were suffering from anxiety. paiva ce et al. (18) found that 12.3%of doctors had depression (hads-d ≥ 11), and 19.4% had anxiety (hads-a ≥ 11). a systematic review of 29 studies showed that the prevalence of anxiety and depression among students in medical schools in europe, the uk, and elsewhere in the englishspeaking world outside of north america was 7.7-65.5% and 6.0-66.5%, respectively (19) . similarly, a cross-sectional survey showed that the prevalence of anxiety symptoms in nurses was 43.4% (20) . another cross-sectional survey indicated that the prevalence rate of anxiety among female nurses was 41.1% (21) . maharaj s et al. (22) found that the prevalence rates of depression and anxiety among australian nurses were 32.4% and 41.2%, respectively. so, our conclusions were not consistent, and this difference might come from the use of different investigation tools. interestingly, we found that the anxiety level (x 2 = 7.019. p=0.011) of nurses was significantly higher than that of doctors, but there was no difference in depression (x 2 = 0.108. p=0.756) between the two groups. so we need to pay more attention to nurses in order to relieve their anxiety. in the present study, we found that being male (t=2.970, p=0.004, 95%ci: 2.667~13.521) was a protective factor for depression in doctors. there is considerable discourse surrounding the disproportionate diagnosis of men with depression as compared to women, often times cited at a rate around 1:2 (23) . however, the view that depression rates are universally higher in women is challenged, as biological determinants, sex role changes, and social factors might also contribute to this difference (24) . what's more, meta-analyses of diagnoses and symptoms show that the gender difference peaks in adolescence but then will decline and remain stable in adulthood, and cross-national analyses also indicate that larger gender differences are found in nations with greater gender equity for major depression, but not depression symptoms (25) . but beyond that, a systematic review of nineteen studies indicates that the male gender is significantly associated with suicide in individuals with depression (26) . so, the relationship between gender and depressive symptoms needs to be verified by a large-scale longitudinal study. we also found that a history of anxiety or depression was a risk factor for anxiety symptoms in doctors, and a common risk factor for anxiety and depression symptoms in nurses. osasona so et al. (27) found that previous mental illness was significantly associated with anxiety, depression, or general psychiatric morbidity in a sample of inmates in a nigerian prison. ahmed a et al. (28) found that a history of depression and stress was associated with depressive and anxiety symptoms in a sample of 615 women in saskatchewan from pregnancy to 5 years postpartum. stafford l et al. (29) found that women with a psychiatric history and high neuroticism are at the greatest risk for future morbidity after adjusting for confounders, such as age, education, and living alone. therefore, our conclusions are consistent. by using partial correlation analysis (controlled for gender and history of depression or anxiety), we finally found that a positive coping style was a protective factor for anxiety(r=-0.182, p=0.002) and depression (r=-0.253, p=0.001), suggesting that a positive coping style was helpful in resisting negative emotions. mahmoud js et al. (30) found that reducing maladaptive coping behaviors might have the most positive impact on reducing anxiety, depression, and stress in young adult college students. wang y et al. (31) found that perceived stress had some positive effects on psychological distress, and coping style might be a mediator in this relationship among chinese physicians. in addition, holz ne et al. (32) pointed out that stress exposure would increase rates of depression and anxiety in adults, particularly in females, and had been associated with maladaptive changes in the anterior cingulate cortex (acc), while positive coping styles could help to increase the acc volume. so our conclusions were consistent. we have to admit that our research has certain limitations. first, it was just a cross-sectional study that could not establish a causal link. second, the sample size used was relatively small and therefore reduced the reliability of the study. third, we used the selfassessment scale to evaluate the depression and anxiety symptoms of the medical staff, which might have a certain result deviation. the first-line anti-epidemic medical staff have high anxiety and depression symptoms, and adopting a positive coping style will help to improve their negative emotions. the datasets analyzed in this article are not publicly available because the datasets are part of an unpublished database and the database is still being used for other manuscripts in preparation. requests to access the datasets should be directed to 156892477@qq.com. the studies involving human participants were reviewed and approved by the ethics committee of the second clinical medical college of lanzhou university. the patients/ participants provided their written informed consent to participate in this study. written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. wl and ls contributed to the study concept and design. jz acquired the data. lz, hw, and af collected the data. sx and by analyzed the data and drafted the manuscript. all authors read and approved the final manuscript. case of the index patient who caused tertiary transmission of covid-19 infection in korea: the application of lopinavir/ritonavir for the treatment of covid-19 infected pneumonia monitored by quantitative rt-pcr suggestions for prevention of 2019 novel coronavirus infection in otolaryngology head and neck surgery medical staff. zhonghua er bi yan hou tou jing wai ke za zhi = chin j otorhinolaryngol head neck surgery stress-induced mechanisms in mental illness: a role for glucocorticoid signalling association between depression and enterovirus infection: a nationwide population-based cohort study anxiety and depression symptoms in a general population and future risk of bloodstream infection: the hunt study is there any association between toxoplasma gondii infection and depression? a rating instrument for anxiety disorders a self-rating depression scale screening for anxiety and depression: reassessing the utility of the zung scales comparison of hospital anxiety and depression scale (hads) and zung self-rating anxiety/ depression scale (sas/sds) in evaluating anxiety and depression in patients with psoriatic arthritis correlation of depression and anxiety with social support and quality of life in patients with chronic wounds zhong nan da xue xue bao yi xue ban = j cent south university core self-evaluation and burnout among nurses: the mediating role of coping styles work-family conflict and job burn-out among chinese doctors: the mediating role of coping styles application and practice of "questionnaire star" in c language flipped classroom teaching mental health and related factors of hospital nurses determinate factors of mental health status in chinese medical staff: a cross-sectional study prevalence of anxiety disorders and depression among junior doctors and their links with their work doctor, are you healthy? a cross-sectional investigation of oncologist burnout, depression, and anxiety and an investigation of their associated factors medical student depression, anxiety and distress outside north america: a systematic review anxiety symptoms among chinese nurses and the associated factors: a cross sectional study serial multiple mediation of organizational commitment and job burnout in the relationship between psychological capital and anxiety in chinese female nurses: a cross-sectional questionnaire survey prevalence and risk factors of depression, anxiety, and stress in a cohort of australian nurses an illness of power: gender and the social causes of depression gender differences in depression gender differences in depression in representative national samples: meta-analyses of diagnoses and symptoms risk factors for suicide in individuals with depression: a systematic review prevalence and correlates of depression and anxiety disorder in a sample of inmates in a nigerian prison trajectories of maternal depressive and anxiety symptoms from pregnancy to five years postpartum and their prenatal predictors anxiety and depression symptoms in the 2 years following diagnosis of breast or gynaecologic cancer: prevalence, course and determinants of outcome the relationship among young adult college students' depression, anxiety, stress, demographics, life satisfaction, and coping styles perceived stress and psychological distress among chinese physicians: the mediating role of coping style positive coping styles and perigenual acc volume: two related mechanisms for conferring resilience? key: cord-258856-7hgdlrpi authors: an, ping; chen, hongbin; ren, haixia; su, juan; ji, mengyao; kang, jian; jiang, xiaoda; yang, yifei; li, jiao; lv, xiaoguang; yin, anning; chen, di; chen, mingkai; zhou, zhongyin; dong, weiguo; ding, yijuan; yu, honggang title: gastrointestinal symptoms onset in covid-19 patients in wuhan, china date: 2020-11-12 journal: dig dis sci doi: 10.1007/s10620-020-06693-6 sha: doc_id: 258856 cord_uid: 7hgdlrpi background: early detection is critical in limiting the spread of 2019 novel coronavirus (covid-19). although previous data revealed characteristics of gi symptoms in covid-19, for patients with only gi symptoms onset, their diagnostic process and potential transmission risk are still unclear. methods: we retrospectively reviewed 205 covid-19 cases from january 16 to march 30, 2020, in renmin hospital of wuhan university. all patients were confirmed by virus nuclei acid tests. the clinical features and laboratory and chest tomographic (ct) data were recorded and analyzed. results: a total of 171 patients with classic symptoms (group a) and 34 patients with only gi symptoms (group b) were included. in patients with classical covid-19 symptoms, gi symptoms occurred more frequently in severe cases compared to non-severe cases (20/43 vs. 91/128, respectively, p < 0.05). in group b, 91.2% (31/34) patients were non-severe, while 73.5% (25/34) patients had obvious infiltrates in their first ct scans. compared to group a, group b patients had a prolonged time to clinic services (5.0 days vs. 2.6 days, p < 0.01) and a longer time to a positive viral swab normalized to the time of admission (6.9 days vs. 3.3 days, respectively, p < 0.01). two patients in group b had family clusters of sars-cov-2 infection. conclusion: patients with only gi symptoms of covid-19 may take a longer time to present to healthcare services and receive a confirmed diagnosis. in areas where infection is rampant, physicians must remain vigilant of patients presenting with acute gastrointestinal symptoms and should do appropriate personal protective equipment. electronic supplementary material: the online version of this article (10.1007/s10620-020-06693-6) contains supplementary material, which is available to authorized users. an outbreak of a novel coronavirus pneumonia has rapidly spread in china and is pandemic worldwide [1] [2] [3] . this novel coronavirus was successfully isolated from the human airway epithelial cells and was officially named as sars-cov-2 (severe acute respiratory syndrome coronavirus 2) [4] . chinese researchers shared the virus complete genome sequences and extremely facilitated the studies and confirmation of infected patients [4, 5] . early detection of infected patients is one of the most important steps to take early isolation and mitigate the spread of the virus [6, 7] . fever, cough and other respiratory symptoms were reported as common presentations of the novel coronavirus infection , and patients with these classical symptoms warrant further screening for viral infection [3, 5, 8] . although recent studies have reported gastrointestinal (gi) symptoms in covid[9, 18] , we report in detail the disease trajectory of gi symptom-only covid-19 infection including the onset, duration of symptoms, and time to diagnosis in our population in wuhan. the study protocol was approved by the ethics committee of renmin hospital of wuhan university, and waiver of informed consent was obtained. we retrospectively reviewed 205 hospitalized covid-19-confirmed cases from january 16 to march 30, 2020, in renmin hospital of wuhan university (wuhan, hubei province, china) which was the designated hospital for covid-19 infection. all covid-19 patients enrolled in this study were diagnosed according to who guideline [10] . severity was defined as follows according to diagnostic and treatment guideline for covid-19-infected pneumonia (trial version 6) by chinese national health committee: (1) nonsevere including mild (with mild symptoms but without obvious pneumonia radiological images) and moderate cases (with symptoms and radiological images showing limited pneumonia), and (2) severe cases: with one of the following criteria: (a) respiratory distress with respiratory rate ≥ 30/ min, (b) pulse oximeter oxygen saturation ≤ 93% at rest; (c) oxygenation index (artery partial pressure of oxygen/ inspired oxygen fraction, pao 2 /fio 2 ≤ 300 mmhg, and (d) significant progress (> 50%) in radiological changes, and (3) critical severe cases: with one of the following criteria: (a) respiratory failure and required mechanical ventilation; (b) shock; (c) with other organ function failure and required icu care. the flowchart for patient inclusion is shown in fig. 1 . the demographic data, clinical characteristics (including exposure history, medical history, comorbidities, signs, and symptoms), laboratory findings, chest-computed tomographic (ct) scans, and clinical outcomes were obtained through data collection tables in electronic medical records. the date of symptoms onset, initial clinic visit, hospital admission, ct scans, and virus nuclei acid tests, as well as the severity of patient condition, were also recorded. data were reviewed by a trained team of experienced physicians and analyzed by three independent researchers. a questionnaire was sent to all patients with only gi symptoms for collecting the infection history of their family members. to detect the presence of 13 respiratory virus targets and bacteria (including influenza a virus, influenza a virus h1n1 (2009), influenza a virus h3n2, influenza b virus, parainfluenza viruses, orthopneumovirus, metapneumovirus, coronavirus, rhinovirus, adenoviruses, bocaparvovirus, and mycoplasma pneumoniae, chlamydia), oropharyngeal swab specimens were tested by using multiple respiratory pathogen multiple detection kit (resp13) (haiershi, china) according to the manufacturer's instructions [11] . all covid-19 patients enrolled in this study had a confirmatory oropharyngeal swab which detected the presence of sars-cov-2 rna by real time polymerase chain reaction (rt-pcr). in brief, nasal and oropharyngeal swab specimens were collected and transferred into sterile tube with viral transport media and total rna was extracted within 2 h. two target genes for sars-cov-2 rna, including nucleocapsid protein (np) gene and open reading frame (orf) 1ab gene, were subsequently amplified and tested by using sars-cov-2 nucleic acid test kits according to the manufacturer's protocol (shanghai bio-germ medical technology co ltd.). positive amplification of either np or orf 1ab gene or both confirmed sars-cov-2 rna infection. descriptive data were presented as mean ± sd for normally distributed data and as medians with iqr for non-normally distributed data. categorical variables were expressed as counts and percentages. when the data were normally distributed, independent t tests were used to compare the mean of continuous variables. otherwise, the mann-whitney test is used. although fisher's exact test was used with limited data (n < 40), the chi-squared test was used to compare the proportion of categorical variables. the analysis of variance or kruskal-wallis rank-sum test was used for comparison between multiple groups. for multiple hypothesis testing, if results indicated significance, post hoc analysis was performed further. all statistical analyses were performed using spss version 13.0 software. a p value of less than 0.05 is statistically significant. a total of 205 hospitalized covid-19 patients were included in this study, with 171 patients presented with classic symptoms including fever, fatigue, and respiratory symptoms (dry cough, sputum) and 34 (16.6%) patients presented with only gi symptoms including anorexia, diarrhea, nausea, vomit, and abdominal pain ( . only 3 cases were severe and with no death. it is also striking that non-severe (mild and moderate) patients in group b had obvious infiltrates on their first chest ct scans but did not have any respiratory symptoms. in a total of 159 non-severe patients, 128 (80.5%) presented with classic symptoms. of these, 91 had classic symptoms without gi symptoms (group a1) and 37 had classic symptoms with gi symptoms (group a2). 31 patients (19.5%) presented with gi symptoms only (group b). (table 2 ). there were similar comorbidities regarding hypertension, diabetes, malignant tumors, cardiovascular, cerebrovascular disease and chronic renal failure, history of smoking, and exposure to confirmed or suspected covid-19 patients between each group. the common clinics for group a patients to visit were fever clinic (53.5%, 85/159), pulmonary department (12.6%, 12/159), and emergency department (10.1%, 16/159), while 83.9% (26/31) group b patients with only gi symptoms selected or were designated to gastroenterology department. it is worth noting that the gi symptoms onset in group b patients were not chronic which occurred 1-8 days before their clinic visits (fig. 2b ). there was no significant difference in systolic pressure, oximetry saturation, respiratory rate, complete blood counting, c-creative protein, liver function ( we further analyzed the durations for patient presentation to healthcare services and clinical diagnosis of covid-19. compared to group a, from detectable symptoms onset, patients in group b (with only gi symptoms) took a longer time to present to healthcare services (5.0 days vs. 2.6 days, p < 0.01), obtained chest ct scans (6.6 days vs. 3.8 days, p < 0.01) and viral swabs (7.6 days vs. 4.2 days, p < 0.01) (fig. 2) . furthermore, group b patients had longer durations to hospital admission after initial clinic presentations (8.2 days vs. 3.7 days, p < 0.01) and to virus rna confirmation (6.9 days vs. 3.3 days, p < 0.01) in contrast to group a. as for hospitalization days, there was no difference between these two groups (17.4 days in group b vs. 18.2 days in group a, p > 0.05) ( table 2 ). in total, patients with only gi symptoms spent a longer time from their detectable symptoms to hospital admissions (13.2 days in group b vs. 6.3 days in group a, p < 0.01) (fig. 2b) . it is important to evaluate the transmission risk of patients with only gi symptoms, especially for their potential misdiagnosis or delayed diagnosis. the infection history of patient families in group b was collected. on january 23, 2020, wuhan was locked down and all citizens were in quarantine. after 10 to 11 days, 2 patients in group b occurred gi symptoms including diarrhea and anorexia (fig. 3) . seven and eight days later, their family members (2 persons in patient 1 family and 1 person in patient 2 family) started to present symptoms such as fever, respiratory symptoms, anorexia, and diarrhea. three members were later diagnosed as covid-19. one member of patient 2 was entirely asymptomatic and was diagnosed as a virus carrier. recent published studies indicated that the most common onset symptoms of covid-19 pneumonia were fever, cough, and myalgia or fatigue. most infected patients had fever, while cough (76%) and fatigue (44%) were also usually presented onset [3] . less common illness presentations included sputum production, headache, hemoptysis, and data are presented as means (iqr) and n/n (%) or means ± std. group a: patients with classic symptoms; group a1: patients with only classic symptoms; group a2: patients with both classic symptoms and gi symptoms; group b: patients with only gi symptoms. abbreviations: gi, gastrointestinal. p values indicate differences between group a1 and group a2 or between group a and group b. p < 0.05 was considered statistically significant data are presented as means (iqr) and n/n (%) or means ± std. group a: patients with classic symptoms; group a1: patients with only classic symptoms; group a2: patients with both classic symptoms and gi symptoms; group b: patients with only gi symptoms. abbreviations: gi, gastrointestinal. p values indicate differences between group a1 and group a2 or between group a and group b. p < 0.05 was considered statistically significant although previous studies reported gi symptoms in covid-19 patients, the clinical characteristics, diagnostic duration, and transmission risk for patients with only gi symptoms were still unclear. here, demographic and clinical characteristics analysis revealed that gi symptoms were presented in 38.5% (79/205) patients (table 1) which were not less common as previously reported [3] . additionally, patients with both classic and gi symptoms were more severe which resulted in higher morbidity and mortality than those with only classic symptoms. for patients in group b, gi symptoms were not chronic and always not severe. awareness and recognition of these acute and mild gi presentations might benefit early screening and clinical diagnosis of covid-19. although gi symptoms in patients with classic symptoms (group a2) were related to more severe cases which could be because of viral infection in the digestive tract, multi-organ failure, or preexisting comorbidities (table 1) , most patients [91.2% (31/34)] with only gi symptoms (group b) were non-severe. importantly, 73.5% patients with only gi symptoms already had obvious infiltrates in their first chest ct scans. mild gi symptoms with sub-clinical covid-19 pneumonia possibly led to patient misdiagnosis and facilitated the spread of disease. three severe cases in group b also needed close monitoring. it is also critical for clinicians to follow-up patients with gi symptoms suspicious of covid-19 because classic symptoms can have a later onset. early identification and management of these patients can benefit pandemic covid-19 control (supplementary figure 1) . data extracted from clinical process indicated that the common clinics for patients with only gi symptoms were gastroenterology department but not fever clinic, pulmonary department and emergency department which were mostly visited by patients in group a (table 2) . furthermore, only 38.7% group b patients were positive for the first virus swabs, while most of them had positive serum antibodies. therefore, we strongly suggest virus nuclei acid testing and antibody testing are done simultaneously. if patients test positive for igm antibodies, repeat viral swabs are advised. it is also imperative that gastroenterology and endoscopy staff do the appropriate ppe to reduce the risk of nosocomial transmission. the duration of clinical visits and clinical diagnosis was further investigated. it was evident that group b patients presented later to healthcare services (5.0 days in group b vs. 2.6 days in group a, p < 0.01). mild symptoms possibly contributed to the clinic visit delay. patients in group b also needed more time to obtain ct scans (6.6 days vs. 3.8 days, p < 0.01), virus nuclei acid tests (7.6 days vs. 4.2 days, p < 0.01) ,and finally hospitalizations (8.2 days vs. 3.7 days, p < 0.01) when compared to group a (fig. 2a) . patients in wuhan were screened for covid-19 by rt-pcr testing tbil, total bilirubin; alp, alkaline phosphatase; ast, alanine aminotransferase; ast, aspartate aminotransferase; ldh, lactate dehydrogenase; sars-cov, severe acute respiratory syndrome coronavirus; mers-cov, middle east respiratory syndrome coronavirus; ace2, angiotensin-converting enzyme ii from nasal and oropharynx swabs, complete blood tests, virus antibody tests (igm and igg), and chest ct scans. patients had characteristic lung infiltrates with or without classic symptoms but negative for viral rna which were identified as suspected patients and needed further nuclei acid testing; especially, positive virus igm was detected. limited experiences of clinicians, awareness of these patients with only gi symptoms, and variability of virus tests were the possible reasons for delayed diagnosis and treatment. in this study, patients with only gi symptoms took an obviously longer time from their symptoms onset to hospital admissions (13.2 days in group b vs. 6.3 days in group a, p < 0.01) (fig. 2b) . these results indicated that gi symptoms were easily neglected or underestimated and might be misdiagnosed. although anorexia sometimes was not considered as a gi symptom, it was one of the commonest symptoms for patients in china to search gi clinic services. here, we strongly recommended healthcare workers to pay more attention to extra-pulmonary symptoms of previous studies demonstrated that gi symptoms also occurred in severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov) infection [12] [13] [14] . a metallopeptidase, angiotensin-converting enzyme ii (ace2) is proved to be the host cell receptor for covid-19 recognition, the same as sars-cov infection [15] [16] [17] . researchers postulated that besides the most recognized mode of transmission through aerosol droplets, feco-oral transmission was also a potential route of covid-19 transmission. [18] just recently, studies revealed that in digestive system, ace2 expressed in esophagus upper and stratified epithelial cells and absorptive enterocytes from ileum and colon [18, 19] . more importantly, hoffmann et al. demonstrated sars-cov-2-s used ace2 for entry into target cells and offered important implications for sars-cov-2 transmissibility and pathogenesis [20] . these results provided evidence of digestive tract as a potential invasive target for sars-cov-2 which possibly contributed to gastrointestinal symptoms. finally, two family clusters of sars-cov-2 infection in patients group b were reported (fig. 3 ). all these two family members were quarantined at home 10 to 11 days before the detectable gi symptoms of the first patients. in family 1 (fig. 3a) , the husband of the patients occurred typical symptoms in the followed 7 days, while their daughter felt ill 1 day later. in family 2 (fig. 3b) , on the 8th day of the gi symptoms onset occurred in the husband, the wife had a fever. their son was later diagnosed as asymptomatic carrier by the positive virus rna but normal chest ct scans. although these familiar clusters did not provide evidence of fecal-oral transmission in covid-19, they indicated the possibility of transmission risk for patients with only gi symptoms. this study has limitations. first, small scale in current retrospective study was studied, which could cause biases in clinical observation. it would be better to include more patients. second, further progression and prognosis were not assessed yet for all patients' current hospitalization. third, elevation of serum covid-19 igm and igg levels was observed in most patients and its role in diagnosis and disease progress was a very interesting topic and needed further in-depth exploration. fourth, stool testing for virus nuclei acid needed further investigation including the lasting time and positive rates. in conclusion, we recommend physicians remain vigilant of covid-19 infection in patients who present with acute gi illness, and screen patients accordingly if suspicious for covid-19. we also recommend that appropriate ppe be worn by all staff working in gastroenterology. the continuing 2019-ncov epidemic threat of novel coronaviruses to global health-the latest 2019 novel coronavirus outbreak in wuhan, china european centre for disease prevention and control. outbreak of acute respiratory syndrome associated with a novel coronavirus clinical features of patients infected with 2019 novel coronavirus in wuhan coronaviruses: genome structure, replication, and pathogenesis a novel coronavirus from patients with pneumonia in china preparedness and proactive infection control measures against the emerging wuhan coronavirus pneumonia in china the centre for health protection closely monitors cluster of pneumonia cases on mainland. press release of the department of health a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster clinical characteristics of covid-19 patients with digestive symptoms in hubei, china: a descriptive, cross-sectional, multicenter study clinical management of covid-19. world health organization. interim guidance clinical evaluation of a singletube multiple rt-pcr assay for the detection of 13 common virus types/subtypes associated with acute respiratory infection human intestinal tract serves as an alternative infection route for middle east respiratory syndrome coronavirus crossing barriers: infections of the lung and the gut tissue distribution of ace2 protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis cryo-electron microscopy structures of the sars-cov spike glycoprotein reveal a prerequisite conformational state for receptor binding discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and 1 its potential bat origin evolution of the novel coronavirus from the ongoing wuhan outbreak and modeling of its spike protein for risk of human transmission the digestive system is a potential route of 2019-ncov infection: a bioinformatics analysis based on single-cell transcriptomes genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding the novel coronavirus 2019 (2019-ncov) uses the sars-1 coronavirus receptor 2 ace2 and the cellular protease tmprss2 for entry into target cells conflict of interest all authors declared no conflict of interest. key: cord-265596-o6jdvlya authors: pan, lei; mu, mi; yang, pengcheng; sun, yu; wang, runsheng; yan, junhong; li, pibao; hu, baoguang; wang, jing; hu, chao; jin, yuan; niu, xun; ping, rongyu; du, yingzhen; li, tianzhi; xu, guogang; hu, qinyong; tu, lei title: clinical characteristics of covid-19 patients with digestive symptoms in hubei, china: a descriptive, cross-sectional, multicenter study date: 2020-04-14 journal: am j gastroenterol doi: 10.14309/ajg.0000000000000620 sha: doc_id: 265596 cord_uid: o6jdvlya objective: since the outbreak of coronavirus disease 2019 (covid-19) in december 2019, various digestive symptoms have been frequently reported in patients infected with the virus. in this study, we aimed to further investigate the prevalence and outcomes of covid-19 patients with digestive symptoms. methods: in this descriptive, cross-sectional, multicenter study, we enrolled confirmed patients with covid-19 who presented to 3 hospitals from january 18, 2020, to february 28, 2020. all patients were confirmed by real-time polymerase chain reaction and were analyzed for clinical characteristics, laboratory data, and treatment. data were followed up until march 18, 2020. results: in the present study, 204 patients with covid-19 and full laboratory, imaging, and historical data were analyzed. the average age was 52.9 years (sd ± 16), including 107 men and 97 women. although most patients presented to the hospital with fever or respiratory symptoms, we found that 103 patients (50.5%) reported a digestive symptom, including lack of appetite (81 [78.6%] cases), diarrhea (35 [34%] cases), vomiting (4 [3.9%] cases), and abdominal pain (2 [1.9%] cases). if lack of appetite is excluded from the analysis (because it is less specific for the gastrointestinal tract), there were 38 total cases (18.6%) where patients presented with a gastrointestinal-specific symptom, including diarrhea, vomiting, or abdominal pain. patients with digestive symptoms had a significantly longer time from onset to admission than patients without digestive symptoms (9.0 days vs 7.3 days). in 6 cases, there were digestive symptoms, but no respiratory symptoms. as the severity of the disease increased, digestive symptoms became more pronounced. patients with digestive symptoms had higher mean liver enzyme levels, lower monocyte count, longer prothrombin time, and received more antimicrobial treatment than those without digestive symptoms. discussion: we found that digestive symptoms are common in patients with covid-19. moreover, these patients have a longer time from onset to admission, evidence of longer coagulation, and higher liver enzyme levels. clinicians should recognize that digestive symptoms, such as diarrhea, are commonly among the presenting features of covid-19 and that the index of suspicion may need to be raised earlier in at-risk patients presenting with digestive symptoms. however, further large sample studies are needed to confirm these findings. on january 7, 2020, a novel coronavirus was isolated and named as severe acute respiratory syndrome coronavirus 2 (sars-cov-2) by the international committee on taxonomy of viruses (ictv) in the wake of an outbreak of pneumonia of unknown cause in wuhan city, china (1, 2) . this pneumonia was called coronavirus disease 2019 by the world health organization on february 11, 2020. as of this writing, the covid-19 outbreak has become a pandemic that is threatening global health, undermining the global economy, and destabilizing societies across the world (3) (4) (5) . it is well established that most patients with covid-19 have fever along with respiratory signs and symptoms, such as cough and dyspnea (6) (7) (8) (9) . to date, there is some uncertainty about the prevalence of extrapulmonary symptoms, such as those arising from the gastrointestinal tract. however, with the evolution of the pandemic and the accumulation of case data, we are now able to describe the initial clinical presentations of patients with covid-19; and our experience is revealing that digestive symptoms are very common (10) . in particular, our initial observations with covid-19 indicate that many patients present initially with diarrhea, anorexia, and vomiting, not necessarily with respiratory symptoms at first. in this study, we enrolled patients confirmed to have covid-19 from 3 hospitals in hubei province and investigated the prevalence, clinical characteristics, and outcomes of covid-19 patients with vs without digestive symptoms. this descriptive, cross-sectional, multicenter study was conducted in china, from january 18, 2020, to february 28, 2020. all patients were recruited from 3 hospitals in hubei province, including wuhan hanan hospital, wuhan union hospital, and huanggang central hospital. this study was approved by the ethics committee of the above 3 hospitals. we randomly selected 310 patients with pneumonia of unknown cause from general wards and intensive care units (icus) in the 3 hospitals as the initial study population. we applied 2 inclusion criteria: (i) all adult patients were confirmed by real-time polymerase chain reaction and were diagnosed as having covid-19 according to who interim guidance and (ii) all patients who underwent chest computerized tomography (ct) and complete panel of routine laboratory tests, including compete blood count, urinalysis, blood biochemistry, and blood coagulation function. patients who did not meet the above inclusion criteria were excluded from the study. the epidemiological history, demographics data, clinical characteristics, laboratory data, treatment programs, and outcome measures were obtained from the patients' medical records. clinical outcomes were followed up to march 18, 2020 . data were collected as comprehensively as possible through a combination of chart review and, when necessary, through communication with attending doctors and other medical workers to fill in the missing data. all data were separately extracted by 2 authors (l.t. and m.m.). throat swab specimens from the upper respiratory tract obtained from all patients at admission were immediately maintained in a viral transport medium and were tested to confirm covid-19 by real-time polymerase chain reaction (11) . in addition, other respiratory viruses including influenza a virus, influenza b virus, and respiratory syncytial virus were also examined. all patients underwent chest ct. we extracted the epidemiological history (i.e., clear contact history and unclear contact history), demographic data, clinical characteristics including respiratory symptoms and digestive symptoms on admission, comorbidities, laboratory data, treatment programs, and clinical outcomes (discharged and died). descriptive data were presented as mean (6sd) for normally distributed continuous variables and as median with interquartile range for non-normally distributed data. categorical variables were presented as percentages. for laboratory results, we also assessed whether the measurements were outside the normal range. all statistical analyses were performed using spss version 20 (spss, chicago, il). two independent samples were tested by the student t-test; the analysis of variance or kruskal-wallis rank-sum test was used for comparison between multiple groups. the x 2 test was performed to compare count data, and a 2-tailed value of p , 0.05 was considered statistically significant. to build our final study sample, we began by randomly selecting 310 patients with pneumonia of unknown cause admitted to the general wards and icu in the partner hospitals during the study period (january 18, 2020-february 28, 2020), which coincided with the initial outbreak of covid-19 in the region. we excluded 96 patients who lacked complete data, such as no chest ct, missing nucleic acid of sars-cov-2 test, a negative sars-cov-2 test, or lacked a full set of laboratory data. this resulted in an analyzable population of 204 covid-19-positive patients, of whom 70 (34%) were critically ill. the last follow-up at the time of writing this study was march 18, 2020. a detailed flowchart of participants is presented in figure 1 . the baseline characteristics of 204 patients with covid-19 are provided in table 1 . the average age was 52.9 years (sd 6 16.0), including 107 men and 97 women. the average time from symptom onset to hospital admission was 8.1 days (sd 6 4.9). based on epidemiological history, we found that most patients could not recall a clear history of a known exposure. there were 44 (21.6%) patients with cardiovascular diseases, 24 (11.8%) patients with endocrine system diseases, and others with respiratory diseases (9 [4.4%]), malignant tumors (13 [6.3%]), and other disorders, as shown in table 1 . after admission, there were 184 (90.2%) patients receiving antiviral treatment (e.g., lopinavir-ritonavir), 141 (69.1%) on antibiotics, 80 (39.2%) on glucocorticoids, 96 (47.1%) on nebulized a-interferon, 56 (27.5%) on intravenous immunoglobulin, and 10 (4.9%) on antifungal treatment. in addition, 16 patients were transferred to the icu (7.8%), 168 were discharged (82.4%), and 37 (17.7%) died. among the patients, the average hospital stay was 17 days (sd 6 9.0), and the average length of stay in the icu was 8.9 days (sd 6 6.9). the clinical features and medical treatment of covid-19 patients with digestive symptoms are shown in table 1 . one hundred three patients (50.5%) admitted to the hospital were found to present with one or more digestive symptoms. of these 103 patients, 97 had developed respiratory symptoms along with digestive symptoms and 6 presented with only digestive symptoms in the absence of respiratory symptoms. among the 101 patients without digestive symptoms, 84 presented only with respiratory symptoms and 20 neither had respiratory nor digestive symptoms as their chief complaint or as an accompanying symptom. figure 2 shows a breakdown of these categories. patients with digestive symptoms had a significantly longer time from onset to hospital admission vs patients without digestive symptoms (9.0 days vs 7.3 days, p 5 0.013). in table 2 cases of diarrhea were usually not high volume or clinically severe, but more commonly presented as nondehydrating loose stools, typically up to thrice daily. we found that 69.2% and 100% of moderate and severe patients, respectively, had lack of appetite on presentation. as the severity of the disease increased, digestive symptoms become more pronounced. however, there was no significant difference in discharge time, days of intensive care, or mortality between the 2 groups. in addition, we found that the number of patients with elevated alt and ast (.50 u/l) were significantly higher in patients with digestive symptoms (alt: 21 [20.4%], ast: 17 [16.5%]) than those without the digestive symptoms (alt: 6 [5.9%], ast: 5 [5.0%]) (p alt 5 0.002, p ast 5 0.008). therefore, those patients with digestive symptoms were more likely to suffer liver injury, although the mean alanine aminotransferase and aspartate aminotransferase were in the normal range (table 3) . monocyte counts were lower in patients with digestive symptoms. no significant differences were found in complete blood count, electrolytes, and kidney function when comparing patients with vs those without digestive symptoms. however, we did find that prothrombin time prolongation was more significant in patients with vs without digestive symptoms (13.1 vs 12.5 seconds), whereas other indicators of coagulation function were not significantly different. as compared to those with digestive symptoms, patients without digestive symptoms were less likely to receive antibiotic treatment 62 (61.4%) vs 79 (76.7%), interferon 39 (38.6%) vs 57 (55.3%), and immunoglobulin 17 (16.8%) vs 39 (37.9%). the present study was conducted by reviewing the medical records of patients with covid-19 from january 18, 2020, to february 28, 2020, in 3 heavily affected hospitals during the initial outbreak in hubei province, where 83% of cases in china were reported. we found that digestive symptoms are a common complaint in patients with covid-19. by the policy of the local government, wuhan union hospital was deployed as the key medical center to treat severe patients. given the proximity of this hospital to the epicenter of the outbreak and the designation of this hospital to receive severe illness, patients in this sample were more critically ill than in other covid-19 studies. the other 2 hospitals were designated to hospitalize mild-to-moderate covid-19 patients: wuhan hannan hospital, a secondary hospital 50 km from union hospital, and huanggang central hospital, a newly-built hospital specifically constructed for covid-19 patients, about 80 km away from wuhan. our initial purpose in this study was to investigate the prevalence and characteristics or extrapulmonary digestive symptoms that might otherwise be under-recognized, thus helping to bring attention to these symptoms to facilitate earlier recognition of covid-19 and thus to offer earlier treatment before mild disease progresses to severe illness. at the time of this writing in march 2020, the covid-19 pandemic remains severe and expanding. in clinical practice, patients with covid-19 are still mainly affected by the respiratory system but evidence of damage to other system organs has been reported (12,13), and especially critical patients are susceptible to multiple organ dysfunction (14) . our results indicate that nearly one-half of patients with covid-19 admitted to the hospital reported digestive symptoms, most commonly anorexia and diarrhea. this is important because if clinicians solely monitor for respiratory symptoms to establish case definitions for covid-19, they may miss cases initially presenting with extrapulmonary symptoms or the disease may not be diagnosed later until respiratory symptoms emerge. this theory is supported by our finding that patients with digestive symptoms had a significantly longer time from onset to admission than those without digestive symptoms, possibly because they did not initially exhibit typical respiratory symptoms and thus did not receive timely diagnoses and treatment for covid-19. of note, it was reported that many medical staff in china were infected at the beginning of the epidemic. although this was related to improper protection of medical personnel early on, it may also have resulted from failing to consider covid-19 in the face of atypical extrapulmonary symptoms, especially those with digestive symptoms at the beginning of the outbreak. less attention of digestive system symptoms by the public might also hepatitis b 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) cholecystitis 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) cholangitis 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) pancreatitis 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) contribute to the transmission inside the family or in the community. there are many reasons why covid-19 seems to cause digestive symptoms. first, sars-cov-2 is similar to sars-cov and can invade the human body by binding to the human angiotensin converting enzyme 2 (ace-2) receptor, which causes liver tissue injury by the upregulation of ace-2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells (15) . second, sars-cov-2 indirectly or directly damages the digestive system through an inflammatory response. the chain reaction of inflammatory factors and viremia may injure the digestive system. studies reveal that viral nucleic acid is detected in stool samples in up to 53.4% of patients (16) (17) (18) . enteropathic viruses may directly damage the intestinal mucosa and cause digestive symptoms, but further research is needed to confirm this possibility. third, the intestinal flora is colonized in the human intestine, and their numbers are astonishing and diverse. the intestinal flora plays a variety of important physiological roles in the body, such as affecting the body's nutritional metabolism, regulating the development and maturation of the body's immune system, and antibacterial effects (19) . the virus itself may cause disorders of the intestinal flora, which could result in digestive symptoms. we are currently in the process of collecting stool samples for the testing of intestinal flora diversity to explore the role of intestinal flora in this disease. finally, the intestine is the largest immune organ in the body. changes in the composition and function of the digestive tract flora affect the respiratory tract through the common mucosal immune system, and respiratory tract flora disorders also affect the digestive tract through immune regulation. the effect is called the "gut-lung axis" (20, 21) , which may further explain why patients with covid-19 pneumonia often have digestive symptoms. curiously, our data indicate that patients with digestive symptoms in our case series rarely had underlying digestive diseases. unlike other studies (12,13), we did not find significant liver injury, which was similar to the findings of wu et al. (22) . it is difficult to speculate why there are variations in liver test abnormalities among studies, but these variations should be further investigated to better understand how and when covid-19 affects the hepatic function. nevertheless, we found that patients with digestive symptoms were more likely to exhibit elevated liver tests, such an ast and alt, compared with patients without digestive symptoms. this is a topic worthy of attention. we have noted that as the severity of the disease increases, digestive symptoms become more pronounced. one possibility is that digestive symptoms indicate viral load and replication within the gastrointestinal tract, which leads to more severe disease. another possibility is that patients with extrapulmonary symptoms reported later for care because they did not initially have typical respiratory symptoms, and thus presented at a later and less curable stage of disease. these hypotheses deserve close examination in future research. the present study has several limitations. first, our analysis was based on a retrospective study with a relatively small sample, which might cause bias and limit the reliability or generalizability of our results. second, we did not test for rna of sars-cov-2 in the stool of patients with covid-19, so we cannot correlate digestive symptom prevalence and severity with the presence of viral rna in stool specimens. future research needs to focus on this relationship to further explore the prognostic value of stool testing as both a diagnostic and prognostic indicator in covid-19. third, blood biochemical examinations are based on a comparison of means in our study that not being subdivided to patients with individual abnormalities. furthermore, a detailed analysis would be useful to mark some differences. finally, given the dynamic nature of the current covid-19 pandemic, the relationship between these patients' prognosis and digestive symptoms remains to be investigated with more data worldwide. in summary, we have found that patients with covid-19 are prone to digestive symptoms and nearly half report a digestive symptom in addition to fever and/or respiratory symptoms on presentation to the hospital. in rare instances, patient can even present with digestive symptoms in the absence of respiratory symptoms. compared with covid-19 patients without digestive symptoms, those with digestive symptoms have a longer time from onset to admission and evidence of more laboratory derangements, including prolonged coagulation and higher liver enzymes tests. these results obligate additional research evaluating the prevalence, incidence, predictors, and outcomes of digestive symptoms in this still emerging pandemic. in the meantime, clinicians must bear in mind that digestive symptoms, such as diarrhea, may be one among the presenting features of covid-19; in some cases, they may arise before the respiratory symptoms, and on rare occasions, it is the only presenting symptom of covid-19. clinicians should raise their index of suspicion when atrisk patients, such as those exposed to covid-19, present with fever and digestive symptoms, even in the absence of respiratory symptoms. this knowledge may help with earlier identification of covid-19, faster time to treatment, earlier quarantine, and lower exposure to bystanders. guarantor of the article: lei pan, md, phd, guogang xu, md, phd, and lei tu, md, phd, accept full responsibility for the conduct of the study. the novel coronavirus originating in wuhan, china: challenges for global health governance sars-cov-2 is an appropriate name for the new coronavirus are high-performing health systems resilient against the covid-19 epidemic? the sars-cov-2 outbreak: diagnosis, infection prevention, and public perception the 2019 novel coronavirus outbreak-a global threat clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china evaluation and treatment coronavirus (covid-19). statpearls: treasure island epidemiologic features and clinical course of patients infected with sars-cov-2 in singapore epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study 2019 novel coronavirus infection and gastrointestinal tract clinical features of patients infected with 2019 novel coronavirus in wuhan, china clinical characteristics and influencing factors of patients with novel coronavirus pneumonia combined with liver injury in shaanxi region novel coronavirus pneumonia related liver injury: etiological analysis and treatment strategy clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a singlecentered, retrospective, observational study exploring the mechanism of liver enzyme abnormalities in patients with novel coronavirus-infected pneumonia detection of novel coronavirus by rt-pcr in stool specimen from asymptomatic child comparison of different samples for 2019 novel coronavirus detection by nucleic acid amplification tests evidence for gastrointestinal infection of sars-cov-2. gastroenterology 2020 symbiotic gut microbes modulate human metabolic phenotypes emerging pathogenic links between microbiota and the gut-lung axis gut-lung axis: the microbial contributions and clinical implications clinical characteristics of imported cases of covid-19 in jiangsu province: a multicenter descriptive study 3 covid-19 is currently a pandemic that threatens global health.3 most patients with covid-19 present with typical respiratory symptoms and signs.3 however, early experience with the outbreak in wuhan, china, revealed that many people experienced extrapulmonary digestive symptoms on presentation. 3 digestive symptoms are common in covid-19 in addition to fever and respiratory symptoms and are reported in nearly half of patients presenting to the hospital. in rare cases, digestive symptoms may occur in the absence of any respiratory symptoms 3 when focusing only on diarrhea, in contrast to other digestive symptoms, 17% of patients with covid-19 in this series reported loose stools on the initial presentation.3 covid-19 patients with digestive symptoms have a longer time from symptom onset to admission than that of patients without digestive symptoms; this may reflect diagnostic delay because typical respiratory symptoms were not initially predominant.3 covid-19 patients with digestive symptoms have laboratory evidence of prolonged coagulation and higher liver tests as compared to those without digestive symptoms, emphasizing the importance of including symptoms such as diarrhea to diagnose covid-19 early. key: cord-017366-tpsf7as1 authors: espinoza, david; sisk, thomas; chiampas, george; mares, aaron v. title: return to play in asthma and pulmonary conditions date: 2017-09-04 journal: return to play in football doi: 10.1007/978-3-662-55713-6_57 sha: doc_id: 17366 cord_uid: tpsf7as1 in football (soccer), an athlete’s cardiopulmonary system consistently operates in a sinusoidal manner with numerous episodes of lowand high-intensity surges. this demand requires an athlete to have the most ideal function to perform at a high level. multiple pulmonary processes can influence an athlete’s ability to perform by interfering with the pulmonary system’s primary function of ventilation and perfusion to try to optimize gas exchange. in this chapter, we will discuss some of the more common pathology that can affect this delicate balance. some of the more common, but important, conditions such as asthma, exercise-induced bronchoconstriction (eib), pneumothorax, and pulmonary infections will be addressed, as each are readily seen, by sports medicine teams, caring for the football players. the discussion will begin with how those conditions are diagnosed through history and advanced testing and will be followed by treatment with environmental trigger modification, pharmacologic interventions, and lastly return to play criteria. football (soccer) is a sport of tremendous physical demand. the dynamic nature of the sport places great stress on an individual athlete. those sports-specific demands not only involve the musculoskeletal system but also place a lot of stress on the cardiopulmonary system. in this chapter, we will address the effect of asthma and other pulmonary conditions in the football athlete. and high-intensity varies throughout a football match. the body must be able to meet the metabolic needs during those variances. there are many pathologic conditions that may affect an athlete's ability to inspire, exchange gases, and expire. one of those conditions is asthma. asthma in sports tends to break down into two main categories: exercise-induced asthma (eia) and exercise-induced bronchospasm (eib). eia is exercise causing bronchial obstruction in patients with clinical asthma, while eib is an airway obstruction in association with exercise without a clinical diagnosis of asthma [2] . other topics of discussion will include pneumothorax and pulmonary infections. finally, this chapter will try to address the current dogma and recommendations on return to play in each of those conditions. asthma is a chronic pulmonary condition that can negatively affect athletes to varying degrees with regard to airway inflammation, hyperresponsiveness, and reversible obstruction. asthma affects approximately 25 million people in the united states, 7 million of which are children [3] . the prevalence of asthma in athletes overall is actually higher than the general population ranging from 23% to 55%, with higher rates noted in endurance athletes [4] . in asthmatics there is a chronic underlying inflammatory state in the lungs with increased levels of cytokines and inflammatory molecules within the epithelium of the bronchial tree. when exposed to certain triggers, such as pollen, mold, allergens, cold air, or exercise, these inflamma-tory markers induce a cascade of molecular reactions that result in increased mucus production, swelling of the bronchial epithelium, and bronchial muscle tightening. the previously discussed changes in asthma lead to airway narrowing and obstruction. athletes will present with symptoms including cough, wheezing, shortness of breath, or chest tightness-in severe cases, these symptoms can lead to a life-threatening state of hypoxia due to obstruction of the airways. the diagnosis of asthma can typically be made by taking a thorough history with athletes that have had episodes of reversible symptoms. these episodes are typically associated with certain triggers that may also be identified with skilled history taking. lung function testing with spirometry can be used to diagnose the condition with objective evidence. spirometry is a functional test used to diagnose asthma. this test can objectively measure the forced expiratory volume in 1 second (fev 1 ) as the athlete forcibly exhales, and if that value is <80% predicted and the fev 1 /forced vital capacity (fvc) ratio is <70%, then asthma is the diagnosis as long as there is reversibility by a fev 1 increase of >12% from baseline or ≥10% of the predicted fev 1 after the use of a short-acting beta-agonist inhaler such as albuterol [5] . based on history and spirometry results, the diagnosis of asthma can be classified into four separate categories that will guide treatment depending on the severity of symptoms as shown in when it comes to treatment of asthma in footballers, it is important to verify which medications may be prohibited based on the world anti-doping agency. this agency bans all inhaled beta-agonists, except salmeterol, salbutamol (1600 μg maximum over 24 h), and formoterol (54 μg maximum over 24 h) [6] . however one recent study did show that inhaled salbutamol up to 1600 μg did not improve lung exercise performance [7] . the medical commission of the international olympic committee imposed its ban on inhaled beta-agonists in 1993 due to the growing concern of increased use among elite athletes in order to help improve oxygen uptake and thus lead to an unfair advantage in endurance, speed, and strength. other organizations have imposed their bans as well, and it is important to be aware of sport governing bodies when it comes to treating asthma and bronchospasm. along with the pharmacological treatment of asthma, education and prevention of symptoms is also a key component to maintaining adequate control of the athlete's symptoms. the athlete should attempt to identify triggers for their symptoms, which may vary from seasonal allergies, like pollen to dust mites or even weather changes. for example, cold weather changes can be correlated to the development of asthma symptoms. an individual must demonstrate vigilance to keep their symptoms under control by altering environmental exposures and utilizing controller medication. these environmental changes may include changing practice locations based on the weather, using a humidifier or anti-allergen air filters at home, or even avoiding the use of nsaids, as they may predispose athletes to asthma flares [8] . also, as part of the education process, athletes should be reminded of their asthma action plan that provides them with a step-by-step process of what to do when their symptoms start to become uncontrolled ( fig. 57.1) . the athlete and medical provider should be aware of when the last asthma exacerbation took place, if the athlete was ever hospitalized, and if they ever had to have a breathing tube placed (intubation) due to severe symptoms. peak flows may also be utilized to monitor asthma symptom severity; however, this may be unfeasible or cumbersome when it comes to its proper and judicious use among the athletic population. other modifying factors include increasing endurance training as studies have shown that endurance athletes tend to have higher lung volumes by way of strengthening respiratory muscles, reducing resistance through bronchial canals, and increasing lung elasticity and alveolar expansion in order to adapt to the demands brought forth by endurance training [9] . this training may theoretically help reduce incidences of asthma exacerbation and symptoms that can prevent footballers from participating at their highest ability. it is generally acceptable to allow an athlete to return to sport once his or her lung function has returned to baseline and is able to participate in all sport-related activities without adverse pulmonary symptoms. medications have demonstrated quicker improvement in symptoms and may allow for a sooner return to play timeline. exercise-induced bronchoconstriction (eib) is a pulmonary condition characterized by transient reversible airway narrowing that increases respiratory resistance resulting in coughing, shortness of breath, wheezing, or chest tightness shortly after vigorous exercise. eib is present in 7-20% of the general population. however, its prevalence in athletes has been found to be much higher with one study finding up to 50% depending on the sport and environmental conditions [10] . eib is a condition outside that of asthma, as these patients have no symptoms while at rest. symptoms will typically present after 5-10 minutes of vigorous exercise and may last up to 20-30 minutes after exercise has concluded [8] . the key factor is that symptoms are reversible and do not occur at rest. symptoms may also be influenced by other factors including weather, allergens, and intermittent bursts of exercise intensity during match play [11] . the etiology of eib is centered on the idea of having to warm and condition air that is normally done so by the upper airway prior to the cool air reaching the lower airway and bronchial tree. while at rest, the upper airway's ability to warm the air is adequate secondary to the respiratory rate being slow enough to complete the task. however, when athletes exert themselves and the respiratory rate increases, this allows for the cool environmental air to reach the lower airways, thus giving the distal bronchial tree the task of warming and conditioning the air. it is this alteration in physiologic role that may lead to changes in an individual's symptoms. there are two main theories as to the pathophysiology of eib, thermal expenditure and osmotic. the thermal expenditure theory states that the airway cooling from the increased respiratory rate will cause vasoconstriction surrounding the lower airway bronchial tree and that upon the rewarming of the airway, the surrounding vasculature will dilate to engorge and rewarm the bronchial epithelium and leads to vascular leakage and airway edema [10] . the osmotic theory focuses on the water loss mechanisms that the bronchial epithelium and submucosa utilize in an attempt to warm the cool air that reaches the lower airways, which then causes changes in the epithelial ph and creates a hyperosmolar state that then leads to a cascade of molecular changes that release immune-modulators and mediators instigating bronchial constriction [10] . though no one theory is definitive, it is likely a combination of the two that leads to the manifestation of eib. the diagnosis of eib is typically made through history and physical exam; however, it must be noted that this can lead to either overdiagnosis or underdiagnosis of the condition given the vast variance of symptom severity and presentation as well as a refractory period that some individuals may have. the refractory period is the time following spontaneous resolution of eib symptoms where athletes will not experience any further symptoms for the next 1-2 hours, however, may have return of symptoms following this grace period [6] . this period may mask the diagnosis as athletes may not report the issue to their medical staff but then have recurrence of symptoms afterward. to properly diagnose the condition, pulmonary function tests (pfts) should be conducted while at rest to rule in or out any underlying chronic asthma. following this, other pathologies should be ruled out including vocal cord dysfunction, gastroesophageal reflux, and cardiac abnormalities. the diagnosis of eib can be made with the use of an exercise challenge test, eucapnic voluntary hyperventilation test (evh), hyperosmolar saline challenge test, mannitol challenge test, or a direct challenge test with the use of methacholine to induce bronchoconstriction. the most commonly used tests are the exercise challenge test and the evh, which focus on the fev1 and its decline from baseline following provocation with either exercise or voluntary hyperventilation measured at various time limits following introduction of the stimulus. a decline in fev1 of >10% in evh or peak expiratory flow rate (pefr) of 15% or greater indicates positive results with these tests [8, 11] . when it comes to the treatment of eib, it is important to look at all modifiable factors as well as pharmacologic options to maximize a football player's pulmonary capabilities. the use of gaiters, scarves, or masks can theoretically limit the amount of cool air that reaches the lower respiratory tree, thus limiting the effects of bronchoconstriction. short warm-ups 15-20 min prior to activity at 80-90% of maximum exertion, calisthenics, and proper cooldown post-workouts have also been shown to limit the eib response with athletes [4] . many of the same medications that treat asthma can be utilized. two to four puffs of a short-acting beta-agonist (saba) inhaler ( fig. 57.2) , 20 min prior to exercise or a match, can help control the onset of symptoms, if exercise is expected to last no more than 6 h. if there is a tournament or the player is expected to exert themselves for a longer period of time, then a long-acting beta-agonist (laba) can be considered as their effects can last up to 12 h after administration. leukotriene antagonists and cromolyn can also be utilized for those that cannot tolerate the beta-agonist inhalers; however, these may not be as effective. inhaled corticosteroids do not play a role in the management and treatment of eib. the use of these medications has shown improvement of symptoms and have allowed for quicker resolution as well. a football player experiencing symptoms of eib should be removed from play and evaluated properly on the sideline. if a baseline pefr is known, then a repeat at the time of symptom onset should be conducted to assist in the evaluation of symptom severity [9] . if the pefr is below 15% from baseline, then two puffs of a saba may be utilized. if symptoms are still present after 5 min, then two more puffs may be administered [9] . serial pefr readings can be conducted until the value returns to normal limits or back to baseline. if values do not return to normal or baseline, then the athlete should be evaluated more properly off the sideline in case further treatment modalities are indicated, including emergency options as the condition could progress to a life-threatening state such as status [9] . once the athlete's respiratory function has improved and he or she is no longer symptomatic, then he or she may return to the playing field. a pneumothorax (ptx) is a rare but potentially life-threatening pulmonary condition that requires prompt recognition and expedited treatment and care. the condition is defined as a collection of air within the pleural space between the chest wall and the lung. due to the intrinsic intrathoracic negative pressure created by inspiration, the accumulation of this air can eventually reach enough pressure to induce collapse of the lung and potentially lead to cardiopulmonary compromise. only 2% of all adult pneumothoraces are associated with sports and can be spontaneous or tension-related [12] . spontaneous ptx is found more often in tall, thin, and young individuals. it will occur, as its name suggests, spontaneously from primary or secondary etiology, secondary being in the setting of underlying pulmonary disease including pneumonia, asthma, cystic fibrosis, or interstitial lung disease. tension ptx is much less common and typically occurs due to blunt or penetrating trauma from a fracture rib that disrupts the pleura. particular to football, blunt trauma causing tension ptx is typically the result of thoracic collisions at high speed; athletes are more prone to this type of injury during keeper attacks or going for headers. patients can present with difficulty in breathing, pleuritic chest pain with inspiration, rapid respiratory rates, increased heart rate, or even a presence of anxiety. these symptoms will most often develop in a progressive nature, which highlights the importance of serial exams. associated pathology must be excluded including internal organ injury following blunt trauma as well, including pulmonary contusion, hemothorax, pneumomediastinum, splenic rupture, kidney laceration, rib fracture, or other internal derangement. examination with a focus on primary assessment that includes airway, breathing, circulation, and frequent vital sign checks is crucial to obtaining rapid treatment in order to avoid progressive lung collapse or potential cardiovascular compromise. the physical exam plays an essential role in determining the potential concern for a pneumothorax. the pulmonary exam may include diminished breath sounds, rales, hyperresonance on percussion, hypoxia, hypotension, or even tracheal deviation away from the affected side. it is also imperative to assess for thoracic cage injury including rib fractures and potential cardiac involvement with a full cardiovascular exam. imaging studies are also useful in making the diagnosis. chest x-ray (cxr) (fig. 57.3 ) and ultrasound are good initial studies; however, helical ct imaging could also be utilized once the patient is stabilized in order to assess for any other associated pathology such as pulmonary contusion, laceration, and rib fractures. once the diagnosis is even suspected, the transport of the athlete to a nearby emergency department for higher-level care, evaluation, and treatment is necessary if there is concern for respiratory compromise and overall decompensation. football players will typically have high health reserve that may allow them to compensate for a period of time before becoming limited by ptx symptoms; therefore, a high index of suspicion is required with serial physical exams in order to make the diagnosis. following blunt trauma that is limiting the player, he or she should be evaluated thoroughly as a missed diagnosis of ptx could result in serious complications. treatment for an uncomplicated pneumothorax may be observational depending on size. an example of this would be a non-tension pneumothorax <10%. however, if a tension pneumothorax is suspected, supplemental oxygen and needle decompression with either a 14-or 16-g needle can be performed. the needle is inserted into the second intercostal space in the midclavicular line to relieve the pressure, which may be followed by a rush of air [4, 13] . following this procedure, the placement of a chest tube to allow for lung re-expansion is needed. repeat cxr to visualize re-expansion of the lung and ensure proper chest tube placement is recommended (fig. 57.4 ). this should be followed up with serial cxrs, a minimum of 2 days later, to ensure stability. if the ptx remains resolved, then the chest tube can be removed after 2-3 days of monitoring in an acute care setting. with regard to a spontaneous ptx, the american college of chest physicians published that a small ptx (<3 cm apex-to-cupola distance) in a hemodynamically stable patient with-out significant symptoms may be managed by observation alone with close follow-up after the exclusion of progression with 3-6 h of observation and repeat cxr in an emergency setting; larger ptx (>3 cm) should re-expanded with decompression [13] . there are no consensus guidelines when it comes to return to play (rtp) from a resolved pneumothorax. case reports and opinion typically cite return to play ranging anywhere from 2 to 10 weeks, with an average of 3-4 weeks prior to rtp [13] . air travel should be avoided in the first 1-3 weeks following a pneumothorax as the change in air pressure may result in hypoxemia and gas expansion in a closed parenchymal space. recommends may differ if an athlete has associated pathology like multiple rib fracture or flail chest. during this time, repeat cxr should be obtained to ensure continued resolution of the ptx, and treatment with a pulmonary toilet including beta-agonists, mucolytics, and cough close follow-up should also be implemented to ensure that the development of acute respiratory distress syndrome (ards) does not occur. all in all, a slow return to physical activity with using pain as a guide is typically the mainstay of return to play from this pulmonary condition. respiratory infections and their associated symptoms are a very common complaint among the general population as well as the athletic population. symptoms can present in a variety of ways and in different orders. the most common symptoms are nasal congestion, sore throat, cough, postnasal drip, headache, fatigue, nausea, and fever. although the symptoms may be similar, it is important to keep a broad differential when determining the etiology, as many ailments could present with those symptoms. types of infection include, among others, viral upper respiratory infection (uri), bacterial or viral pharyngitis, mononucleosis, viral or bacterial sinusitis, peritonsillar abscess, lower respiratory infection (lri), bronchitis, and/or pneumonia. the athlete diagnosis is made mostly through history and physical exam; however, at times, it may be necessary to rule out other potential causes if red flags exist, and, thus, lab work including a cbc, cmp, ebv titers, or even a cxr may be needed to make the correct diagnosis. once the etiology of the symptoms is determined, the proper course of treatment can then be initiated. viral uris can be treated symptomatically with decongestants, antihistamines, or other over-the-counter medications as indicated based on symptoms. vitamin c and zinc may also play a role in symptom duration as well. most viralinduced uris typically will resolve after 4-5 days. if the etiology for the athlete's symptoms is determined to be bacterial in origin, then the proper antibiotic is indicated with special attention paid to the most likely bacterial culprit, age, medical allergies, or other specific issues that may alter the antibiotic selection (table 57 .2). it is also important to monitor the athlete's hydration status and ensure that they are obtaining the proper nutrient and caloric intake during their illness. return to sports decisions should be made in conjunction with close follow-up, as reevaluation and examination may be necessary. one special consideration to be mindful of when it comes to return to play is the presence of a fever greater than 101 °f. if an athlete engages in sports with a fever greater than 101 °f, then he or she does have an increased risk of developing myocarditis, a condition that affects cardiac function and output, and should be held from practice until the fever resolves without the use of antipyretic for 24 h. also, it is important to ensure that the symptoms are not due to mononucleosis and ebv, as this ailment could lead to splenic enlargement and prohibit a footballer from playing for at least 3 weeks from symptom onset. there are no clear "return to play" guidelines when it comes to uri or lri; however, the "above the neck" rule is typically implemented for most athletes, including those in football. this rule refers to that if the symptoms of sore throat, nasal congestion, and others are mainly "above the neck" without other systemic involvement, then the athlete may continue with training uninterrupted. if the symptoms are present "below the neck" or include systemic symptoms such as fever or myalgia, then it may be necessary for the athlete to rest until they improve. return to play guidelines with pneumonia are limited as well, but typically the athlete should rest for 10-14 days as needed. however, this timeline is variable and depends on the individual athlete and his or her ability to safely play [6] . pulmonary conditions in football athletes present a diverse spectrum of challenges to a sports medicine team. to adequately diagnose and appropriately manage, a strong understanding of each pathologic entity is necessary. a thorough clinical history accompanied by a systematic physical exam will frequently establish the diagnosis. with respect to non-emergent scenarios, peak flow measurements, environment exposure management, pulmonary conditioning, pharmacological management, and action plans are useful modalities. in emergent scenarios, diligent attention should be placed on assessment of airway, breathing, and circulation as well as prompt diagnosis. it is stressed that return to play criteria should be determined on case-by-case bases and that recommendations may vary depending on an athlete's individual circumstances. return to play following exerciseinduced bronchoconstriction asthma and exercise-induced respiratory symptoms in the athlete: new insights closed lung trauma managing respiratory problems in athletes what is prohibited exercise-induced bronchoconstriction respiratory adaptations in different types of sport fitness evaluation and exercise prescription acsm's sports medicine: a comprehensive review 1st edition sports-related pneumothorax american academy of allergy, asthma and immunology work group report: exercise-induced asthma misdiagnosis of exercise-induced bronchoconstriction in professional soccer players boulet key: cord-229612-7xnredj7 authors: pal, ankit; sankarasubbu, malaikannan title: pay attention to the cough: early diagnosis of covid-19 using interpretable symptoms embeddings with cough sound signal processing date: 2020-10-06 journal: nan doi: nan sha: doc_id: 229612 cord_uid: 7xnredj7 covid-19 (coronavirus disease 2019) pandemic caused by sars-cov-2 has led to a treacherous and devastating catastrophe for humanity. at the time of writing, no specific antivirus drugs or vaccines are recommended to control infection transmission and spread. the current diagnosis of covid-19 is done by reverse-transcription polymer chain reaction (rt-pcr) testing. however, this method is expensive, time-consuming, and not easily available in straitened regions. an interpretable and covid-19 diagnosis ai framework is devised and developed based on the cough sounds features and symptoms metadata to overcome these limitations. the proposed framework's performance was evaluated using a medical dataset containing symptoms and demographic data of 30000 audio segments, 328 cough sounds from 150 patients with four cough classes ( covid-19, asthma, bronchitis, and healthy). experiments' results show that the model captures the better and robust feature embedding to distinguish between covid-19 patient coughs and several types of non-covid-19 coughs with higher specificity and accuracy of 95.04 $pm$ 0.18% and 96.83$pm$ 0.18% respectively, all the while maintaining interpretability. the novel coronavirus (covid-19) disease has affected over 31.2 million lives, claiming more than 1.02 million fatalities globally, representing an epoch-making global crisis in health care. at the time of writing, no specific antivirus drugs or vaccines are recommended to control transmission and spread infection. the current diagnosis of covid-19 is made by reverse-transcription polymer chain reaction (rt-pcr) testing, which utilizes several primer-probe sets depending on the assay utilized (emery et al., 2004) . however, this method is time-consuming, expensive, and not easily available in straitened regions due to lack of adequate supplies, healthcare facilities, and medical professionals. a low-cost, rapid, and an easily accessible testing solution is needed to increase the diagnostic capability and devise a treatment plan. computed tomography(ct) helps clinicians perform complete patient assessments and describe the specific characteristic manifestations in the lungs associated with covid-19 (li et al., 2020) . hence, serving as an efficient tool for early screening and diagnosis of covid-19. in analyzing medical images, ai-based methods have shown great success (du et al., 2018; heidari et al., 2018 heidari et al., , 2020 . these methods are scalable, automatable, and easy to apply in clinical environments (ahmed et al., 2020; shah et al., 2019) . significant attempts have been made to use x-ray images for automatic diagnosis of covid-19 (pereira et al., 2020; narin et al., 2020; zhang et al., 2020; apostolopoulos and mpesiana, 2020) . studies dealing with the classification of covid-19 show promising results in this task. however, in (cohen et al., 2020) work, the classification limitations of x-ray images are examined since the network may learn more unique features to the dataset than those unique to the disease. despite its success, the ct scan displays similar imaging characteristics, making it difficult to distinguish between covid-19 and other pneumonia types. moreover, ct-based methods can be integrated only with the healthcare system to help clinical doctors, radiologists, and specialists detect covid-19 patients using chest ct images. unfortunately, an individual cannot utilize this method at home. to obtain the ct scan image and report, one must visit a well-equipped clinical facility or diagnostic center, which may increase the risk of exposure to the virus. according to the who and cdc official report, the four primary symptoms of the covid are dry cough, fever, tiredness, and difficulty in breathing. (cdc). however, cough is more common as it is one of the early symptoms of respiratory tract infections. studies show that it occurs in 68% to 83% of the people showing up for the medical examination. cough classification is usually carried out manually during a physical examination, and the clinician may listen to several episodes of voluntary or natural coughs to classify them. this information is crucial in diagnosis and treatment. in previous studies, several methods with speech features have been proposed to automate different cough types classification. in the study published by (knocikova et al., 2008) , the sound of voluntary cough in patients with respiratory diseases was investigated. later, in 2015, (guclu et al., 2015) published the study on the analysis of asthmatic breathing sounds. these studies utilized the wavelet transformation, which is a type of signal processing technique, generally used on non-stationary signals. in a study by (swarnkar et al., 2012) , a logistic regression model was utilized to classify the dry and wet cough from pediatric patients with different respiratory illnesses. for pertussis cough classification, three separate classifiers' performance was analyzed in (parker et al., 2013) research. several aibased approaches, motivated by prior work, have been presented to detect patients with covid-19 using cough sound analysis. (deshpande and schuller, 2020) gives an overview of audio, signal, speech, nlp for covid-19, (orlandic et al., 2020; brown et al., 2020; sharma et al., 2020) have collected a crowdsourced dataset of respiratory sounds and shared the findings over a subset of the dataset. imran et al. (2020); furman et al. (2020) performed similar analyses on cough data and achieved good accuracy. most studies use short-term magnitude spectrograms transformed from cough sound data to the convolutional neural network (cnn). however, these methods have the following limitations : • ignoring domain-specific sound information cough is a non-stationary acoustic event. cnn is based only on a spectrogram input; some domain-specific important characteristics (besides spectrogram) of cough sounds might be overlooked in the feature space. • using cough features only these methods exploit the cough features only, ignoring patient characteristics, medical conditions, and symptoms data. both cough features and other symptoms accompanied by demographic data are responsible for covid-19 infection. wherein the prior carries vital information about the respiratory system and the pathologies involved, the latter encodes patient characteristics, signs, and health conditions (fever, chest pain, dyspnea). however, their existence alone is not a precise enough marker of the disease. therefore, determining the symptoms (besides cough) presented by suspected cases, as best predictors of a positive diagnosis would be useful to make rapid decisions on treatment and isolation needs. • lack of interpretability in ai research, the model is not limited to accuracy and sensitivity reports; instead, it is expected to describe the predictions' underlying reasons and enhance medical understanding and knowledge. clinical selection of an algorithm depends on two main factors, its clinical usefulness, and trustworthiness. when the prediction does not directly explain a particular clinical question, its use is limited. to overcome the limitation of the existing methods, a novel interpretable covid-19 diagnosis ai framework is proposed in this study, which uses symptoms and cough features to classify the covid-19 cases from non-covid-19 cases accurately. a three-layer deep neural network model is used to generate cough embeddings from the handcrafted signal processing features and symptoms embeddings are generated by a transformer-based self-attention network called tabnet. arik and pfister (2020) finally, the prediction score is obtained by concatenating the symptoms embeddings with cough embeddings, followed by a fully connected layer. in a sensitive discipline such as healthcare, where any decision comes with an extended and long term responsibility, making wrong predictions can lead to critical judgments in life and death situations. in this study, it is illustrated that this framework is not limited to accurate predictions or projections. instead, it explains the underlying reasons for the same and answers the question as to why the model predicts it. the contributions of the paper can be summarized as follows: • a novel explainable & interpretable covid-19 diagnosis framework based on deep learning (ai) uses the information from symptoms and cough signal processing features. the proposed solution is a low-cost, rapid, and easily accessible testing solution to increase the diagnostic capability and devise a treatment plan in areas where adequate supplies, healthcare facilities, and medical professionals are not available. • in this study, an interpretable diagnosis solution is presented, capable of explaining and establishing a dialogue with its endusers about the underlying process. hence, resulting in transparent human interpretable outputs. • three binary and one multi-class classification tasks are developed in this study; task 1 uses only cough features to classify between covid-19 positive and covid-19 negative. in task 2, only demographic and symptoms data is used, and in task 3, both types of information are used, which helps the model learn deeper relationships between temporal acoustic characteristics of cough sounds and symptoms' features and hence perform better. in task 4, multiclass classification is performed to explain the proposed model's effectiveness in classifying between four cough types, including bronchitis, asthma, covid-19 positive, and covid-19 negative. • an in-depth analysis is performed for different cough sounds. the observations and findings are presented, distinguishing covid-19 cough from other types of cough. • a python module was developed to extract better and re-boost cough features from raw cough sounds. this module is opensourced to help users, developers, and researchers. those are not necessarily experts in domain-specific cough feature extraction, contributing to real-time cough based research application, and provide better mobile health solutions. • this study hence provides a medicallyvetted approach. the model architecture consists of two subnetworks components, including the symptoms embedddings and cough embeddings , that process the data from different modalities. symptoms embeddings capture the hidden features of patient characteristics, diagnosis, symptoms. a feature that has been masked a lot has low importance for the model and vice-versa. averaged attention masks are used to explain the overall importance of symptoms features. tabnet stacks the subsequent ds one after the other. decision steps are composed of a feature transformer(ft) appendix b.0.2, an attentive transformer(at)appendix b.0.3 and feature masking. symptoms features are mapped into a d-dimensional trainable embeddings q ∈ r b×d , where b is the batch size, and d is the feature dimension. a batch normalization (bn) is performed across the whole batch. for the selection of specific soft features and explain the feature importance tabnet uses a learnable mask m[i] ∈ r b×d . each decision step has a specific mask and selects its own features; steps are sequential, so the second step needs the first to be finished. we obtain the mask(m) output at each decision step by multiplying the mask with normalised symptoms features q i m[i] · q normalized domain features are passed to ft, and a split block divides the processed representation into two chunks for the next decision step. where d[i] ∈ r b×n d and a[i] ∈ r b×n a . and n d , n a are size of the decision layer and size of the attention bottleneck respectively. after n th step two outputs are produced. • mask outputs are aggregated from all the decision steps to provide model interpretability result. figure 7 and figure 8 shows the interpretability result. • the final output is a linear combination of the all the summed decision steps, similar to the decision tree result. pairwise dot product was computed between output d out and fc layer to obtain the symptoms embeddings s e ∈ r b×f where b is the batch size and f is the output dimension. tabnet uses regularized sparse entropy loss to control the sparsity of attentive features. the regularization factor is a mathematical aggregation of the attention mask. (3) where ε is a small positive value. cough embeddigs learn and capture deeper features in temporal acoustic characteristics of cough sounds. before extracting cough features and feeding it to deep neural networks(dnn), some preprocessing of raw audio data is needed. each cough recording was downsampled to 16 khz; normalization was applied to the cough signal level with a target amplitude of -28.0 dbfs to normalized features were split into cough segments based on the silence threshold. let s[t] be the discrete-time cough sound recording. the expression of signal s[t] can be written as: see appendix c for detailed information about our data collection process. the final feature matrix was grouped by chunks of n consecutive feature matrix, and a total of 44 cough features were extracted by taking the mean and standard deviation for all the cough features in each chunked matrix. later we feed the final feature matrix to 3 layers deep neural network(dnn) with relu activation function to get the final cough embeddings c e ∈ r b×f where b is the batch size and f is the output dimension. in multi-class classification setting, we use categorical crossentropy loss function to calculate the loss of cough embeddings where n is the number of classes in dataset,ŷ i denotes the i-th predicted class in the model out we get the prediction score by concatenating the symptoms embeddings with cough embeddings followed by a fc layer. (7) figure 1 shows the overall structure of the proposed architecture. after this, total loss was calculated as follows (8) where α is a small constant value to balance the contribution of the different losses. in this section, a comprehensive evaluation is carried out to investigate the results of four clinical classification tasks. based on the dataset collected, the model was trained on the following combination of features. • task 1, using cough data only in this experiment setup, only cough features were utilized from the collected dataset to train the model and distinguish between covid-19 positive and negative cases. cough features were extracted using the signal processing pipeline, as described in section 1. • it is demonstrated that the proposed framework benefits from the high accuracy and generality of deep neural networks and tabnet's interpretability, which is crucial for ai-empowered healthcare. figure 7 and figure 8 visualizes the symptoms of a healthy and covid-19 infected individual. it shows that the model comprehends the hidden pattern in symptoms data and its relationship with cough sounds. to intuitively show the representation's quality, the cough features using t-sne and symptoms correlation matrix are visualized in figure 9 and figure 10 an in-depth analysis is conducted for different cough sounds diagnosed with different diseases based on the collected data. different types of cough samples are visualized in figure 6 . based on the analyzed data, the findings are as follows. the coughing sound consists of three phases-phase 1-initial burst, phase 2-noisy airflow, and phase 3-glottal closure. it is observed that in the cough sample of healthy individuals, phase 3 finished with vocal folds activity. figure 2 shows that after phase 1, i.e., initial burst, the energy levels are high at higher frequencies. it is observed that covid-19 cough is continuous; energy distribution is spread across frequencies preceded by a short catch. by analyzing the mean energy distribution of many covid-19 cough sounds, energy distribution was high in phase 2 and phase 3. the abnormal oscillatory motion in the vocal folds may be produced by altered aerodynamics over the glottis due to respiratory irritation. figure 5 shows the result mass covid-19 monitoring has proved essential for governments to successfully track the disease's spread, isolate infected individuals, and effectively "flatten the curve" of the infection over time. in the wake of the covid-19 pandemic, many countries cannot conduct rapid enough tests; hence an alternative could prove very useful. this study brings forth a low cost, accurate and interpretable ai-based diagnostic tool for covid-19 screening by incorporating the demographic, symptoms, and cough features and achieving mean accuracy, precision, and precision in the mentioned tasks. this significant achievement supports large-scale covid-19 disease screening and areas where healthcare facilities are not easily accessible. data collection is being performed daily. experiments will be carried out in the future by incorporating different voice data features such as breathing sound, counting sound (natural voice samples), and sustained vowel phonation. the results prove to be transparent, interpretable, and multi-model learning in cough classification research. (10) where i = 1, 2, . . . , l, l denotes the cepstrum order, e(m) and m are the filter bank energies and total number of mel-filters respectively. to calculate the log energy of each sub-segment, the following formula was used: where ε is a minimal positive value. zcr is used to calculate the number of times a signal crosses the zero axis. to detect the cough signal's periodic nature, we compute the number of zero crossings for each sub-segment. where π[a] is a indicator function and is defined as skewness is the third order moment of a signal, which measures the symmetry in a probability distribution. where µ and σ is mean and stand deviation of the sub-segment y i [t] respectively. we compute the entropy for each sub-segment of the cough signal to capture the difference between signal energy distributions. a.6. formant frequencies in the analysis of speech signals, formant frequencies are used to capture a human vocal tract resonance's characteristics. we compute the formant frequencies by peak picking the linear predictive coding(lpc) spectrum. we used the levinson-durbin recursive procedure to select the parameters for the 14th order lpc model. the first four formant frequencies(f1-f4) are enough to discriminate various acoustic features of airways. kurtosis can be defined as the fourth-order moment of a signal, which measures the peakiness or heaviness associated with the cough subsegment probability distribution. where µ and σ is mean and stand deviation of the sub-segment y i [t] respectively. to estimate the fundamental frequency (f0) of the cough sub-segment, we used the centerclipped auto-correlation method by removing the formant structure from the auto-correlation of the cough signal. the feature transformer is one of the main components of tabnet; it consists of 4 glu layers, two are shared across the entire network, and two are step-dependent across each decision step allowing for more modeling flexibility. glu layers are concatenated with each other after being multiplied by a constant scaling factor( √ 0.5). feature transformer process the filtered features by looking at all the symptoms features assessed and deciding which ones indicate which class. attention transformer is another main component of tabnet architecture. it utilizes sparse intense wise features selection based on learned symptoms dataset and directs the model's attention by forcing the sparsity into the feature set, focusing on specific symptoms features only. it is a powerful way of prioritizing which features to look at for each decision step. the fc handles the learning part of this block. tabnet uses the sparsemax, martins and astudillo (2016) an alternative of softmax function for soft feature selection. sparsemax activation function is differentiable and has forward and backward propagation. due to projection and thresholding, sparsemax process sparse probabilities lead to a selective and more compact attention focus on symptoms features. all the covid-19 data utilized in this study were obtained from 200 subjects in a dr. ram manohar lohia hospital, new delhi, india. out of 100 were confirmed positive from covid-19 reverse transcription-polymerase chain reaction (rt-pcr) results. the clinical trials registry-india (ctri) had approved the study protocols and the patient recruitment procedure. after data preprocessing and out of 200 samples, 50 samples were discarded due to low data quality. aside from covid-19 and healthy data, we also collected bronchitis and asthma cough from different online and offline sources. the data collection person followed all the clinical safety measures and inclusion-exclusion criteria and the cough sounds, breathing sounds, counting 1 to 10 ( natural voice samples ), sustained phonation of 'a,' 'e,' 'o' vowel, demographic, symptoms data such as fever, headache, sore thorat, or any other medical conditions were also collected at the same time. the average interaction time with the subject was 10-12 mins. artificial intelligence with multi-functional machine learning platform development for better healthcare and precision medicine covid-19: automatic detection from x-ray images utilizing transfer learning with convolutional neural networks tabnet: attentive interpretable tabular learning exploring automatic diagnosis of covid-19 from crowdsourced respiratory sound data on the limits of cross-domain generalization in automated x-ray prediction language modeling with gated convolutional networks an overview on audio, signal, speech, & language processing for covid-19 bin zheng, and yuchen qiu. classification of tumor epithelium and stroma by exploiting image features learned by deep convolutional neural networks real-time reverse transcription-polymerase chain reaction assay for sars-associated coronavirus the remote analysis of breath sound in covid-19 patients: a series of clinical cases classification of asthmatic breath sounds by using wavelet transforms and neural networks prediction of breast cancer risk using a machine learning approach embedded with a locality preserving projection algorithm development and assessment of a new global mammographic image feature analysis scheme to predict likelihood of malignant cases train longer, generalize better: closing the generalization gap in large batch training of neural networks ai4covid-19: ai enabled preliminary diagnosis for covid-19 from cough samples via an app wavelet analysis of voluntary cough sound in patients with respiratory diseases using artificial intelligence to detect covid-19 and community-acquired pneumonia based on pulmonary ct: evaluation of the diagnostic accuracy martins and ramón fernandez astudillo. from softmax to sparsemax: a sparse model of attention and multi-label classification automatic detection of coronavirus disease (covid-19) using x-ray images and deep convolutional neural networks the coughvid crowdsourcing dataset: a corpus for the study of large-scale cough analysis algorithms. arxiv, abs detecting paroxysmal coughing from pertussis cases using voice recognition technology covid-19 identification in chest x-ray images on flat and hierarchical classification scenarios artificial intelligence and machine learning in clinical development: a translational perspective coswara -a database of breathing, cough, and voice sounds for covid-19 diagnosis automated algorithm for wet/dry cough sounds classification viral pneumonia screening on chest x-ray images using confidence-aware anomaly detection key: cord-254288-duukt2wh authors: chew, nicholas w.s.; lee, grace k.h.; tan, benjamin y.q.; jing, mingxue; goh, yihui; ngiam, nicholas j.h.; yeo, leonard l.l.; ahmad, aftab; ahmed khan, faheem; napolean shanmugam, ganesh; sharma, arvind k.; komalkumar, r.n.; meenakshi, p.v.; shah, kenam; patel, bhargesh; chan, bernard p.l.; sunny, sibi; chandra, bharatendu; ong, jonathan j.y.; paliwal, prakash r.; wong, lily y.h.; sagayanathan, renarebecca; chen, jin tao; ying ng, alison ying; teoh, hock luen; tsivgoulis, georgios; ho, cyrus s.; ho, roger c.; sharma, vijay k. title: a multinational, multicentre study on the psychological outcomes and associated physical symptoms amongst healthcare workers during covid-19 outbreak date: 2020-04-21 journal: brain behav immun doi: 10.1016/j.bbi.2020.04.049 sha: doc_id: 254288 cord_uid: duukt2wh objective: since the declaration of the coronavirus 2019 (covid-19) outbreak as pandemic, there are reports on the increased prevalence of physical symptoms observed in the general population. we investigated the association between psychological outcomes and physical symptoms among healthcare workers. methods: healthcare workers from 5 major hospitals, involved in the care for covid-19 patients, in singapore and india were invited to participate in a study by performing a self-administered questionnaire within the period of february 19 to april 17, 2020. healthcare workers included doctors, nurses, allied healthcare workers, administrators, clerical staff and maintenance workers. this questionnaire collected information on demographics, medical history, symptom prevalence in the past month, depression anxiety stress scales (dass-21) and the impact of events scale-revised (ies-r) instrument. the prevalence of physical symptoms displayed by healthcare workers and the associations between physical symptoms and psychological outcomes of depression, anxiety, stress, and post-traumatic stress disorder (ptsd) were evaluated. results: out of the 906 healthcare workers who participated in the survey, 48 (5.3%) screened positive for moderate to very-severe depression, 79 (8.7%) for moderate to extremely-severe anxiety, 20 (2.2%) for moderate to extremely-severe stress, and 34 (3.8%) for moderate to severe levels of psychological distress. the commonest reported symptom was headache (32.3%), with a large number of participants (33.4%) reporting more than four symptoms. participants who had experienced symptoms in the preceding month were more likely to be older, have pre-existing comorbidities and a positive screen for depression, anxiety, stress, and ptsd. after adjusting for age, gender and comorbidities, it was found that depression (or 2.79, 95% ci 1.54–5.07, p = 0.001), anxiety (or 2.18, 95% ci 1.36–3.48, p = 0.001), stress (or 3.06, 95% ci 1.27–7.41, p = 0.13), and ptsd (or 2.20, 95% ci 1.12–4.35, p = 0.023) remained significantly associated with the presence of physical symptoms experienced in the preceding month. linear regression revealed that the presence of physical symptoms was associated with higher mean scores in the ies-r, dass anxiety, stress and depression subscales. conclusions: our study demonstrates a significant association between the prevalence of physical symptoms and psychological outcomes among healthcare workers during the covid-19 outbreak. we postulate that this association may be bi-directional, and that timely psychological interventions for healthcare workers with physical symptoms should be considered once an infection has been excluded. on december 31, 2019, the china office of world health organization (who) was notified regarding some cases of pneumonia of unknown etiology in wuhan city of hubei province. it was subsequently termed coronavirus disease 2019 (covid-19) by the who. the rapid global spread of the disease led to the declaration of covid-19 as a pandemic on march 11, 2020 (organization, 2020) . being a global hub with high international traffic, singapore observed an increasing spread of covid-19. accordingly, the disease outbreak response system condition (dorscon) alert level was escalated to orange on february 7, 2020, which indicates that the outbreak is deemed to have moderate to high public health impact, necessitating additional measures like quarantine and temperature screening to minimize risk of further virus transmission in the community (s k. singapore raises cornavirus outbreak alert to orange: what does it mean., 2020; sk ca-l, 2020). similarly, being a densely populated country, the indian authorities imposed a lockdown on march 24, 2020, which involved barring of all public transport and prohibiting opening of public spaces (the times of india, 2020). between february 19 to april 17, 2020, singapore reported slightly over 5000 confirmed covid-19 cases with 11 deaths, while india has reported > 13,000 confirmed cases with > 400 deaths (the times of india, 2020; ministry of health singapore, 2019). much uncertainty revolved around the nature of spread of covid-19, its severity, associated mortality and the availability of essential resources like facial masks, hand sanitizers and digital thermometers. widespread fear of imposed quarantine and lockdown measures led to the unusual displays of panic in the form of frenzied buying of goods by the general public observed in many countries (coronavirus: hong kong shoppers snap up rice and noodles as fears over outbreak mount., 2020; 'it's pandemonium': virus panic-buying hits los angeles., 2020; t a. coronavirus: politicians, supermarkets urge calm amid panic-buying of groceries, 2020). infectious disease outbreaks are known to have psychological impact on healthcare workers as well as the general population. a notable example would be the psychological sequelae observed during the severe acute respiratory syndrome (sars) outbreak in 2003 (mcalonan et al., 2007 ministry of health s, 2004) . studies on the sars outbreak revealed that healthcare workers experienced acute stress reactions (tam et al., 2004; grace et al., 2005) . in addition to the specific physical manifestations of various diseases, some symptoms may arise due to the psychological sequelae of these infection outbreaks. such psychosomatic symptoms have been reported with increased prevalence during and after the outbreaks, such as the sars and ebola virus (lam et al., 2009; lee et al., 2005; marco et al., 2015; tucker, xxxx; xiang et al., 2020) . the commonly reported symptoms range from more specific symptoms like pain (lam et al., 2009 ) to non-specific ones like fatigue, weakness and lethargy (leow et al., 2005) . in some cases, symptoms not perceived to be directly related to a particular infectious disease may be reported. for instance, some survivors of sars outbreak developed chronic extra-pulmonary symptoms during outpatient clinical follow-up (leow et al., 2005) . it is important to understand the prevalence and patterns of such somatic manifestations since they can lead to undesirable overcrowding of hospital emergency departments (farr, 2020; abelson, 2020) , causing additional workload to the already constrained healthcare systems. we investigate the association between various physical symptoms and psychological distress amongst healthcare workers in singapore and india during the current covid-19 outbreak. from february 19 to april 17, 2020, we recruited healthcare workers from major tertiary healthcare institutions in singapore and india. during the study period, the healthcare institutions were actively involved in the care of covid-19 patients. study participants included doctors, nurses, allied healthcare workers (pharmacists, physiotherapists, occupational therapists), technicians, administrators, clerical staff and maintenance workers. written informed consent was obtained from all participants and the study was approved by the institutional review board, in accordance to the principles in the declaration of helsinki. the study questionnaire, written in english, comprised five main components-demographic characteristics, medical history, symptom prevalence in the previous month, depression anxiety stress scales (dass-21) and the impact of events scale-revised (ies-r) instruments. baseline demographic characteristics such as gender, age, ethnicity, marital status, occupation and past medical history were recorded. participants had to indicate if they experienced any of the 16 listed physical symptoms, general or respiratory-related symptoms, during the previous month and rated the severity of the reported symptoms (supplementary material 1). the study questionnaire was adopted from our previous study related to the psychological impact on healthcare workers in singapore during the covid-19 outbreak (tay et al., 2020) . depression, anxiety and stress were assessed using dass-21 (lp, ls, 1995), which is a validated screening instrument for use among patients and general populations. it is a self-reported 21-item system developed by the university of new south wales, australia, which provides independent measures of depression, stress and anxiety with recommended severity thresholds for the depression, stress and anxiety subscales. the scores for each of the three components were calculated by summing up the scores for the relevant items, and multiplying by two to calculate the final score. cut-off scores of > 9, > 7 and > 14 represent a positive screen of depression, anxiety and stress, respectively. on the dass-21 depression subscales, scores of 10-13 were deemed as "mild", 14-20 as "moderate", 21-27 as "severe", and 28-42 as "extremely severe" depression. the dass-21 anxiety subscale score was assessed as "mild" (8-9), "moderate" (10-14), "severe" (15-19), and extremely severe" (20-42). the dass-21 stress subscale score was divided into "mild" (15-18), "moderate" (19-25), "severe" (26-33), and "extremely severe" stress (34-42) (tay et al., 2020) . the psychological distress of the outbreak was assessed using the ies-r25, (weiss, 2007) , which is a validated 22-item self-report that measures the subjective distress caused by traumatic events. it has 3 subscales (intrusion, avoidance and hyperarousal), which are closely affiliated with post-traumatic stress disorder (ptsd) symptoms. participants were asked to rate the level of distress for each component during the previous seven days of their interview. the total ies-r score was graded for severity from normal (0-23), mild (24-32), moderate (33-36), and severe psychological impact (> 37). a cut-off score of 24 was used to define ptsd of a clinical concern (creamer et al., 2003; weiss, 2007) . both dass-21 and ies-r have been validated for use in a recent chinese study investigating the psychological impact of covid-19 on the general population (wang et al., 2020a; ho et al., 2014) . we evaluated the prevalence of physical symptoms reported by the healthcare workers during previous one month before the survey administration period. additionally, we investigated the association between the presence of various physical symptoms and psychological outcomes, namely the dass-21 score and ies-r score. categorical variables are expressed as absolute values (percentage) and continuous variables were expressed as mean value ± (standard deviation). student's t-test was used to examine the association between continuous variables and pearson's chi-square test (or fisher's exact test, where appropriate) was used to evaluate categorical variables. multivariable logistic regression was used to adjust for the effect of confounders when appropriate to determine independent associations of binary outcomes. linear regression was employed to evaluate for associations between baseline characteristics, risk status, physical symptoms and the mean scores for dass-21 and ies-r components. a p-value of < 0.05 was deemed significant for this study. all statistical analyses were performed using ibm spss statistics for windows, version 25.0. armonk, ny. of the 1000 invited healthcare workers from the major hospitals in singapore and india, 906 (90.6%) agreed to participate in this study. of which, 480 respondents were from singapore and 426 from india. majority (583, 64.3%) were female and the median age was 29 (interquartile range: 25-35) years (table 1) . most (55.1%) of the participants were indian, followed by chinese (33.7%) and malay (4.8%) ethnicity. being a relatively younger study population, 50.2% of the participants were unmarried. two hundred and five (22.6%) participants had pre-existing comorbidities, migraine (9.6%) being the most prevalent followed by eczema (4.1%) and asthma (4.0%). nurses comprised 39.2% of the study population, followed by physicians (29.6%) and allied healthcare professionals (10.6%) ( table 1) . the commonest reported symptoms were headache (289, 31.9%), throat pain (304, 33.6%), anxiety (242, 26.7%), lethargy (241, 26.6%), and insomnia (190, 21.0%) (fig. 1) . while 302 (33.3%) respondents did not report any symptom within the preceding 1-month of the survey administration date, 115 (12.7%) reported one symptom, 113 (12.5%) reported two, 73 (8.1%) reported three, and 303 (33.4%) reported more than four symptoms. importantly, the symptoms were generally mild in severity. using our predefined cut-offs for the dass-21 scoring system to screen for depression, anxiety and stress, we found anxiety in 142 (15.7%), depression in 96 (10.6%) and stress in 47 (5.2%) study participants. there was no difference in psychological outcomes between study participants from the two countries (table 2 ). the overall mean dass-21 depression subscale score was 3.08 (sd 4.86). of the 96 healthcare workers who screened positive for depression, 50% of them (48) were scored as moderate to very severe depression. the overall mean dass-21 anxiety subscale score was 3.21 (sd 4.29) . of the 142 patients who screened positive for anxiety, 55.6% of them (79) showed moderate to very severe anxiety. in terms of the dass-21 stress subscale, the overall mean score was 4.62 (sd 5.54). stress was moderateto-severe in 20 of the 47 participants (42.6%) who screened positive for it (fig. 2) . healthcare workers rated their levels of psychological distress according to the ies-r during the preceding 7 days. the mean total ies-r score was 8.29 (sd 9.79) while the means (sd) for ies-r subsets for intrusion, avoidance and hyperarousal were 0.39 (0.49), 0.38 (0.50) 0.36 (0.46), respectively. of note, 67 (7.4%) of the study cohort screened positive for clinical concern of ptsd, of which 34 demonstrated moderate to severe levels of psychological distress. the group which displayed presence of symptoms in the preceding month had less female participants compared to the group without symptoms (odds ratio (or) 0.68, 95% confidence interval (ci) 0.50-0.91, p = 0.010). on the other hand, participants with physical symptoms were more likely to have pre-existing comorbidities (or 2.87, 95% ci 1.94-4.24, p < 0.001) and older in age (mean difference 2.22, 95% ci 0.88-3.55, p = 0.001). in terms of study outcomes, those with physical symptoms were more likely to have a positive screening for depression (or 3.23, 95% ci 1.80-5.80, p < 0.001), anxiety (or 2.66, 95% ci 1.69-4.20, p < 0.001), stress (or 3.59, 95% ci 1.51-8.56, p = 0.002), and ptsd (or 2.70, 95% ci 1.40-5.24, p = 0.002) ( table 2) . in the multivariable logistic regression model, after adjustment for table 1 baseline characteristics of study participants (n = 906) . (table 3) . linear regression revealed that the presence of physical symptoms was associated with higher mean scores in the ies-r, dass-21 anxiety, stress and depression subscales. this association was present across the three respiratory-related symptoms (sore throat, breathlessness and cough) as well as constitutional symptoms like lethargy, myalgia, poor appetite. however, there was no statistical significance between the association of coryza and psychological distress (table 4) . this multinational, multicenter study found significant association between adverse psychological outcomes and physical symptoms displayed by healthcare workers during the current covid-19 pandemic. our findings mirror the trend in recent studies on the psychological impact of the covid-19 epidemic among the general population in china during its initial stages (wang et al., 2020a; li et al., 2020; kang et al., 2019) . we have previously reported that the psychological impact (specifically anxiety) of covid-19 was more common among nonmedically trained healthcare workers when compared to the medically trained personnel (tay et al., 2020) . symptoms of covid-19 infection are wide-ranging, and may be non-specific and similar to other viral infections (guan et al., 2019) . therefore, when healthcare workers develop any such symptoms, they often faced the dilemma of whether to apply for medical leave of absence, or to continue working alongside their over-worked colleagues categorical variables displayed as n (%). during this critical period. even though healthcare workers are entitled to take paid sick leave for a given number of days, little is known about the employment risks posed, especially to the low-paid non-medically trained healthcare contract workers in the event of a prolonged absence. psychological distress levels may also be exacerbated by the fear of being a carrier of the virus, causing transmission amongst fellow healthcare workers and their own families if they choose to continue to work. the fear of transmission is especially high due to the reports of asymptomatic transmission of covid-19, including high transmission rates amongst healthcare workers during in china where as many as 3000 healthcare workers contracted the infection and 22 of them succumbed (adams and walls, 2020) . such prevailing and overwhelming thoughts in the current pandemic atmosphere often have adverse psychological sequelae and may lead to various somatic symptoms (joob and wiwanitkit, 2020) . moderate to severe psychological symptoms were reported amongst the general population in a recent chinese study during the covid-19 outbreak (wang et al., 2020a; wang et al., 2020b) . this is in sharp contrast to a low prevalence of moderate to severe psychological impact in our study (3.8% compared to 58% reported in the chinese study). furthermore, compared to the chinese study population, our cohort had lower prevalence rates of moderate to severe depression (5.3% versus 16.5%), anxiety (8.7% versus 28.8%) and stress levels (2.2% versus 8.1%). however, despite our lower prevalence rates of emotional distress, our study population displayed higher prevalence rates of physical symptoms such as headache (32.3% versus 9.7%) and sore throat (33.6% versus 11.5%) when compared to the chinese cohort. the true association of physical symptoms and psychological stress is indeed challenging to determine, especially in the current climate where the active infection needs to be urgently excluded in every suspected case before giving much importance to the 'non-specific' symptoms. nevertheless, somatic symptoms may be more prevalent during periods of stress and these are hypothesized to represent a way of communicating emotions (basant et al., 2014) . we hypothesize that the increased prevalence of self-reported physical symptoms is likely to have been contributed by the psychological impact of the outbreak. another possible contributing factor could be the social stigma associated with mental health issues, which may have resulted in individuals having a higher tendency to express their psychological distress via physical symptoms instead (yl, 2007) . headache was the most commonly reported symptom in this study. a recent study on headache associated with personal protective equipment (ppe) among healthcare workers during the covid-19 pandemic demonstrated that 81% of respondents reported ppe associated headaches, with a pre-existing primary headache diagnosis reported as an independent predictor for ppe associated headaches (ong et al., 2020) . similarly, migraine was the most commonly reported comorbidity in our study. hence, the common presenting complaint of headache may be related to the increased adverse psychological impact or an exacerbation of their pre-existing condition. notably in prior studies, fatigue was the most commonly reported symptom among sars survivors in both healthcare workers and the general public. (lam et al., 2009) interestingly, even in our study, lethargy was one of the most commonly reported symptom amongst healthcare workers. in a previous study from hong kong, lam et al demonstrated that the prevalence of chronic fatigue was significantly higher among sars survivors which persisted through the acute phase of infection till one month after the disease outbreak (lam et al., 2009) . interestingly, healthcare workers infected by sars were more likely to give up their employment, and the occupational risks faced by the healthcare workers during an epidemic may potentially lead to psychiatric morbidity, physical symptoms such as fatigue, and eventually burnout. although fatigue and headache may be vague and often unsubstantiated, it is crucial not to neglect such physical symptoms as they may be a reflection of underlying psychological distress (lam et al., 2009) . the association of psychological distress and physical symptoms is table 4 linear regression of physical symptoms in the past one month associated with the psychological impact of the covid-19 outbreak (n = 906) . * p-value < 0.05; ** p-value < 0.001. n.w.s. chew, et al. brain, behavior, and immunity xxx (xxxx) xxx-xxx poorly understood. in addition to the fear of transmitting the infection to colleagues and family members coupled with the dilemma of applying for sick leave in an already strained healthcare sector, many healthcare workers develop burnout and may experience a sense of intense fear, stigmatization and ostracism when displaying physical symptoms suggestive of the virus infection, which often leads to negative psychological pain (nezlek et al., 2012; troyer et al., 2020) . this phenomenon has already been described in the studies during the current covid-19 outbreak (wang et al., 2020a) as well as previous ebola crisis (matua and van der, 2015) . we postulate a bi-directional complex relationship between psychological distress and physical symptoms, where an inadvertent psychological distress exacerbates physical symptoms and vice versa (fig. 3) . accordingly, the physical symptoms related to high levels of arousal in a stressful environment of a disease outbreak may lead to over-reporting of cardiovascular, respiratory, neurological or gastrointestinal symptoms (mcfarlane et al., 1994) . furthermore, a known stressor may precipitate or worsen specific physical symptoms. for example, a previous study has reported increased prevalence of respiratory symptoms seen in fire-fighters suffering from ptsd as a result of the psychological stress of smoke inhalation (mcfarlane et al., 1994) . we believe that various symptoms of throat pain, cough and myalgia during the current covid-19 outbreak may be over-represented as a result of the psychological stress, and further exacerbated by the presence of various comorbidities (mcfarlane et al., 1994) . this observation is also commonly evident in patients with depression, with the somatization of back pain and headache (von knorring et al., 1983) . this is in line with our finding of the significant association of the presence of comorbidities and physical symptoms amongst healthcare workers. targeted multidisciplinary interventions are needed to support healthcare workers by addressing both the psychological manifestations and physical symptoms. all efforts should be made to offer psychological support and interventions once an acute infection has been excluded. dedicated counselling may be arranged to allay their fear of transmitting the infection to their family members (wang et al., 2020a) as well as to boost the confidence and morale of our healthcare workers. given that this is a multinational, multicentre study, with similar prevalence of psychological outcomes in both countries, the observed psychological and physical symptoms findings are more likely generalizable. however, our study has its limitations. firstly, the crosssectional nature of the study does not allow interpretation for causality. whilst we found a strong association between presence of physical symptoms and prevalence of psychological distress, we are unable to conclude that psychological distress had resulted in the manifestation of these physical symptoms. secondly, we did not assess if study participants had taken medical leave of absence, or if they sought the testing for covid-19 during the manifestation of physical symptoms. thirdly, owing to the stringent hospital infection control protocols to minimize contact between healthcare workers, the questionnaire had to be selfadministered and information provided on symptoms was not verified by a medical professional. fourthly, we did not record socioeconomic status and education level, which could have influenced our results. we intend to re-evaluate our study participants if the current covid-19 outbreak escalates further in the region, as well as after it subsides to obtain much reliable explanations about the association of psychological sequelae and various physical symptoms. this study describes an expansive range of physical symptoms experience by healthcare workers during the ongoing covid-19 outbreak. there is a significant association between the prevalence of physical symptoms and psychological distress, which is probably bi-directional. we recommend the provision for timely psychological support and interventions for healthcare workers who present with physical symptoms once an infection has been excluded. visualization, writing. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. disclosures vks is the current recipient of senior clinician scientist award from national medical research council, ministry of health, singapore. other authors have no financial disclosures. doctors and patients turn to telemedicine in the coronavirus outbreak supporting the health care workforce during the covid-19 global epidemic revision notes in psychiatry, 3rd. united states of america coronavirus: hong kong shoppers snap up rice and noodles as fears over outbreak mount psychometric properties of the impact of event scale -revised how hospitals hope to keep "worried well" from flooding emergency rooms during coronavirus outbreak the occupational and psychosocial impact of sars on academic physicians in three affected hospitals clinical characteristics of coronavirus disease 2019 in china impact of 2013 south asian haze crisis: study of physical and psychological symptoms and perceived dangerousness of pollution level traumatization in medical staff helping with covid-19 control impact on mental health and perceptions of psychological care among medical and nursing staff in wuhan during the 2019 novel coronavirus disease outbreak: a cross-sectional study mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up the experience of sarsrelated stigma at amoy gardens hypocortisolism in survivors of severe acute respiratory syndrome (sars) vicarious traumatization in the general public, members, and non-members of medical teams aiding in covid-19 control manual for the depression anxiety stress scales ebola and psychological stress of health care professionals living under the constant threat of ebola: a phenomenological study of survivors and family caregivers during an ebola outbreak living under the constant threat of ebola: a phenomenological study of survivors and family caregivers during an ebola outbreak immediate and sustained psychological impact of an emerging infectious disease outbreak on health care workers singapore: ministry of health, singapore. ministry of health singapore. updates on covid-19 (coronavirus disease 2019) local situation ostracism in everyday life headaches associated with personal protective equipment -a cross-sectional study among frontline healthcare workers during covid-19 who characterizes covid-19 as a pandemic singapore raises cornavirus outbreak alert to orange: what does it mean? singapore ups outbreak alert to orange as more cases surface with no known links; more measures in force coronavirus: politicians, supermarkets urge calm amid panic-buying of groceries severe acute respiratory syndrome (sars) in hong kong in 2003: stress and psychological impact among frontline healthcare workers psychological impact of the covid-19 pandemic on health care workers in singapore the times of india the times of india. govt fresh guidelines for lockdown 2.0 are we facing a crashing wave of neuropsychiatric sequelae of covid-19? neuropsychiatric symptoms and potential immunologic mechanisms psychiatric disorders seen in sars patients pain as a symptom in depressive disorders. ii. relationship to personality traits as assessed by means of ksp 2020 a longitudinal study on the mental health of general population during the covid-19 epidemic in china immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china the impact of event scale: revised. in: cross-cultural assessment of psychological trauma and ptsd timely mental health care for the 2019 novel coronavirus outbreak is urgently needed application of mental illness stigma theory to chinese societies: synthesis and new directions no funding reported. supplementary data to this article can be found online at https:// doi.org/10.1016/j.bbi.2020.04.049. key: cord-288568-fjdjuksm authors: huang, yuanyuan; wang, yanxia; zeng, lingyun; yang, jiezhi; song, xiuli; rao, wenwang; li, hehua; ning, yuping; he, hongbo; li, ting; wu, kai; chen, fengjuan; wu, fengchun; zhang, xiangyang title: prevalence and correlation of anxiety, insomnia and somatic symptoms in a chinese population during the covid-19 epidemic date: 2020-08-28 journal: front psychiatry doi: 10.3389/fpsyt.2020.568329 sha: doc_id: 288568 cord_uid: fjdjuksm background: anxiety has been a common mental state during the epidemic of coronavirus disease 2019 (covid-19) and is usually closely related to somatization. however, no study on somatization in anxiety and its relationship with insomnia has been conducted. therefore, this study aimed to identify the prevalence of anxiety, somatization and insomnia and explore the relationships between different psychological states in the general population during the covid-19 outbreak. methods: a total of 1,172 respondents were recruited from 125 cities in mainland china by an online questionnaire survey. all subjects were evaluated with the 7-item generalized anxiety disorder (gad-7) scale, the somatization subscale of the symptom checklist 90-revised (scl-90-r), and the 7-item insomnia severity index (isi). results: the percentages of anxiety, somatization, and insomnia were 33.02%, 7.59%, and 24.66%, respectively. the prevalence of somatization was 19.38% in participants with anxiety. compared to the anxiety without somatization group, the anxiety with somatization group had a significantly higher percentage of patients with a history of physical disease and insomnia, as well as higher gad-7 scores and scl-90 somatization subscores (all p < 0.001). the scl-90 somatization subscores were positively correlated with age, history of physical disease, gad-7 scores, and isi scores (all p < 0.001). furthermore, multivariate logistic regression showed that gad-7 score, isi score, and age were risk factors for somatization in the anxious population. conclusions: somatic and psychological symptoms were common in the general population during the covid-19 outbreak. somatic symptoms, anxiety, and insomnia are closely related, and improving anxiety and sleep quality may help relieve somatic symptoms. the covid-19 epidemic is a major public health emergency because of the disease's rapid spread, wide range of infections and difficulty to prevent and control (1) . according to the data released by the world health organization on april 5, the covid-19 epidemic has affected more than 200 countries and regions around the world, with more than 1.13 million confirmed cases. during the period of epidemic pressure, people's psychology, physiology and behavior change accordingly (2, 3) . if an individual's response is inappropriate or excessive, it can impact physical and mental health (4, 5) , causing anxiety, fear, insomnia, or somatic symptoms. a previous study revealed that psychological factors could play a crucial role in public health strategies to control epidemics and pandemics (6) . understanding and studying the psychological state of the public during the turbulent epidemic period is of practical significance for helping psychological professionals and the government to provide psychological support and behavioral guidance. anxiety is a common mental state that affects psychology and the body in the short and long term. a recent national survey in china showed that anxiety has the highest prevalence of all mental disorders at 4.98% (7) . approximately 10-30% of the public worried about the possibility becoming infected with virus during an influenza outbreak (8) (9) (10) . with the suspension of business and school and, in some cases, the closure of cities, personal anxiety becomes more complicated by the ongoing covid-19 epidemic (8) . wang c et al. (10) found that during the early stage of the epidemic, over 28% of chinese respondents suffered from moderate or severe anxiety symptoms. a crosssectional survey showed that approximately 25% of college students experienced anxiety during the outbreak (8) . to date, many studies have reported factors associated with anxiety during the outbreak. an increasing amount of evidence has revealed that being female, being a medical health worker, being acquainted with someone who has been infected and having organic disease elevate the risk of anxiety, while age greater than 40 years and family income stability decrease the risk (3, 8, 11, 12) . somatization and anxiety are usually closely related. in the general population, anxiety disorders often overlap with a variety of somatic symptoms (13) ; however, the correlation between physical symptoms and anxiety is inconsistent. some studies have identified that somatic symptoms are linked with psychological or physiological abnormalities, which could indicate a pathological condition (14) . meanwhile, raffagnato a et al. reported that patients expressed their mental state through somatization symptoms (15) . for example, approximately, 15%-45% of patients with persistent pain suffer from various degrees of anxiety (16, 17) . in contrast, previous studies showed that physical symptoms may occur independent of anxiety symptoms (18, 19) , but the mechanism underlying this finding is not yet clear. furthermore, several demographic and socioeconomic risk factors for somatic symptoms have been revealed, such as gender (female), age (older), marital status, chronic illnesses, and employment status (20) . insomnia and anxiety symptoms were also considered risk factors for somatic symptoms in a general population of hong kong (21) . few studies have examined somatic symptoms during the covid-19 epidemic. for instance, a survey of 1,255 nonmedical health workers found that the prevalence rate of somatization was 0.4% (12) . at present, several studies have reported the prevalence of anxiety, depression, insomnia, and other psychological states in the general population during the epidemic (1, 6-8, 10-12). however, there is a lack of research on the relationship between different mental states during this particular period, and no study on the prevalence of somatic symptoms in a population with anxiety and its relationship with insomnia or other mental states have not been reported. therefore, we investigated the public's mental health during the covid-19 epidemic and aimed to (1) explore the prevalence of anxiety, somatization, and insomnia in a chinese population; (2) examine the correlation between physical symptoms and psychological symptoms; and (3) provide a theoretical basis for intervention measures provided by psychologists and the government. using a cross-sectional design, an anonymous online questionnaire survey was used to assess the public's psychological status during the covid-19 epidemic. we adopted a snowball sampling strategy to focus on recruiting ordinary people who lived on the chinese mainland during the covid-19 epidemic. the online survey was initially distributed among college students, who were encouraged to pass it on to others. all respondents completed the survey in chinese by using ranxing technology "surveystar" to reduce faceto-face interaction. data collection was carried out during the covid-19 epidemic (from february 14 to march 29, 2020). inclusion criteria included (1) chinese individuals living on the mainland and (2) willingness to complete the survey. any subjects with psychotic disorders diagnosed in a medical institution were excluded. this study was approved by the ethics committee of the institute of psychology of the chinese academy of sciences. all participants provided informed consent before answering questions, and they could terminate the investigation at any time. in this study, the structured questionnaire included the following sections: (1) sociodemographic characteristics; (2) history of exposure to covid-19; (3) history of physical disease; and (4) psychological health status. sociodemographic data included sex, age, weight, height, marital status, education level, occupational status (student or not a student), economic loss, smoking status, and drinking status. furthermore, we asked an additional question: do you have relatives or friends who have been infected with covid-19? in addition, body mass index (bmi) was calculated based on height and weight. age was divided into four groups: 20 years old or below, 21-30 years old, 31-40 years old, and older than 40 years old. anxiety, physical symptoms, and insomnia in the general population were assessed by the chinese version of the 7-item generalized anxiety disorder (gad-7) scale, the chinese version of the somatization subscale of the symptom checklist 90-revised (scl-90-r), and the 7-item insomnia severity index (isi). these self-reported scales have good reliability and validity for measuring psychological status (11, 22, 23) . the gad-7 was used to screen for generalized anxiety and assess the severity of symptoms. scores range from 0 (not present) to 21 points (extremely severe), and a score of ≥ 5 indicates the presence of anxiety symptoms (24, 25) . the isi scale was used to evaluate the presence and severity of insomnia. the total score of the isi scale varies from 0 (not present) to 28 points (severe), and a cut-off value of 8 indicates the presence of insomnia (26) . somatic symptoms were identified by the somatization subscale of the scl-90-r, which consists of 12 items (cronbach's a = 0.83) scored on a five-point likert scale: none (1), mild (2), moderate (3), fairly severe (4), and severe (5) . the total score of the subscale ranges from 12 (not present) to 60 points (extreme); the higher the score, the stronger the participant's physical discomfort is. according to results normed on a chinese population, a total score higher than 24 points (single factor score ≥ 2) indicates the presence of somatic symptoms (12, 27) . data analysis was conducted using spss (version 18.0) software. normally, distributed data are presented as the mean ± standard deviation (sd), and count data are presented as the number of people (%). demographic and clinical variables were compared between groups by analysis of variance (anova) for continuous variables and chi-squared tests for categorical variables. since the original scores of all scales are not normally distributed (kolmogorov-smirnov test, p < 0.05), the data are expressed as medians with interquartile ranges. the nonparametric mann-whitney u test was used to compare each symptom between groups. relationships between scl-90 somatization subscores and demographic and clinical variables were examined using spearman correlation analysis. multivariate logistic regression analysis ("enter" model) was then used to assess the relevant factors associated with somatization symptoms. somatic symptoms (yes or no) in anxious participants were regarded as the dependent variable, while factors that showed statistical significance in chi-squared tests and u tests were regarded as the independent variables. a p value <0.05 (twotailed) was considered statistically significant. altogether, 1,172 respondents (812 females and 360 males) were recruited from 125 cities in china. their average age was 28.39 ± 10.49 years. among them, 287 people (24.49%) were aged ≤ 20 years, 443 people (37.80%) were aged 21-30 years, 285 people (24.32%) were aged 31-40 years, and 157 people (13.39%) were above 40 years old. education levels were as follows: high school degree or below (167, 14.25%), technical or mechanical degree (223, 19.03%), bachelor's degree (675, 57.59%), and master's degree or above (107, 9.13%). more than half of the participants (587, 50.09%) were students. approximately half of the participants (585, 49.91%) experienced economic loss during the epidemic period. a total of 153 participants (13.05%) had a history of physical diseases. only 8 (0.68%) participants had relatives and friends who suffered from covid-19. the detailed sociodemographic information is presented in table 1 . the prevalence of anxiety, somatization, and insomnia in a chinese population during the covid-19 epidemic was 33.02% (387/1172), 7.59% (89/1172), and 24.66% (289/1172), respectively. the proportion of somatization among participants with anxiety was 19.38% (75/387). as shown in table 1 , there was no significant difference in demographic characteristics between the subjects with anxiety (n = 387) and subjects without anxiety (n = 785; all p > 0.05), except for economic loss (p = 0.001), history of physical disease (p < 0.001), and drinking (p = 0.044). furthermore, the anxiety group had higher gad-7 scores, scl-90 somatization subscores, and isi scores than the non-anxiety group (all p < 0.05). multivariate logistic regression analyses found that participants who experienced economic loss had a 1.3 times higher probability of anxiety symptoms than participants without economic loss (or = 1.30, 95% ci: 1.05-1.57, wald x 2 = 5.74, p = 0.017), while no significant difference in history of physical disease and drinking was found (p >0.05). higher scl-90 somatization subscores (or = 1.10, 95% ci: 1.07-1.14, wald x 2 = 37.15, p < 0.001) and isi scores (or = 1.17, 95% ci: 1.13-1. 19 , wald x 2 = 104.25, p < 0.001) were associated with a greater risk of anxiety. the demographic data of participants with anxiety in the nonsomatization group (n = 312) and the somatization (n = 75) group are presented in table 2 . there was a significant difference in age between the two groups (c2 = 8.608, p = 0.035). among those with anxiety, a higher proportion of subjects over 40 years old showed somatization, and a lower proportion of those aged 20 years or younger showed somatization. compared to the non-somatization subgroup of anxious participants, a significantly higher percentage of anxious participants with somatization group had a history of physical disease (c2 = 10.490, p = 0.030) and insomnia (c2 = 39.316, p < 0.001). mann-whitney u test analysis showed that in the anxiety group, participants with somatization had higher gad-7 scores, scl-90 somatization subscores and isi scores than nonsomatization participants (all p < 0.001). however, there was no significant difference in sex, bmi, marital status, education level, occupation, economic loss, smoking, and drinking between the participants in the somatization and non-somatization subgroups (all p > 0.05). as shown in table 3 , multivariable logistic regression analysis was used to explore the risk factors for anxiety with somatization symptoms. the findings showed that gad-7 scores (or = 1.158, 95% ci: 1.085-1.236, wald x 2 = 19.446, p < 0.001), isi scores (or = 1.087, 95% ci: 1.036-1.140, wald x 2 = 11.697, p = 0.001), and age (or = 1.743, 95% ci: 1.049-2.894, wald x 2 = 4.606, p = 0.032) were associated with somatization symptoms in anxiety participants, while no difference in history of physical disease was found (p > 0.05). in the participants in the anxiety with somatization group, spearman correlation analysis showed that scl-90 somatization subscores were positively correlated with age (r = 0.192, p < 0.001), bmi (r =0.100, p = 0.049), history of physical disease (r = 0.236, p < 0.001), gad-7 scores (r = 0.378, p < 0.001), and isi scores (r = 0.434, p < 0.001) (figure 1) . however, in the anxiety without somatization group, scl-90 somatization subscores were only positively correlated with gad-7 scores (r = 0.197, p < 0.001) and isi scores (r = 0.316, p < 0.001), and no significant correlation was found between scl-90 somatization subscores and age, history of physical diseases, and bmi (all p > 0.05). to the best of our knowledge, this is the first study to explore the prevalence of somatic symptoms and their related factors in a population with anxiety during the covid-19 epidemic in mainland china. the main findings of this study are as follows: (1) the prevalences of anxiety, somatization, and insomnia were 33.02%, 7.59%, and 24.66%, respectively; (2) the prevalence of somatization in the population with anxiety was 19.38%; (3) patients in the anxiety with somatization group were more likely to have a history of physical disease and insomnia, older age, and higher gad-7 scores; and (4) somatic symptoms were closely associated with anxiety and insomnia. in our study, approximately one-third of the mainland chinese respondents reported anxiety symptoms using the gad-7 scale, which was consistent with most previous studies conducted during the covid-19 outbreak. for example, a number of studies revealed that a relatively high proportion of the public (20-30%) experienced anxiety symptoms (8, 10) . due to the adverse effects of epidemics, such as fears of infection, limitations of social activities and daily life, and inevitable stress, mental health problems might arise (28) . a survey including 600 subjects from china showed that only 6.33% of participants felt anxious (3). the differences in these studies might be partly attributed to differences in survey areas, interviewees, periods of the epidemic (initial, outbreak, and remission), measurements, etc. in addition, a consistent conclusion is that compared with the percentage (less than 5%) of the public with anxiety symptoms during the non-epidemic period (7, 13), a larger proportion of people present anxiety symptoms during the outbreak. the government and psychologists should constantly focus on the mental health of the public during this unique period. furthermore, our study found that anxiety was associated with economic loss, a history of physical disease, and increased isi scores, which is in line with previous studies (8, 29, 30) . interestingly, our study also demonstrated that anxious people were likely to have more somatic symptoms than people without anxiety symptoms. our survey further revealed a high proportion (19.38%) of somatic symptoms among the population with anxiety; this proportion was over 2 times more than the proportion of somatization for the whole sample (7.59%). in previous studies, the probability of somatization among people with anxiety fluctuated widely (ranging from 1.5% to 25%), depending on the different definitions of somatization used (31) (32) (33) (34) . most studies defined physical symptoms in terms of both physical and psychological aspects (35) . however, our study defined somatization as any discomfort, including unexplained and explained physical symptoms, that was equally strongly associated with anxiety (20) . using different self-rating scales instead of a standardized diagnosis to assess physical symptoms may be another reason for the inconsistent results (36, 37) . moreover, when people with physical diseases experience various physical discomforts, some of these symptoms can presented as psychological symptoms (38) . rosmalen and his panel reported that 11.8% of subjects in the general population with somatic symptoms suffered from depression or anxiety disorders (39) . a 3-year follow-up study showed that the proportion of physical symptoms (both unexplained and explained symptoms) comorbid with any anxiety disorder was 17.4% (40) . in addition, because findings regarding somatization show significant discrepancies and few studies have reported on somatization in anxiety, it is of great significance to investigate the factors related to the presence of somatic symptoms in people with anxiety. our study also found a significant difference in the history of physical diseases between the somatization and non-somatization subgroups of respondents with anxiety, which was similar to the findings of previous studies showing that chronic illness was highly correlated with somatic symptoms (12, (41) (42) (43) . unlike the findings from a population-based survey conducted in a chinese general population, chronic illness was not related to somatic symptoms (21) . the presence of different types of physical diseases may partly explain the differences between the two studies (21) . specifically, some diseases (osteoporosis, gout, arthritis, and low back pain) cause pain, while others (psychiatric illness, hypertension, diabetes, etc.) rarely cause pain. similar to an early study in hong kong (20) , age was identified as a risk factor for somatization in individuals with anxiety. nevertheless, other studies did not observe significant differences between different ages (21) . moreover, in contrast to previous studies (10, 44) , no significant differences were observed in occupation status (students or others) and sex (male or female) between the two different anxiety subgroups, indicating that people with different occupations and genders suffered from similar physical and psychological states during this epidemic. compared with respondents without somatic symptoms, a greater proportion of respondents with anxiety and somatization suffered from insomnia and had higher isi scores. additionally, the correlation analysis further explained the positive correlation between insomnia scores and scl-90 somatization subscores. a cross-sectional study involving 47,000 participants indicated that insomnia was closely related to somatic symptoms, similar to our results (45) . we also demonstrated that the gad-7 score was positively correlated with anxiety with comorbid somatization. the findings were consistent with those of several previous studies suggesting a close association between anxiety and somatization (12, 21, 44) . a similar study (46) reported that compared with nonanxious people, anxiety patients were more sensitive to physical changes and had higher scores for psychological and physical symptoms, which could be explained by certain biological mechanisms (21) . for example, an increasing level of anxiety can cause an increase in heart rate and blood pressure (47) , which may also play a role in physical discomfort, such as the feeling of heart pressure. in addition, anxiety may trigger pain, which is related to increased muscle tension (48) . wilson and his colleagues also reported that anxiety may cause visceral allergies, resulting in exacerbated gastrointestinal discomfort (49) . gad-7 and isi scores were regarded as predictive indicators of somatization in people with anxiety in the multivariate logistic regression analysis. moreover, our research also demonstrated that somatization, anxiety, and insomnia coexist in the general population (13, 21) . anxiety may affect sleep quality by causing changes in hormone levels (such as increasing cortisol levels and decreasing melatonin synthesis) (50) . improving anxiety and sleep quality may help alleviate physical symptoms (21) . however, due to the defects of cross-sectional studies, our study only reflected certain associations, and longitudinal studies are required to demonstrate causal relationships in the future. several limitations should be considered. first, due to the covid-19 outbreak, a survey conducted by online questionnaires may have selection bias. these voluntary online surveys cannot artificially set the male-to-female ratio, and the imbalance between males and females may impact the results; thus, gender differences must be analyzed in the future. moreover, the system cannot count the number of people who opened the connection but did not complete the questionnaire, so it is impossible to report the response rate. second, clinical symptoms were assessed by a self-assessment scale instead of a standardized psychiatric diagnosis; however, the self-assessment scale has good reliability and validity. third, this is a cross-sectional study, and it cannot explain internal causal relationships. fourth, due to the requirements of epidemic prevention and control, covid-19 patients (including asymptomatic infections) are admitted to hospital for isolation treatment, so we do not include diagnosed patients in this study, which may affect causal analyses. fifth, in this study, we excluded any subjects who had been clearly diagnosed with psychotic disorders in a medical institution, which may have a certain impact on the incidence of anxiety, insomnia, and somatization. in conclusion, our study demonstrated that anxiety, insomnia, and somatic symptoms were common in the general population during the covid-19 epidemic. moreover, somatic symptoms, anxiety, and insomnia are closely related, and improving anxiety and sleep quality may help relieve somatic symptoms. therefore, we should pay attention to the mental state of the public during the covid-19 epidemic and formulate relevant measures to intervene in cases of psychological problems. all datasets presented in this study are included in the article/ supplementary material. the studies involving human participants were reviewed and approved by the ethics committee of the institute of psychology of the chinese academy of sciences. the patients/participants provided their written informed consent to participate in this study. a novel coronavirus outbreak of global health concern study on the public psychological states and its related factors during the outbreak of coronavirus disease 2019 (covid-19) in some regions of china facilitating collective psychosocial resilience in the public in emergencies: twelve recommendations based on the social identity approach psychological impact of the 2015 mers outbreak on hospital workers and quarantined hemodialysis patients how health anxiety influences responses to viral outbreaks like covid-19: what all decision-makers, health authorities, and health care professionals need to know prevalence of mental disorders in china: a cross-sectional epidemiological study the psychological impact of the covid-19 epidemic on college students in china the impact of communications about swine flu (influenza a h1n1v) on public responses to the outbreak: results from 36 national telephone surveys in the uk immediate psychological responses and associated factors during the initial stage of the covid-19) epidemic among the general population in china factors associated with mental health outcomes among health care workers exposed to coronavirus disease mental health and psychosocial problems of medical health workers during the covid-19 epidemic in china the overlap of somatic, anxious and depressive syndromes: a population-based analysis depression and pain: an overview using the body when there are no words for feelings: alexithymia and somatization in self-harming adolescents depression and pain comorbidity: a literature review relationships among pain, anxiety, and depression in primary care genetic and environmental contributions to the overlap between psychological, fatigue and somatic symptoms: a twin study in sri lanka the structure of genetic and environmental risk factors for syndromal and subsyndromal common dsm-iv axis i and all axis ii disorders psychometric properties of the chinese 15-item patient health questionnaire in the general population of hong kong anxiety and insomnia as modifiable risk factors for somatic symptoms in chinese: a general population-based study sensitivity to change and minimal clinically important difference of the 7-item generalized anxiety disorder questionnaire (gad-7) insomnia severity index: psychometric properties with chinese community-dwelling older people a brief measure for assessing generalized anxiety disorder: the gad-7 clinical characteristics and related factors of somatization symptoms in outpatients with psychiatric disorders of the department of cardiology in general hospitals individually tailored internet treatment in routine care: a feasibility study psychological results of 438 patients with persisting gastroesophageal reflux disease symptoms by symptom checklist 90-revised questionnaire a cross-sectional survey of disability attributed to mental disorders and service use in china effect of transcranial alternating current stimulation for the treatment of chronic insomnia: a randomized, double-blind, parallel-group, placebo-controlled clinical trial negative life events and mental health of chinese medical students: the effect of resilience, personality and social support somatoform disorders in general practice: prevalence, functional impairment and comorbidity with anxiety and depressive disorders physician-based estimates of medically unexplained symptoms: a comparison of four case definitions classification characteristics of the patient health questionnaire-15 for screening somatoform disorders in a primary care setting whether medically unexplained or not, three or more concurrent somatic symptoms predict psychopathology and service use in community populations systematic review of measurement properties of questionnaires measuring somatization in primary care patients distinct associations of dsm-5 somatic symptom disorder, the diagnostic criteria for psychosomatic research-revised (dcpr-r) and symptom severity in patients with irritable bowel syndrome the epidemiology of multiple somatic symptoms beyond "somatization" and "psychologization": symptom-level variation in depressed han chinese and euro-canadian outpatients empirical foundations for the diagnosis of somatization: implications for dsm-5 medically unexplained and explained physical symptoms in the general population: association with prevalent and incident mental disorders depressive symptoms in people with chronic physical conditions: prevalence and risk factors in a hong kong community sample adèr hj, van der feltz-cornelis cm. a high physical symptom count reduces the effectiveness of treatment for depression, independently of chronic medical conditions adverse effects of multiple physical symptoms on the course of depressive and anxiety symptoms in primary care alexithymia and somatization in depressed patients: the role of the type of somatic symptom attribution the epidemiology of insomnia: associations with physical and mental health. hunt-2 study somatic symptoms and physiologic responses in generalized anxiety disorder and panic disorder: an ambulatory monitor study autonomic nervous system activity in emotion: a review muscle tension in generalized anxiety disorder: a critical review of the literature the psychobiological etiology of gastrointestinal distress in sport: a review melatonin and its analogs in insomnia and depression conflict of interest: the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited all authors contributed to the study design and data interpretation. fw and xz were responsible for the management and oversight of the study. yh and yw were responsible for general omnibus data analyses and were the key contributing authors of the manuscript. lz, jy, xs, hl, fc, and tl were responsible for all research interviews and clinical chart reviews associated with this study. yn and bh provided guidance on the design of the primary analyses. wr and kw assisted with all data collection, analysis, and writing of the manuscript. all authors contributed to the article and approved the submitted version. the authors thank all the participants who shared their experiences for this survey. key: cord-151118-25cbus1m authors: murray, benjamin; kerfoot, eric; graham, mark s.; sudre, carole h.; molteni, erika; canas, liane s.; antonelli, michela; visconti, alessia; chan, andrew t.; franks, paul w.; davies, richard; wolf, jonathan; spector, tim; steves, claire j.; modat, marc; ourselin, sebastien title: accessible data curation and analytics for international-scale citizen science datasets date: 2020-11-02 journal: nan doi: nan sha: doc_id: 151118 cord_uid: 25cbus1m the covid symptom study, a smartphone-based surveillance study on covid-19 symptoms in the population, is an exemplar of big data citizen science. over 4.7 million participants and 189 million unique assessments have been logged since its introduction in march 2020. the success of the covid symptom study creates technical challenges around effective data curation for two reasons. firstly, the scale of the dataset means that it can no longer be easily processed using standard software on commodity hardware. secondly, the size of the research group means that replicability and consistency of key analytics used across multiple publications becomes an issue. we present exetera, an open source data curation software designed to address scalability challenges and to enable reproducible research across an international research group for datasets such as the covid symptom study dataset. the join operation is the most memory-intensive operation that is typically carried out on tabular datasets. exetera implements highly scalable versions of left, right and inner joins; left join is the most typical join performed so we focus on its performance here. a left join operation involves the mapping of data from one table onto another table, based on the key relationships between the two tables. values in the right table are mapped to values in the left table. for example, patient data may be joined to assessment data so that assessments can be processed with patient-level features such as age or bmi (body mass index). an illustrated example of a left join can be seen in figure 1 . to test the performance of the join operator when exetera and pandas are used, we generate a dataset composed of a left primary key (int64), a right foreign key (int64) and 1, 2, 4, 8, 16 , and 32 fields respectively of random numbers corresponding to entries in the right table (int32). the resulting join performance for both is shown in table 4 . the left and right tables have the same number of rows for each test, listed in the first column. it should be noted that exetera organises data into groups, which may be considered logical tables, but the user typically loads the data on a field by field basis when working with it. exetera's merging api allows the user to think in a tabular fashion by accepting tuples of exetera fields, which only load their contents when specifically requested. exetera achieves its scalability through two techniques; firstly, by calculating the map and then applying it to each field in turn, and secondly, by exploiting the natural sorted order to convert the mapping into a streaming merge. the result is a merge operation that is fast and scales to billions of rows. exetera can combine snapshots of datasets to create a journaled dataset, keeping multiple, timestamped copies of otherwise destructive changes to corresponding records between the snapshots. table 5 shows the results of journaling together shapshots of the covid symptom study from the august 1st 2020 and september 1st 2020, and the time taken to do so. exetera provides the ability to load data very efficiently, as seen in table 2 and 3 . once loaded, analytics can be performed through use of libraries such as numpy and matplotlib 11 , using tools that researchers are familiar with, such as jupyter notebook 12 . figure 2 shows a histogram of healthy and unhealthy assessment logs bucketed into seven day periods that must parse 189 million assessments to generate its results. in this work, we present exetera, a data curation and analytics tool designed to provide users with a low complexity solution for working on datasets approaching terabyte scale, such as national / international-scale citizen science datasets like the covid symptom study. exetera makes this possible without the additional complexity of server-based datastores, and thus simplifies access to such datasets for both academic and independent researchers who are versed in the python scientific programming ecosystem. exetera provides features for cleaning, journaling, and generation of reproducible processing and analytics, enabling large research teams to work with consistent measures and analyses that can be reliably recreated from the base data snapshots. its ability to store multiple snapshots in a journaled format enables researchers to perform full longitudinal analysis on otherwise unjournaled datasets and facilitates the ability to move between snapshots whilst being able to properly explore the impact of doing so on analyses. exetera has been a key part in enabling analysis of the covid symptom study dataset, including being used for analysis in the following manuscripts [13] [14] [15] [16] . although exetera was developed to provide data curation for researchers working on the zoe symptom study, this software is being developed to be generally applicable to large-scale relational datasets for researchers who work in python. however, this requires further work to separate core exetera functionality from covid symptom study-specific functionality. while our goal is to closely emulate a pandas-style api, additional work is still required to ensure this is available to the user across the whole api. the sorting and journaling apis, for example, are accessed through the low-level operations api rather than through abstractions to more closely emulate pandas, and work is ongoing to make the api more consistent in the presentation and manipulation of the data as logical tables. exetera is currently built on top of numpy and pandas functionality. the ability to scale is provided through implementations of key operations that can stream large collections from drive. this enables processing of large datasets, but, at present, exetera doesn't take advantage of multiple cores or processors, nor is it able to process across a cluster. future development will make use of dask 17 a library designed to convert operations on numpy and pandas to a directed acyclic graph of sub-operations that can be distributed to multiple cores and nodes, and focus on provision of the elements of scalable processing, such as multi-key argsorts and tableless merges that dask lacks. dask is also integrated with more specialised back-ends such as nvidia's rapids 18 , which enables execution of distributed graph processing across gpu clusters. the integration of dask should allow exetera to execute over datasets well into the multi-terabyte range. reproducibility relies on immutability of the algorithms deployed during analysis. at present, exetera achieves this through a convention that algorithms are treated as immutable once implemented and deployed. a more robust system is being designed to provide algorithmic immutability without this constraint. hdf5 has proven to be fragile to interruptions while data is being written to it; an interrupted write is capable of rendering the entire dataset unreadable and so all writes must be protected from user interrupts and other exceptions. additionally, hdf5 does not allow the space from deleted fields to be properly reclaimed from the dataset. this must be done separately through use of the 'h5repack' tool. the primary benefit of hdf5 to exetera is its ability to flexibly store contiguous fields of data for rapid reading. this can also be achieved through use of alternative columnar data formats such as orc 19 or parquet 19, 20 or, alternatively, through use of the file system as a datastore. storing individual fields as serialized numpy arrays and field metadata in json allows for transparent, robust dataset serialization that can be explored on the file system. exetera as of the 14th october, 2020, the dataset is composed of four tables: patients: 4.701 million patients with 224 data fields. patient records store data such as the patients' physiological statistics, long-term illnesses, lifestyle factors, location and other data that only occasionally changes, at the patient level. assessments: 189.2 million assessments with 66 fields. patients are asked to give regular assessments through the app that cover their current health status and symptoms, aspects of their lifestyle such as potential exposure to covid-19, and, in early versions of the schema, any covid-19 tests that they have had. tests: 1.455 million tests, with 26 fields. test records are kept for each covid-19 test that a patient has had along with the evolving status of that test (typically 'waiting' to some result). diet: 1.563 million diet study questionnaires with 104 fields. these ask people at several time points about their dietary and lifestyle habits. assessments, tests and diet study questionnaires are mapped to patients via ids that serve as foreign keys. this dataset is delivered as daily snapshots in csv format. as of 14th october 2020, the daily snapshot is 42.2 gb in size, and the accumulated daily snapshots are over 3tb in size. the dataset, excepting fine-grained geolocation data, is publicly available at https://healthdatagateway.org. in order to successfully curate the covid symptom study data, it is necessary to be able to handle data that cannot fit into ram. data size and structure, and the set of operations needed to handle the dataset have to be addressed. we can define three scale domains that necessitate a change of approach. this is the scale at which the dataset entirely fits in the computer's ram. commodity laptops and desktops used by researchers typically have between 16 and 32 gb of ram. loading the data can inflate its memory footprint depending on the datatypes used, and operations can multiply memory requirements by a small constant factor, but provided peak memory usage does not dramatically exceed ram, researchers can make use of programming languages with numerical / scientific libraries such as numpy or pandas to effectively analyse the data. at drive scale, only a portion of the dataset can fit into ram at a given time, so specific solutions are required to effectively stream the dataset from drive to memory. datastores become a more compelling option at this scale, as they already have 4/15 memory efficient, streaming versions of the operations that they support, but their usage may not be desirable due to the need to learn a new language or api, and the installation and maintenance burden they represent. this is the scale of dataset that exetera currently targets. at distributed scale, the use of server-based datastores is typically mandatory. it becomes necessary to redesign operations to exploit distributed computing across many nodes. selection of appropriate datastore technology becomes critical, with specific datastore technologies addressing different roles within the overall system. this scale will be targeted by exetera in future development. the exetera software provides functionality that enables a data curation pipeline incorporating data curation best practice. the pipeline has the following steps: • import / preliminary data cleaning and filtering • journaling of snapshots into a consolidated dataset • generation of derived data and analytics the first two stages are generic operations that apply to any tabular dataset being imported into exetera. the third stage is specific to a given dataset, such as the covid symptom study. the import process converts csv data to a binary, columnar format, discussed further in the 'implementation' subsection, that is many orders of magnitude more time efficient for querying in most cases. as part of this process, the data is converted from strings to data types defined by a json schema file. the mapping of data types is from a single csv field to one or more strongly typed fields. how this is done is determined by the json schema and the type specified in the schema. fixed string fields fixed string fields contain string data where each entry is guaranteed to be no longer than the length specified by the field. fixed string fields can handle utf8 unicode data, but this is encoded into bytes and so the specified length must take into account the encoding of the string to a byte array. indexed string fields indexed string fields are used for string data where the strings may be of arbitrary length. the data is stored as two arrays; a byte string of all of the strings concatenated together, and an array of indices indicating the offset to each entry. numeric / logical fields fields which contain a combination of strings to be converted to strongly typed values and empty values, for example "", "false", "true" are converted to the appropriate numeric / logical dataset and a corresponding filter field indicating whether a value is present for a given row of the field. fields containing string values can be processed as categorical fields if specified as such. categorical fields categorical fields map a limited set of string values to a corresponding numeric value. a key is stored along with the field providing a mapping between string and number. a categorical field can also be specified as leaky, in the case that the field is a mixture of categorical values and free text. in this case, a value is reserved to indicate that a given row doesn't correspond to a category, and an indexed string field is created for free text entries. datetime fields datetime fields store date times as posix timestamps in double precision floating point format. the schema can also specify the generation of a 'day' field quantising the timestamp to the nearest day, and can also specify whether the field contains empty values, in which case as filter is also generated, as with numeric fields. data for the covid symptom study project is delivered as a series of timestamped snapshots. the unanonymised data generated by the covid symptom study app is stored in a relational database or similar datastore, that is not accessible to query by the broader research community. instead, the data needs to first be anonymised and bulk exported to csv format. the database is a live view of the dataset, however; users can update data through the app, and, unless the database is explicitly journaled and each entry made immutable, the prior states are erased. as such, a row corresponding to a given entity in two different snapshots can be contain conflicting values. when each snapshot is large, the scaling problem is exacerbated by having to reconcile multiple snapshots. the covid symptom study dataset does not have a field that reliably indicates whether the contents of a given row have changed and so determining whether a row at time t has changed relative to a row at time t + 1 requires a full comparison of all common fields. an example of this can be seen in figure 3 . in addition to the initial data cleaning performed during import, it is useful to perform application specific cleaning and generate ancillary fields that are widely used for downstream analyses. this helps to ensure consistency across analytics and reduces scripting complexity for new users. the covid symptom study data schema has seen rapid iteration since its inception, due to a number of factors. firstly, the initial app was rapidly released to allow users to contribute as soon as possible after the pandemic was declared. secondly, the evolving nature of the pandemic, particularly around prevalence in the population and availability and type of tests has necessitated structural changes to the schema. thirdly, this dataset is novel in terms of its scale and deployment for epidemiological analysis, and the initial wave of papers published by the research group has fed back into the schema. public health surveillance campaigns such as the covid symptom study impose time constraints to software development, with frequent changes in database structure and intense versioning to accommodate iterative refinements. the evolving epidemiology of covid-19, the response of governments and populations to the pandemic, and academic responses to papers based on the dataset all shape the questions that are added to or removed from the app over time. the dataset is only minimally validated at source. the fields often contain data of mixed type, and different fields can be in mutual contradiction. numeric values are only validated for type rather than sensible value ranges. furthermore, the dataset contains multiple competing schema for the same underlying data, and the app version is tied to the schema version, so users who are using older versions of the app are still contributing to otherwise retired schema elements. as such, a considerable amount of data cleaning and processing is required in order to extract data suitable for analysis. the handling of covid-19 tests in the dataset is an example of the complexity created by changes to the schema. testing was initially reported as an assessment logging activity, but this came with a number of problems. firstly, a test needed to be logged on the day it was taken for the assessment date to be treatable as the test date. secondly, some users interpreted the test field as something to be logged only when they took a test or received the result, whilst other users filled in intermediate assessments with the pending status. thirdly, this system did not allow for users to enter multiple tests unambiguously. whilst this was not a problem in the initial months of the pandemic, the ramping up of test availability necessitated a solution. a new test table was introduced in june 2020, giving each test a unique id to allow multiple tests for each patient. however, existing tests recorded in the old schema were not connected with new test entries, although many users re-entered old test results in the new test format. furthermore, new tests continued to be added by users in the old, assessment-based schema format, logging on previous versions of the app. as such, there is no unambiguous way of determining whether tests in the old format are replicated by tests in the new format. this is an example of a postprocessing activity with no unambiguously correct output, which therefore requires at least a single, agreed upon algorithm to be consistently deployed to avoid inconsistencies between related analyses. in the covid symptom study app, user-entered numeric values are only validated to ensure that they are numeric, as of the time of writing. there are no validations of sensible ranges given the user-selected units of measurement. some users enter incorrect values, and some users enter values that appear sensible but only in some other unit (1.8 is a plausible height if the user is entering height in metres, for example). the covid test table has a 'mechanism' field where the user is free to either select a categorical value indicating the test mechanism, or enter free text relating to the test mechanism. some free text clearly indicates the test type, whereas other free text entries only infer the test type weakly, through inference such as 'home test kit'. as such, a set of gradated flags are generated that indicate the quality of the categorisation. in case of multiple daily entries by the users, these assessments can optionally be quantised into a single daily assessment that, for symptoms, corresponds to the maximum value for each symptom that the user reported in the day. this considerably simplifies many downstream analyses. analysis often involves the filtering of patients that are categorised by aspects of the assessments and tests that they have logged. these include metrics such as whether the patient logged as being initially healthy, or whether they have ever logged a positive test result. reproducibility depends on the ability to reproduce a given analysis from a version of the dataset and a set of algorithms run on the dataset. for this to be possible, algorithms must be considered immutable once implemented. this allows any subsequent version of the software to generate results consistent with those of the software version in which the algorithm was introduced. exetera does this by requiring that a version of any given algorithm that is created is treated as immutable in the code base. this means that any target script is guaranteed to exhibit the same behaviour, provided that the following conditions hold. firstly, any algorithms written for exetera are explicitly versioned. secondly, any randomness introduced must be given consistent random seeds and, ideally, multiple sources of randomness should be given different random number generators. once an algorithm is used in analysis, it may no longer be altered in the codebase, even if it subsequently shown to contain errors. this enables researchers to run multiple versions of the same algorithm as part of their analytics and understand how sensitive their results are to changes and corrections. an example for this is the multiple versions of height / weight / body mass index (bmi) cleaning that have been devised over the course of the project; each is available as separate versions of the algorithm for reproducibility. exetera is implemented in the python programming language. python has two aspects that make it suitable for writing software that performs data analytics and numerical analysis. firstly, it is dynamically typed, which reduces code complexity and verbosity 24 . secondly, it has a strong ecosystem of scientific libraries and tools to mitigate the performance and memory penalties that come with using a dynamically typed, byte-code interpreted language and runtime. code that is compiled and run directly in cpython (the reference python implementation) executes in the python interpreter. the python interpreter is extremely slow relative to optimised code such as that generated by compiled, optimised c/c++; in many cases it is orders of magnitude slower. python is dynamically typed, but its type system does not provide light-weight objects to represent primitive types. even numeric values such as integers and floats are stored as full objects, and typically take up 28 bytes for a 4 byte integer value. this overhead precludes efficient memory usage when iterating over large numbers of values. numpy 6, 7 is the python community's main tool for circumventing such time and space inefficiencies. amongst other features, it provides a library for space-efficient representations of multi-dimensional arrays, and a large library of time-efficient operations that can be carried out on arrays. the performance of such operations can be orders of magnitude faster than native cpython, but this is conditional on minimising the number of transitions between python code and the internal compiled code in which the operations are implemented. not all code can be easily phrased to avoid transitions between cpython and numpy internals. where this is not possible, numba 25 is used to compile away the dynamic typing and object overhead, resulting in functions that execute at near optimised c performance levels. csv is a very common way to portably represent large datasets, but it comes with many drawbacks, including a lack of strong typing and an inability to rapidly index to a given location in the dataset. these issues become severely problematic at scale, and so an alternative serialised data representation is required. data representation: row-local vs. column-local data formats data storage formats can be classified as primarily rowlocal or primarily column-local. this choice has key implications for analytics software. row-local data formats store groups of related fields for a given data entry together in memory. column-local data formats store a specific value for a group of data entries together in memory. row-local data format csv format nearly always used in a row-local fashion, i.e. rows are data entries and columns are fields. this typically makes csv very slow to parse for a subset of the data; with csv this is exacerbated because escape-sequenced line-breaks mean that the entirety of each line must be parsed to determine the start of the next row. even without this issue, row-local data formats suffer from locality of reference issues 26 . column-local data format column-local data storage enables very efficient access to a given field. all the entries for a given field are (effectively) contiguous in memory and so loading a single field can be done in an asymptotically optimal fashion. when a dataset has many fields and a given operation operates on a smaller number of those fields, scaling the operation is a far simpler proposition, technically 9, 27 . the ability to load specific subsets of the data with maximal efficiency benefits both the ability to scale and the latency with which operations can be performed on a small subset of the dataset. as such, a column-local data format is a preferable format. hdf5 as the exetera serialised data format hdf5 10 is a data format for storing keys and their associated values in a hierarchically organised, nested collection. in contrast with csv, hdf5 stores data in a column-local format. it also allows for data to be stored as binary, concrete data types. hdf5 permits a user to explore the overall structure of the data without loading fields. fields are loaded at the point that a user specifically requests the contents of a given field. this can be a direct fetch of the entire field or an iterator over the field. this makes it a suitable initial data format for exetera, although alternative columnar data storage formats are being considered to replace hdf5 for future development due primarily to issues of dataset fragility and shortcomings relating to concurrent reading / writing. most analysis of tabular data is performed through a combination of joins, sorts, filters and aggregations. exetera operates on arrays of effectively unlimited length, particularly when certain preconditions are met, using the following techniques. sorting is one of the key operations that must scale in order to process large datasets, as imposition of a sorted order enables operations such as joins to scale. exetera uses several techniques to provide highly scalable sorting. generation of a sorted index rather than sorting data directly, exetera generates a sorted index that is a permutation of the original order. this is used to scale related sort operations, and implement a soft sort, where fields are stored in a natural sorted order and the permuted index applied when the field is read. scaling multi-key sorts on long arrays multi-key sorts are memory intensive when keys are large, and expensive due to the internal creation of tuples in the inner loops of sorts. multi-key sorts in exetera are rephrased as a series of sorts on individual keys from right to left, where the output of each sort step is a sorted index that is the input to the next sort step, using a stable sort. figure 4 shows pseudocode for this operation. scaling sorts on very long arrays exetera has a second sorting algorithm that can be selected if an array is too large to fit into memory in its entirety. such arrays are sorted via a two-phase approach in which the array is divided into subsets; each subset is sorted, and the sorted subsets are merged together by maintaining a heap of views onto the sorted subsets. a separate index is generated and maintained with the sorted chunks, so that the merge phase is stable. figure 5 shows pseudocode for this operation sorting multiple fields the sorts described above, that produce a permutation of the original order, can be used to sort multiple fields in a space-efficient fashion. for large arrays, the array can be permuted in turn and written back to disk, or the permuted order maintained and reapplied when needed. exetera scales to provide this functionality even for very large arrays. operations on sorted fields a number of operations become merges with various predicates when performed on fields that have been sorted by the key field and can be performed in o(m + n) time where m and n are the lengths of the fields to be merged. this includes joins and aggregations. exetera performs these operations as merges when the key field is sorted. importantly, arbitrarily large fields can be operated on in this way. figure 1 . a left join of a simplified dummy patent and assessment dataset. the left join is from patients on the right to assessments on the left to generate a patient_age field in assessment space. . pseudocode for a streaming sort that outputs a sorted index for subsequent application to many fields. a new dawn for citizen science the future of citizen science: emerging technologies and shifting paradigms an analysis of citizen science based research: usage and publication patterns opinion: toward an international definition of citizen science rapid implementation of mobile technology for real-time epidemiology of covid-19 the numpy array: a structure for efficient numerical computation array programming with numpy data structures for statistical computing in python sql databases v. nosql databases matplotlib: a 2d graphics environment jupyter notebooks -a publishing format for reproducible computational workflows key predictors of attending hospital with covid19: an association study from the covid symptom tracker app in 2,618,948 individuals estrogen and covid-19 symptoms: associations in women from the covid symptom study geo-social gradients in predicted covid-19 prevalence and severity in great britain: results from 2,266,235 users of the covid-19 symptoms tracker app diagnostic value of skin manifestation of sars-cov-2 infection dask development team. dask: library for dynamic task scheduling columnar storage formats apache parquet real-time tracking of self-reported symptoms to predict potential covid-19 risk of covid-19 among front-line health-care workers and the general community: a prospective cohort study. the lancet public heal delirium is a presenting symptom of covid-19 in frail, older adults: a cohort study of 322 hospitalised and 535 community-based older adults do programming languages affect productivity? a case study using data from open source projects a llvm-based python jit compiler what every programmer should know about memory c-store: a column-oriented dbms week starting key: cord-261133-m00gcci4 authors: eccles, ron title: understanding the symptoms of the common cold and influenza date: 2005-10-25 journal: lancet infect dis doi: 10.1016/s1473-3099(05)70270-x sha: doc_id: 261133 cord_uid: m00gcci4 the common cold and influenza (flu) are the most common syndromes of infection in human beings. these diseases are diagnosed on symptomatology, and treatments are mainly symptomatic, yet our understanding of the mechanisms that generate the familiar symptoms is poor compared with the amount of knowledge available on the molecular biology of the viruses involved. new knowledge of the effects of cytokines in human beings now helps to explain some of the symptoms of colds and flu that were previously in the realm of folklore rather than medicine—eg, fever, anorexia, malaise, chilliness, headache, and muscle aches and pains. the mechanisms of symptoms of sore throat, rhinorrhoea, sneezing, nasal congestion, cough, watery eyes, and sinus pain are discussed, since these mechanisms are not dealt with in any detail in standard medical textbooks. acute upper respiratory tract viral infections (urtis) are the most common diseases of human beings, with adults having two to five common colds each year and school children having from seven to ten colds per year. 1 the symptoms of urtis are so common that selfdiagnosis of common cold or influenza (flu) is normal among the general public and clinical diagnosis is usually the only diagnosis used by the physician. over 200 serologically different viral types are responsible for human urtis, with the rhinoviruses being the most common cause. 1 there is a large amount of information available about the molecular biology of the viruses associated with urtis but relatively little information on the origins of the symptoms associated with them. an understanding of the pathophysiology of symptoms of urtis is important, as most treatments for urtis are symptomatic and clinical trials on the efficacy of new treatments usually focus on changes in symptom scores as the main parameter of efficacy rather than changes in viral titres in the airway or viral shedding. clinical trials on any new antiviral treatment for urtis aimed at the general population will need to demonstrate changes in symptom severity or duration of symptoms, since these parameters are the key benefits for most patients. differences in clinical presentation are not so useful in identifying the causative agent of an urti but there has been increasing interest in improving the accuracy of symptomatic diagnosis of emerging viral infections such as pandemic influenza 2 and severe acute respiratory syndrome (sars) 3 because early diagnosis is essential for any antiviral therapy and for the initiation of publichealth measures in the community (eg, isolation of infected cases). here, i discuss the mechanisms that generate symptoms associated with urtis, especially common cold and flu, but will not review virology in any detail except as regards relevance to symptoms. the clinical expression of urtis is variable and is partly influenced by the nature of the infecting virus but to a greater extent is modulated by the age, physiological state, and immunological experience of the host. 4 depending on these factors, urtis may occur without symptoms, may kill, or most commonly will be associated with an acute self-limiting illness. "common cold" and "flu" are syndromes of familiar symptoms caused by viral infection of the upper respiratory tract. it is difficult to define the syndromes exactly because of great variation in the severity, duration, and types of symptom. rhinoviruses account for 30-50% of all colds, and coronaviruses are the second most common agent, accounting for 10-15% of colds. 5 influenza viruses account for 5-15% of colds, and cold viruses such as respiratory syncytial virus are responsible for much flu-like illness, 6 demonstrating that there is much overlap in aetiology and symptomatology of common cold and flu syndromes. the common cold syndrome has been defined in terms of experimental colds as a short mild illness with early symptoms of headache, sneezing, chilliness, and sore throat and later symptoms of nasal discharge, nasal obstruction, cough, and malaise. 7 generally the severity of symptoms increases rapidly, peaking 2-3 days after infection, with a mean duration of symptoms of 7-10 days but with some symptoms persisting for more than 3 weeks. 5 experimental colds in the adult are rarely associated with fever, and some subjects have a transient depression of oral temperature during the early phases of a cold. 7 studies on the symptoms generated by different common cold viruses indicate that it is not possible to identify the virus on the basis of the symptoms, since similar symptoms are caused by different viruses. 8 the influenza syndrome is typically of sudden onset and is characterised by fever, headache, cough, sore throat, myalgia, nasal congestion, weakness, and loss of appetite. 2 antiviral agents are available for the treatment of influenza but they are ineffective against any other causes of urtis and therefore there is considerable interest in the early clinical diagnosis of influenza as opposed to common cold. the best predictors for influenza are cough and fever, since this combination of symptoms has been shown to have a positive predictive value of around 80% in differentiating influenza from a population suffering from flu-like symptoms. 2 the symptoms of urtis are triggered in response to the viral infection of the upper airway and the immune response to infection may be the main factor in generating the symptoms, rather than damage to the airway. 9,10 histological surveys of the nasal epithelium during experimental rhinovirus infections have not been able to find any morphological changes in the nasal epithelium of infected volunteers, apart from a substantial increase in polymorphonuclear leucocytes early in the course of the infection. 11 the major cell monitoring the host for the invasion of pathogens is the macrophage, which has the ability to trigger an acute phase response when stimulated with components of viruses or bacteria-eg, viral rna and bacterial cell wall components. 12 the surface of the macrophage exhibits toll-like receptors that combine with the components of viral and bacterial pathogens and trigger the production of cytokines. 12 the cytokines act to recruit other immune cells, trigger inflammation, and generate systemic symptoms such as fever. 13 a complex mix of proinflammatory cytokines and mediators generates the symptoms of urtis. 14 the inflammatory mediator bradykinin is believed to have a major role in generating the local symptoms of urtis (eg, sore throat and nasal congestion), 15, 16 and cytokines are believed to be responsible for the systemic symptoms (eg, fever). 17 a discussion of the mechanisms that generate the urti symptoms is the main topic of this review and each symptom will be discussed in turn. a scratchy sensation of throat irritation is often the first symptom of an urti. this symptom may be related to early viral infection of the nasopharynx rather than the nasal epithelium. 18 point inoculation of rhinovirus on the inferior turbinate caused early infection of the nasopharynx with subsequent spread of infection anteriorly into the nose. 18 the sensation of throat irritation may be caused by the formation of bradykinin in the airway in response to infection, since intranasal administration of bradykinin causes symptoms of rhinitis and a sore throat. 15, 19 the sensation of throat irritation as an early urti symptom may develop into sore throat pain associated with nasopharyngitis, pharyngitis, or tonsillitis and these conditions may also be associated with bacterial infection. 20 the symptom of sore throat is most likely caused by the actions of prostaglandins and bradykinin on sensory nerve endings in the airway and the sensation of pain is mediated by the cranial nerves supplying the nasopharynx and pharynx. sneezing, like sore throat, is a prominent early symptom associated with urtis. 7 sneezing is mediated solely by the trigeminal nerves, which supply the nasal epithelium and the anterior part of the nasopharynx with sensory fibres. 21, 22 sneezing is related to inflammatory responses in the nose and nasopharynx that stimulate the trigeminal nerves. the sneeze response may be mediated via histamine receptors on the trigeminal nerves, since intranasal administration of histamine causes sneezing. 23 the trigeminal nerves relay information to the sneeze centre in the brainstem and cause reflex activation of motor and parasympathetic branches of the facial nerve and activate respiratory muscles. a model of the sneeze reflex is illustrated in figure 1 . the sneeze centre coordinates the inspiratory and expiratory actions of sneezing via respiratory muscles, and lacrimation and nasal congestion via parasympathetic branches of the facial nerve. the eyes are always closed during sneezing by activation of facial muscles, indicating a close relation between the protective reflexes of the nose and eyes. a common phenomenon is the "photic sneeze", caused by a sudden increase in light intensity, again highlighting the overlap of protective nasal and eye reflexes. 24 sneezing activates parasympathetic pathways to nasal glands and there appears to be some cholinergic control of sneezing, since anticholinergics such as ipratropium and first generation antihistamines have been shown to inhibit sneezing. 25, 26 the nasal discharge associated with urtis is a complex mix of elements derived from glands, goblet cells, plasma cells, and plasma exudates from capillaries, with the relative contributions from these different sources varying with the time course of the infection and the the trigeminal nerves provide a sensory input to the "sneeze centre" in the medulla that triggers reflex activation of nasal and lacrimal glands to cause a rhinorrhoea, facial muscles to cause closure of the eyes and grimace, and respiratory muscles to cause inspiration followed by an explosive expiration. facial muscles nasal lacrimal glands trigeminal nerves sneeze centre in medulla severity of the inflammatory response. 27 a watery nasal secretion is an early urti symptom and is often accompanied by sneezing. this early phase of nasal secretion is a reflex glandular secretion that is caused by stimulation of trigeminal nerves in the airway, similar to sneezing. support for the glandular origin of the early nasal secretions comes from studies on anticholinergic medicines such as ipratropium. these studies have demonstrated that nasal secretions in the first 4 days of a common cold are inhibited by intranasal administration of ipratropium. 25 the nasal discharge also consists of a protein-rich plasma exudate derived from subepithelial capillaries, 28 which may explain why anticholinergics only partly inhibit nasal discharge associated with urtis. 27 the colour of nasal discharge and sputum is often used as a clinical marker to determine whether or not to prescribe antibiotics but there is no evidence from the literature that supports this concept, 29 since colour changes in nasal discharge or sputum reflect the severity of the inflammatory response 30 rather than the nature of the infection. much of the literature relates to colour changes in sputum and the lower airways but the same concepts apply to the upper airways and nasal discharge. the colour of nasal discharge may change from clear to yellow to green during the course of an urti. this colour change is related to the recruitment of leucocytes into the airway lumen and is a hallmark of airway disease. 30 neutrophils and proinflammatroy monocytes have azurophil granules that are green because of the green protein myeloperoxidase. nasal discharge with few leucocytes is white or clear, with increasing numbers of leucocytes the nasal discharge appears yellow (pale green), and with large numbers of leucocytes the colour becomes green. 30 nasal congestion is a later symptom of urtis that increases in severity over the first week of symptoms. 7 nasal congestion is caused by the dilation of large veins in the nasal epithelium (venous sinuses) in response to the generation of vasodilator mediators of inflammation such as bradykinin. 31, 32 these sinuses are well developed at the anterior end of the inferior turbinate and nasal septum where congestion of the sinuses in the narrow nasal valve region causes obstruction of the nasal airway. 33 the nasal venous sinuses exhibit phases of congestion and decongestion under the influence of the sympathetic vasoconstrictor nerves, causing reciprocal changes in nasal airflow (often termed the "nasal cycle"). 33 the asymmetry of nasal airflow associated with the nasal cycle is increased with an urti, and this may result in one nasal passage being patent while the other is completely obstructed. 34 figure 2 illustrates the changes in nasal airflow associated with the nasal cycle in health and with an urti. the paranasal sinuses surround the nasal airway and any infection of the airway usually involves the sinuses, causing inflammation and the accumulation of secretions in the sinuses. 35 the origin of sinus pain may be related to several factors-eg, pressure changes in the sinus air space and pressure changes in the blood vessels draining the sinus. 36 the ostia of the paranasal sinuses are often occluded because the nasal epithelium becomes inflamed and congested with an urti; this may result in gas absorption from the sinus and "vacuum maxillary sinusitis". 37 however, sinuses with patent ostia may also be painful, indicating that the generation of inflammatory mediators within the sinus may be sufficient to trigger the sensation of pain either by direct stimulation of pain nerve fibres or via distension of blood vessels that are also served by sensory nerves. 36 changes in posture from sitting to supine cause an increase in sinus pain that may be related to dilation of the blood vessels draining the sinus caused by an increase in venous pressure. pressure changes in the sinus may also cause pain by stimulation of branches of the trigeminal nerve that course in and around the sinuses. 37 watery eyes (epiphora) is a common symptom associated with allergic and infectious rhinitis. 38, 39 in children aged 7 years, 70% of cases of epiphora are related to allergic disease or urtis. 40 the nasolacrimal duct may be obstructed at its opening into the nose by inflammation and congestion of blood vessels in the nasal epithelium around the opening of the duct, causing an accumulation of tears and the symptom of watery eyes. the nasolacrimal duct has been shown to have a vascular plexus of veins (cavernous tissue) similar to the venous sinuses of the nasal epithelium, and congestion of this plexus causes obstruction of the duct. 41 the nasolacrimal cavernous tissue is innervated by parasympathetic and sympathetic nerves that may have a role in controlling the outflow of tears by regulating the congestion and decongestion of the cavernous tissue. 42 cough is a common symptom associated with urtis that may persist for 3 weeks or more, 43 and it represents the largest single cause of consultation in primary care. 44 cough is mediated exclusively by the vagus nerve, meaning that cough is initiated in the airway by stimulation of sensory nerves at the level of the larynx or below. 45 a model of cough control is illustrated in figure 3 . nasal stimulation and inflammation causes sneezing and not cough, indicating that the airway inflammation associated with rhinitis must reach the level of the larynx to trigger cough. the vagus nerve also supplies the external ear, oesophagus, and abdominal organs and cough can be elicited from these areas as with cough associated with gastroesophageal reflux. 44 cough is normally a protective reflex that prevents the aspiration of food and fluid into the airway and also aids in the expulsion of mucus and foreign objects from the lower airway. the first days of an urti are often associated with a dry, unproductive cough that serves no useful function and may cause loss of sleep and exhaustion. the unproductive cough may be caused by the inflammatory response in the upper airways spreading to the larynx. cough associated with urtis is believed to be caused by a hyper-reactivity of the cough reflex that may be due to the effects of inflammatory mediators on airway sensory nerve endings. 46, 47 in health, cough is readily induced by mechanical stimulation of the larynx, but when the larynx is inflamed and hyper-reactive, cough may occur spontaneously or in response to stimuli that would not normally cause cough-eg, the mildly irritating effects of cold air. cough occurs spontaneously with an urti, and some cough may be voluntary rather than reflex; this voluntary cough may be related to a sensation of airway irritation. 48 productive cough usually occurs later in the course of urti and may be related to the inflammation spreading to the lower airways and triggering mucus production. common cold viruses usually do not cause any substantial damage to the airway epithelium, 11 whereas influenza may cause substantial cellular damage to the respiratory epithelium; this difference may be why influenza infection is usually associated with cough 2 whereas common cold often occurs as a "head cold" with little, if any, symptom of cough. headache is a common early symptom associated with urtis. 7 in a clinical trial that recruited patients with sore throat associated with urtis, over 60% of patients experienced headache. 49 the mechanism of headache associated with urtis is unknown but a hypothesis has been proposed that headache associated with infections is caused by cytokines released from immune cells in response to viral infection. 50 administration of cytokines involved in the immune response to infection-eg, tumour necrosis factor and interferons-has been shown to cause headache in human beings. 50 headache is a common side-effect of administration of interferon beta-1a for the treatment of multiple sclerosis; 51 similarly headache is associated with therapy with pegylated interferon alpha-2b for treatment of hepatitis. 52 the mechanism of headache caused by cytokines is unknown but it is interesting that headache induced by cytokines is accompanied by symptoms such as fatigue, anorexia, malaise, nausea, and depression, and these symptoms are commonly associated with urtis. a sensation of chilliness is an early symptom of common cold, 7 and is sometimes explained as an initial stage of fever, since vasoconstriction of skin blood vessels may cause a fall in skin temperature that is perceived as chilliness. common cold in the adult is rarely accompanied by fever and some subjects have a transient fall in body temperature during the early stages of common cold. in a study of 272 patients with sore throat associated with urtis, the mean aural temperature was 36·8ºc and around 35% of these patients said they were suffering from "chills" and "feverish discomfort". 49 the sensation of chilliness may be unrelated to any change in skin or body temperature. in a study of human volunteers, a sensation of chill still develops on administration of exogenous pyrogen even though the volunteers are immersed in a water bath that maintains a neutral skin temperature (34·5ºc). 53 the sensation of chilliness occurred after visible signs of shivering in the volunteers. chilliness and shivering occurred even though there was no change in skin temperature and body temperature was actually rising in response to skin vasoconstriction. this finding indicates that the sensation of chilliness may be a central sensation closely linked to control of shivering. chilliness and shivering are most likely induced by the effects of cytokines on the temperature regulating centres of the hypothalamus and perceived at the level of the cerebral cortex. fever in response to infection is found in a wide range of animals and is believed to be beneficial as regards the host response to infection. 54 fever is usually associated with novel or severe viral infections, especially emerging viral infections where the virus is novel to the host, as in influenza epidemics and sars. 2, 3 as discussed, fever is uncommon in adult cases of common cold, but is common in infant cases, presumably because the adult has been exposed to numerous common cold viruses and subsequent infections do not trigger a strong immune response, whereas the viruses are novel to the infant. cytokines have been implicated as endogenous pyrogens that are released from macrophages and other leucocytes in response to infection, and there is considerable evidence for pyretic and antipyretic effects of cytokines. 17 the proinflammatory cytokines interleukin 1, interleukin 6, and tumour necrosis factor alpha, as well as the anti-inflammatory cytokines interleukin-1 receptor antagonist and interleukin 10 have been investigated for their pyrogenic or antipyretic action. 17 interleukin 1 and interleukin 6 are believed to be the most important cytokines that induce fever. 55 cytokines are believed to cross the blood-brain barrier or interact with the vagus nerve endings to signal the temperature control centre of the hypothalamus to increase the thermal set point. 55, 56 the hypothalamus then initiates shivering, constriction of skin blood vessels, and a sensation of chilliness (figure 4). the presence of physical features of urtis-eg, nasal congestion, rhinorrhoea, and cough-may cause discomfort, attention deficit, and mood changes but there is increasing evidence that the psychological changes associated with urtis may also be caused by the effects of cytokines on the central nervous system. 57 urtis have been shown to lead to a reduction in subjective alertness and impaired psychomotor functioning 58 but the relative contribution of cytokines to these changes is poorly understood. exogenous administration of interferon alpha is used as a therapy for chronic viral diseases such as hepatitis b and c, and therapy is associated with flulike side-effects similar to those observed with urtiseg, fatigue, fever, chills myalgia, nausea, and mood changes. 59 psychiatric side-effects such as depression, irritability, lack of motivation, impaired concentration, psychoses, and confusional states have been reported to occur in some patients after 2-3 months of therapy with interferon alpha. 59 the present knowledge on the effects of interferon alpha on the brain indicates that there at least two distinct syndromes related to therapy: an early neurovegetative syndrome characterised by psychomotor slowing and fatigue, and a later mood/cognitive syndrome that involves depression. 60 cytokinesincluding tumour necrosis factor and interleukins 1, 2, and 6-have been reported to induce the syndrome of "sickness behaviour" with anhedonia, cognitive dysfunction, anxiety/irritability, psychomotor slowing, anergia/fatigue, anorexia, sleep alterations, and increased sensitivity to pain. 60 these cytokines are also associated with urtis and may mediate mood changes associated with these infections. anorexia is a common behavioural response to urtis, and this response has entered the folklore as advice to the cytokines may act on vagal nerve endings or enter the brain to cause a resetting of the temperature control centre in the hypothalamus. the hypothalamus causes shivering and constriction of skin blood vessels and also initiates a sensation of chilliness that is perceived at the level of the cerebral cortex. il=interleukin; tnf=tumour necrosis factor. "feed a cold and starve a fever". 61 in association with fever, decreased food and water consumption are the most common signs of infection. 13 there is growing evidence that anorexia associated with infections such as urtis is mediated by cytokines that are released from leucocytes in response to infection, and that these cytokines cause inhibition of feeding by effects on the feeding centre in the hypothalamus. 62 the cytokines implicated in anorexia are those involved in the acute phase response to infection-eg, interleukins, tumour necrosis factor, and interferons. 62 in support of the folklore advice to starve a fever, evidence indicates that acute anorexia in response to infection is beneficial and that it is an important behavioural response to help overcome infection. anorexia may aid in eliminating infection by saving energy that would be otherwise used in finding food, reducing heat loss from the body that would be lost by convection, reducing the availability of micronutrients such as iron and zinc that are essential for the growth of pathogens, and enhancement of immune function by enhancing monocyte and macrophage activity. 13, 62 muscle aches and pains (myalgia) are a common symptom of urtis, with around 50% of patients with common cold experiencing these symptoms. 49 myalgia is a symptom of the acute phase response to infection and there is evidence that the symptom is caused by the effects of cytokines on skeletal muscle. 63 proinflammatory cytokines have been implicated as inducing the breakdown of muscle proteins, and tumour necrosis factor was initially referred to as cachetin because of its role in causing muscle wasting or cachexia. 64 the breakdown of muscle protein in response to urti can be viewed as beneficial because it mobilises proteins and aminoacids that can be converted in the liver to opsonins and other components of the immune response. 64 fever associated with urtis is usually accompanied by other systemic symptoms such as myalgia and there is much evidence that indicates that both these symptoms are caused by the production of prostaglandin e2 in response to circulating cytokines. 63 the cytokine-induced generation of prostaglandin e2 and the breakdown of skeletal muscle in vitro is inhibited by indomethacin, 63 and similarly myalgia associated with urtis is relieved with acetylsalicylic acid. 49 prostaglandin e2 is a mediator of pain by its effects on peripheral pain receptors. 65 the cytokine stimulation of prostaglandin e2 production in skeletal muscle, and the effects of prostaglandin e2 on sensory nerves in muscle, may explain the myalgia associated with urtis. in a study of common cold symptoms induced by challenge with infected nasal secretions, urti symptoms were classified as either "early" or "later" symptoms. 7 the early symptoms were headache, sneezing, chilliness, and malaise, which developed quickly and also declined rapidly after 1-2 days, whereas the later symptoms-malaise, nasal discharge, nasal obstruction, and cough-developed slowly over several days and were still present 1 week after challenge. the time course of an early symptom (sneezing) is compared with that of a later symptom (cough) in figure 5 . the early development of sneezing compared with cough in cases of common cold may be explained on the basis that urtis develops in the upper airways first and subsequently spread to the lower airways. the upper airways are innervated by the trigeminal nerves that mediate sneezing whereas the airways below the larynx are innervated by the vagus nerves that mediate cough. fever is usually an early symptom of influenza but is of short duration (3-4 days) . the systemic symptoms of fever, headache, malaise, myalgia, and anorexia are related to the effects of cytokines released from immune cells and these responses develop rapidly in the first days of infection when the virus is detected by the immune system. the local symptoms of nasal congestion and rhinorrhoea are dependent on the generation of inflammatory mediators such as prostaglandins and bradykinin. the inflammatory mediator response may have a slower onset and longer duration than the cytokine response, which may explain the time course of local symptoms such as congestion and rhinorrhoea. our understanding of the generation of urti symptoms has been helped by the discovery of cytokines and new knowledge about their roles in the acute phase response. urti symptoms-eg, anorexia-that previously were in the realm of folklore now have a physiological explanation in terms of the effects of cytokines on the hypothalamus. the present rationale for the treatment of urtis is for symptom relief, since cough sneezing the symptoms of urti are perceived as a nuisance, but this review suggests that some of the symptoms are an integral part of the acute phase response and may aid in recovery from infection. the unpleasant symptoms of fever, malaise, and anorexia help to overcome infection and it is debatable whether elimination of these symptoms with non-steroidal anti-inflammatory drugs is beneficial. at present there is no evidence that symptomatic treatment of urtis interferes with the course of the common cold or influenza but this is an area that is worthy of more research. i declare that i have no conflicts of interest. epidemiology of viral respiratory infections clinical signs and symptoms predicting influenza infection clinical features and short-term outcomes of 144 patients with sars in the greater toronto area influenza in man the common cold contribution of influenza and respiratory syncytial virus to community cases of influenza-like illness: an observational study transmission of the common cold to volunteers under controlled conditions. 1 the common cold as a clinical entity signs and symptoms in common colds epidemiology, pathogenesis, and treatment of the common cold the host response, not the virus, causes the symptoms of the common cold: comment histopathologic examination and enumeration of polymorphonuclear leukocytes in the nasal mucosa during experimental rhinovirus colds science review: key inflammatory and stress pathways in critical illness-the central role of the toll-like receptors infection-induced anorexia: active host defence strategy pathophysiology of nasal symptoms search strategy and selection criteria data for this review were identified by searches of pubmed, isi web of science, and references from relevant articles; articles were also identified through searches of the files of the author. the main search terms were nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat bradykinin levels during experimental nasal infection with rhinovirus and attenuated influenza virus sites of rhinovirus recovery after point innoculation of the upper airway sore throat following nasal and oropharyngeal bradykinin challenge nasopharyngitis, pharyngitis, and tonsillitis upper airway reflexes and involvement of the lower airway role of histamine and antihistamines in the nose the photic sneeze: literature review and discussion effectiveness and safety of intranasal ipratropium bromide in common colds. a randomized, double-blind, placebo-controlled trial a clinical study to evaluate the efficacy of the antihistamine doxylamine succinate in the relief of runny nose and sneezing associated with upper respiratory-tract infection physiology of nasal secretion mucosal exudation of fibrinogen in coronavirusinduced common colds predictors of an antibiotic prescription by gps for respiratory tract infections: a pilot assessment of airway neutrophils by sputum colour: correlation with airways inflammation microvascular anatomy of the nose anatomy and physiology of the nose and control of nasal airflow nasal airflow in health and disease changes in the amplitude of the nasal cycle associated with symptoms of acute upper respiratory tract infection computed tomographic study of the common cold the relationship between body posture and pressure in occluded maxillary sinus of man infraorbital nerve dehiscence: the anatomic cause of maxillary sinus "vacuum headache epiphora: the role of rhinitis an association between acquired epiphora and the signs and symptoms of chronic rhinosinusitis: a prospective case-control study the natural history of epiphora in childhood the cavernous body of the human efferent tear ducts contributes to regulation of tear outflow innervation of the cavernous body of the human efferent tear ducts and function in tear outflow mechanism duration of cough in acute upper respiratory tract infections epidemiology of cough neurophysiology of the cough reflex pathophysiology of airway viral infections cough induced by airway vibration as a model of airway hyperreactivity in patients with acute upper respiratory tract infection voluntary control of cough effects of acetylsalicylic acid on sore throat pain and other pain symptoms associated with acute upper respiratory tract infection the cytokine theory of headache the long-term safety and tolerability of high-dose interferon beta-1a in relapsingremitting multiple sclerosis: 4-year data from the prisms study the safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis b: predictive factors for dose reduction and treatment discontinuation the chill sensation in fever phylogeny of fever invited review: cytokine regulation of fever: studies using gene knockout mice circulating cytokines as mediators of fever common respiratory tract infections as psychological entities: a review of the mood and performance effects of being ill effects of the common cold on mood and performance interferon-alpha, cytokines and possible implications for mood disorders cytokines and psychopathology: lessons from interferon-alpha feed a cold, starve a fever" folk models of infection in an english suburban community, and their relation to medical treatment anorexia of infection: current prospects stimulation of muscle protein degradation and prostaglandin e2 release by leukocytic pyrogen (interleukin-1). a mechanism for the increased degradation of muscle proteins during fever prostaglandins, pain, and inflammation key: cord-244388-dxrrpxl7 authors: marchiori, chiara; dykeman, douglas; girardi, ivan; ivankay, adam; thandiackal, kevin; zusag, mario; giovannini, andrea; karpati, daniel; saenz, henri title: artificial intelligence decision support for medical triage date: 2020-11-09 journal: nan doi: nan sha: doc_id: 244388 cord_uid: dxrrpxl7 applying state-of-the-art machine learning and natural language processing on approximately one million of teleconsultation records, we developed a triage system, now certified and in use at the largest european telemedicine provider. the system evaluates care alternatives through interactions with patients via a mobile application. reasoning on an initial set of provided symptoms, the triage application generates ai-powered, personalized questions to better characterize the problem and recommends the most appropriate point of care and time frame for a consultation. the underlying technology was developed to meet the needs for performance, transparency, user acceptance and ease of use, central aspects to the adoption of ai-based decision support systems. providing such remote guidance at the beginning of the chain of care has significant potential for improving cost efficiency, patient experience and outcomes. being remote, always available and highly scalable, this service is fundamental in high demand situations, such as the current covid-19 outbreak. shortage of physicians and increasing healthcare costs have created a need for digital solutions to better optimize medical resources. in addition, patient expectations for mobile, fast and easy 24/7 access to doctors and health services drive the development of patient-centered solutions. the need to be triaged, diagnosed and treated remotely or at home without having to wait in crowded rooms has never been more relevant than in outbreak periods as the covid-19 one [1] [2] [3] . symptom checkers and differential diagnosis generators (ddx) developed for the public in form of web and mobile apps are at the crossroad of these needs. already several of these developed over the past few years are established on the market. isabel healthcare is mostly designed for medical doctors (mds). it allows the user to enter some demographic information and symptoms and simply suggests a list of all potential diagnoses, ranking them by likelihood and red flagging the potentially dangerous ones. it also displays many literature and web resources for a further exploration of the potential diagnosis (from popular wikipedia to specialized medical sources such as uptodate). ada is developed for the patient. it has a similar starting point, but then engages in a long dialog with the patient to collect additional information on the initially entered symptom and the presence of additional ones. at the end of the dialog, ada provides a generic and high-level summary on the urgency of the condition and returns a list of the most probable diagnoses (such as "n out of 10 people with the same symptoms had this condition"). for each displayed diagnosis there is an associated recommendation, such as "this condition can usually be managed at home", "seek medical advice", "seek emergency care". the telemedicine triage that we developed, the artificial intelligence triage engine (aite), is an integral part of a rich ecosystem of telemedicine services and is fundamentally different from symptom checkers in several aspects. starting with few input symptoms (see figure 1 ), aite engages in short and focused dialogues to finally provide clear and simple recommendations to patients. patients receive suggestions on which medical service provider to go to depending on the characteristics of their condition. in critical cases, patients are recommended to call the telecare provider immediately for a teleconsultation. if the health condition of the patient is assessed as being less urgent, they can select an appointment of their choice via a phone or video consultation with a trained telecare specialist (see figure 2 ). should patients require physical intervention, they will be referred to an appropriate care provider for a faceto-face consultation. the advantages are clear. by using the mobile application, emergency cases can be treated faster than in standard call center settings. moreover by automatically filtering out patient requiring physical intervention, telemedical resources can invest more time in treating telecare eligible patients. furthermore, to recommend the most appropriate course of action, the app draws from the patient's personal medical history as well as from similar cases handled by the telecare provider in the past. built on case records and guidelines using ai-based methods, the system consists of the following building blocks: 1) an engine for the automated ingestion of unstructured clinical notes, the extraction of relevant medical entities and their organization into a knowledge graph (kg); 2) a data-driven dialog system that allows a conversation with such medical knowledge base and drives the patient interactions; 3) an inference engine able to suggest the most appropriate recommendation in terms of point of care and time frame for treatment. all these components are depicted in figure 2 and will be discussed in detail in the following sections. to build the triage application described here, we used more than 900k case records written in german and collected over more than 7 years. this is only a fraction of the available data, since only records generated by top-ranked doctors (based on years of experience and internal audits) were selected. the records are notes that call center agents and doctors took while talking to the patients over the phone. they are structured in sections that contain demographic data such as age and gender, previous illnesses, and free text descriptions of the patient's current medical condition. it should be noted that in this kind of records, the free text contains a shallow and subjective description of the patient's problem. patient narrative can contain mention of recent surgery or treatments and whether the patient can perform or not a specific test/movement, but no physical exams nor lab tests. potential diagnoses consistent with the symptom description are listed. the descriptions in the records are expressed in formal medical language as well as in layman's terminology. typical for these settings, sentences are not always complete (e.g., subjects or verbs may be missing) and include misspellings, dialect vocabulary, non-standard medical abbreviations and inconsistent punctuation. this is a challenge for the linguistic processing of the case records. a natural language processing (nlp) pipeline extracted medically relevant concepts from each case record. the pipeline consisted of the following stages: (1) data preprocessing for misspelling correction and abbreviation expansion, (2) named entity recognition (ner) and (3) concept clustering for the dynamic creation of an ontology of medical concepts from the corpus. acronyms and abbreviations used unambiguously were linked to the corresponding entities directly in the medical dictionaries. ambiguous acronyms and abbreviations were resolved, when possible, using algorithms that include context for disambiguation. although we were able to detect many entity types, i.e. from anatomy and physiology to medical procedures and medicines, the main focus was on the extraction of current, non-current and negative mentions of symptoms and diagnosis in simple and complex expressions. special attention was devoted to symptom and disease characterization in terms of body part location (e.g. pain in the leg, abscess in the arm), intensity (strong, light), time duration (chronic, acute), activity by which the symptom manifests or changes in character (e.g. dyspnea at rest, exertional dyspnea). for medical entity extraction we used a system based on the combination of dictionary look-up, advanced rules and deep learning. the dictionaries used in the ner were built partly using existing german-language medical dictionaries and ontologies (umls mapped german terms, icd10, meddra, etc.) and partly using the list of words contained in the case records. they therefore contain a mapping of technical and layman's terms, for a total of more than 140k unique words (including declination, capitalization). negated mentions of medical entities are very frequent in this type of records and were detected using german language-specific negation particles or expressions. for relations that associate a medical entity to a specific body part, advanced parsing rules were used to detect short distance relations with high precision, while a deep learning (dl) stage was used to detect distant relations, improving therefore the overall recall. we trained a dl binary classifier with positive and negative examples. the annotated data consisted of 10k triples (e1, r, e2) manually generated on the raw texts; where e1 is a symptom, disease, or operation, e2 is an anatomical location, and r is the positive or negative relation between the two entities. to obtain a good balance of training examples, 50% triplets had r = "located in" and 50% triplets had r = "not located in". this approach can also be used in case of multi-relation extraction by building a binary classifier for every relation, where the use of correctly balanced negated examples helps improve the training. the raw text data was processed by (a) removing stop words, (b) transforming to lower case, (c) normalizing to ascii characters, (d) transforming delimiters (e.g. ";", ",", ".") to word embeddings by adding white spaces, and (e) excluding any non-alphanumerical characters and characters not in the delimiter set. for each word, we concatenated word-, positional-and part-ofspeech-features (pos-features) creating the input feature vector. word features were constructed using pre-trained word embeddings on the raw text data, using either word2vec 4 or elmo2 5 embeddings. positional features were defined as the combination of the relative distances of the current word from the entities e1 and e2 6 . we explored three different architectures convolutional neural network 7 (cnn) and bidirectional gated recurrent unit network (bi-gru), bidirectional long short term memory network (bi-lstm), combining the models proposed in [8] [9] [10] [11] . in the cnn architecture, the input feature vector with dimension k was fed to convolutional layers. these layers encoded the word sequence into n-gram representations, to capture the contextual information. for a given sentence, a weight matrix w ∈ r m×k was applied to generate the new features c i from the window of words x i:i+m−1 where: with m convolutional window. this filter was applied to each possible window of words in the sentence to produce a feature map: with c ∈ r n−m+1 . by applying multiple filters (denoted f ) on x i:i+m−1 , we obtained a new representation of the sentence. by setting different values for m, we obtained different n-gram representations of the sentence which was input to a max pooling layer, similarly to 6, 7, 12 . the last layers of the cnn architecture comprised several fully connected layers with dropout and a softmax for the classification. the architecture schema of the cnn model is shown in the left panel of figure 3 . the dimensions of the word embeddings w, the positional embeddings p, the number and size of the convolutional windows, the number of filters f , the number of fully connected layers and their dimensions, the number of epochs and the dropout rate were tuned during training. in the bi-gru and bi-lstm architectures, the input feature vector with dimension k was fed into bi-gru or bi-lstm layers, followed by an attention and a softmax layer for the classification. the architecture schema of the bi-lstm is given in the right panel figure 3 . for all architectures, we used grid search to find the optimal values of the model-specific hyperparameters. we used a randomly constructed cross-entropy loss function with mini-batch updating and adam optimizer for five epochs. in our experiment, we found optimal values for w = 50 and p = 20. the annotated data was split in 60% training, 10% validation and 30% testing. precision, recall and f-score on the test set on the different architectures are shown in table 1 . notably, the described nlp pipeline is able to ingest one million patient records at run time and extract the relevant medical entities and their relations in about two hours. therefore, if needed, new, improved versions of the system could be produced almost on a daily basis, by ingesting new case records whenever available. a highly performant pipeline is also important for efficient debugging of the nlp algorithms. several approaches have been developed for ontology learning 13, 14 , which is defined as the extraction of terms, concepts, taxonomic relations and non-taxonomic relations from data. an ontology can be built from scratch for example table 1 : prediction results of the different architectures on relation extraction (i.e., predicting whether the relation is r 1 or r 2 ), where p(r k ), r(r k ), f(r k ) are precision, recall and f-score and r 1 = "not located in", r 2 = "located in". similar values were obtained by conducting several experiments and averaging the results. using clustering algorithms or from an existing ontology performing classification tasks. the first step in the creation of the ontology in our application was the grouping of the annotations gathered through the nlp pipeline that describe the same medical concept. for this process we used a hierarchical procedure, named concept clustering. this is important to improve performance of the inference engine to ensure high recall for systems based on patient similarity and reduce feature correlation for machine learning classifiers. it is especially laborious in german, due to the frequent use of complex compound names that can be also expressed by several permutations of the corresponding simple entities. the created medical concepts are then organized in an ontology, where the following relations among medical concepts were considered: 1) child of (taxonomic relations) and 2) located in, negation of, characterization of, specification of (non-taxonomic relations). the relations child-of were automatically built using as a reference the relations contained in two manually curated elementary ontologies, "anatomy" (e.g. augenlid is child of auge -eyelid is child of eye) and "general symptom" (e.g. druckschmerz is child of schmerz), which were derived from standard medical resources(e.g., 15 ). to summarize, more than one million medical expressions were merged into 17k medical concepts specific to medical triage, related to a very broad range of problems (e.g. urinary, digestive, respiratory, locomotive, skin, eye). these medical concepts were organized in a large ontology containing 17k nodes (15k symptoms, 2k diseases) and 100k edges. in addition to a name and its synonyms, each medical concept was also characterized by metadata, used, for example, to assign the semantic type (symptoms, disease), distinguish between red flags and common symptoms, female or male specific conditions, psychological or other types of symptoms. metadata are consumed by the system which drives the dialogue with the end users (q&a system). the diagram of the stages used to construct the ontology is summarized in figure 4 . it should be noted, that this solution allowed for the creation of an ontology of medical concepts directly and automatically from the ingested data, whereby layman's and technical terminology as well as many synonym expressions are mapped to the same concept. in addition, this solution is useful for languages that are not yet well covered by standard ontologies such as umls/snomed. after ontology creation, the input case records together with the extracted medical concepts and metadata were automatically ingested and organized in a language agnostic knowledge graph (kg). kgs are structured knowledge bases (kbs) that store information in form of relationships (edges) between entities (nodes or vertices) [16] [17] [18] . the graph is represented by its sparse adjacency matrices, indicating which vertices are connected with a given relation. the created kg consisted in more than 1m of nodes of the type case record, age, gender, symptom, disease, red flags, historical recommendation and 23m edges linking these entities, such as, for example symptom-to-patient, diseaseto-patient, patient-to-point-of-care, age-group-to-patient. the language agnostic kg was built for multilingual triage applications by first using data in one specific language (german) as a reference and then mapping the medical entities (kg nodes) to numerical codes. to obtain language interoperability, these numerical codes should correspond to international standards, such as the umls concept unique identifier, or icd and snomed codes. however, the coverage of these coding systems for the specific languages can vary considerably and therefore a complete mapping was not possible. an essential part of the triage process is the q&a session, during which additional, carefully chosen symptoms are asked to the patient. as the patients do not have the necessary knowledge for proper triage, this process ensures that they enter all relevant symptoms, even the ones that they might consider irrelevant or unnecessary to input. users might not know correlations between symptoms that are important. the question generation algorithm drives the interaction with the patient. its goal is to identify which medical concepts need to be asked as the most relevant to the initial input provided by the patient, emulating the human expert decision process. in our system, the question generation algorithm is fully learnt from the data: the questions are determined dynamically based on the patient's input and the system's knowledge on the training data. we explored two different approaches. one based on information retrieval algorithms, i.e., pseudo-relevance feedback based query expansion techniques (such as entropy, mutual information) and the second one on neural network techniques. in the first approach question generation and patient risk assessment are jointly optimised so that the collection of additional relevant information from the patient aims to improve the classification task. while in the second approach the two tasks are optimised (i.e., trained) separately. for the neural network based model we constructed a training corpus masking one or multiple medical concepts from each patient case and optimised the network to predict the obscured features. we split the data in 70% for training, 10% for validation and 20% for testing. due to the high number of word features that may be obscured, the prediction task becomes very hard. a random classifier would only achieve an accuracy of 5.6 × 10 −5 (inverse of the number of word features) for the top one (i.e., highest probability) prediction. in table 2 we compared the performance of a neural network based query expansion model 19 with the following rankers: i) frequency-based (f), ii) binary independence model (bim 20 ), iii) χ 2 value (chi 21 ), iv) robertson selection value (rsv 22 ), v) kullback-leibler divergence (kld 23 , relative entropy). for a comprehensive review of those methods see also 24 . the frequency-based ranking of the terms (f) ranks the most often occurring symptoms the highest, while low-occurrent ones lower as in the formula f (s, r) = r∈r i s∈r , where r is the set of relevant cases retrieved, s is the token to be ranked and i the identity if the token s belongs to the set r, zero otherwise. a drawback of this method is that it ranks potentially irrelevant symptoms high, that are only common because they are frequent in the data, hence also in the relevant subset of cases. the binary independence model (bim) ranks symptoms based on the equation below: where s denotes the symptom to be ranked, r is the set of relevant retrieved cases and n is the case base. p(s|r) and p(s|n ) stand for the probabilities of the symptom occurring in the relevant set of cases and the whole case base respectively. the exact probabilities are unknown but can be approximated with the counts. the χ 2 value is used to determine whether there is significant difference in expected values of two events. in our case, these two events are the query occurrence in the relevant set of cases and the occurrence in the whole set of training data. the definition is given in the equation below: the kullback-leibler divergence (kld, relative entropy) of the aforementioned probabilities is also used as a term ranking metric. it is defined as written in the equation below: kld is a measure of how two probability distributions differ from each other. the robertson selection value (rsv) ranks the symptoms based on the product of their differences in occurrence probabilities and their term weight for each document in the relevant records. this is intuitively promising as certain tokens might be low-occurrent compared to others, yet of major importance for the downstream classification task, which is captured by a higher term weight. rsv is described in the equation below: where w(s, r) denotes the weight of term s in the given relevant record r. nn based question generation systems show very promising results in order to generate questions that are medically relevant and consistent with the initially provided symptoms, hence fundamental for the construction of a q&a system. the described experiment has been used to benchmark different algorithms. in real settings, the question generation system is only one component of the dialogue system and only a subset of medical conditions is used. a key aspects in the dialogue is the usage of the medical ontology. central to the development and digitization of ai-based decision support system are user acceptance and user friendliness. in aite, for example, patients can state their symptoms in a natural way since many different forms of expressing the same symptom have been learned from the training data provided by the telemedicine provider. an elastic search engine provides the mapping from the user input to the medical concepts using all variety of symptom expressions extracted from the data and stored in the ontology. the q&a part plays an important role in defining the overall user experience, hence speed and usability are crucial. in order to achieve the best user experience, the q&a was customized according to patient age, gender, and medical status, and special attention was paid to a simple and understandable formulation of the questions. questions should be relevant to the input symptoms and conversations should be short. this required that a final recommendation could be reached in only few interactions, with a short waiting time between these, i.e., less than one second. especially difficult was to design a system to avoid asking "similar questions" that are interpreted by a human as repetitive and redundant. this was partially solved by using the hierarchical structure of the medical ontology, by excluding all the children of a medical concept as possible question candidates, if the patient has denied having their parent. for instance, the system will not ask any symptoms related to a specific part of the abdomen (upper, lower, right, left, center) if the patient denies having an abdomen problem. these key performance indicators (kpis) were explicitly evaluated during several testing campaigns in different settings which led to continuous refinement of the q&a model and logic. the inference engine is the part of the system that will reason on the collected information and give a final recommendation. the are several approaches to build a recommendation engine for patient risk assessment. in one type of approach, patient similarity is calculated on the kg using node and edge weights, to identify the sub-graph region containing the patient data most similar to the user. this region might also be used to retrieve the possible key missing medical conditions, in systems where question generation and recommendation inference are coupled. node and edge weights in the kg are learned from the data and medical guidelines with cross entropy cost minimisation. in a second type of approach, the kg is used as a knowledge base to extract feature vectors, (e.g. by learning embeddings from the graph [25] [26] [27] [28] , combining embeddings learned from the original text with graph features) to build a machine learning classification engine. while it is not possible to report final accuracy levels due to confidentiality, we tested an implementation of this second approach which achieved f-scores as high as 87.5%, 74.0% and 90.4% on high-, medium-and low-risk classes respectively, with a confidence threshold of 0.6. based on cnn methods 7 , it is extensively described in 29 . finally, patient risk assessment can be performed with high classification performance also with advanced dl techniques. in this latter case, however, the methods are perceived as a 'black box" in terms of how they generate the predictions from the input data and the addition of an explanation method is needed for user acceptance 29 . in implementing the first approach, we modeled the retrieval of similar patients on the kg with a sequence of graph operations. the technology was developed on proprietary libraries on sparse linear algebra 16, 17 . the final implementation was extremely efficient and allowed for very fast graph operations. the computation of graph traversals with arbitrary depth for sparse adjacency matrices was of the order of milliseconds (o(ms)) for single graph traversal. high performance was obtained by keeping the kg in memory. the response time for any single query was measured to be well below the four seconds requirement with a single worker, as the system architecture enables scaling, and thus efficient large-scale patient support. the kg was also used for traceability and transparency in the recommendation rationale. the retrieval of similar patients to the users allows to understand why a certain recommendation was given from historical cases. a key requirement for usability and user-friendliness was speed and scalability. patient requests can be spread over the available servers, and speedup from concurrency is linear with the available hardware resources as shown in figure 5 . all patient interactions can be handled on average in less than one second with enough computational resources. clinical testing and validation were fundamental for the certification of the solution. in such a complex system, testing and validation were performed at different levels, encompassing: 1) semi-automated validation of single building blocks (e.g. nlp, ontology, q&a); 2) automated validation of the end-to-end output on a set of clinically validated ground truth cases (automated recommendation testing); (3) validation of the system in real-life and production settings. whenever possible automated testing procedures were streamlined to the execution of the pipeline for the creation of the system, so that they could be run at any update or modification of training corpus or pipeline components. physicians support was fundamental in all testing steps as depicted in the right column of figure 2 . automated recommendation testing was performed by first creating a ground truth set in which patient demographic, symptoms and the corresponding recommendations were known and validated by clinicians. recall, sensitivity, precision and fscore were then calculated by comparing those recommendations with the ones given by the system on the same input. although metric values can not be disclosed, it has to be noted that all had to be above required thresholds (with a special attention to emergency recall) for system release . validation of the system in real life was performed by physicians and other subject matter experts, by evaluating defined kpis on a statistically significant sample during the usage of the tool in different settings. to reduce the time and effort requested to the physicians in these activities, special methods and tools were developed to enable a continuous loop between clinician review and quick implementation. we have presented results, solutions and approaches used to build an interactive, ai-based system for automated medical triage from a large corpus of case records. we have considered various aspects in developing such an endto-end system, from precision on the recommendation, transparency for trust, adoption and end-user friendliness, to the system scalability in terms of number of users served. a key aspect of our research work was the development of a pipeline capable of automatically generating a very rich ontology of medical concepts and a knowledge base, directly from a large corpus of ingested records. this included a highly efficient dl-augmented nlp stage with high precision and recall for the extraction of medical entities and their relations, and a language agnostic implementation of a medical knowledge graph for multilingual applications. a second key aspect was the implementation of reasoning methods on such a knowledge base, comprising a user-friendly, fully data-driven question generation technology and an inference engine for the final recommendation. a third key aspect was that several testing procedures were automated and streamlined to the development activities, for a continuous and consistent feedback implementation. the abstraction and modularity of the underlined solutions are crucial for the reusability of the components in general settings such as automated knowledge ingestion and organisation, development of dialogue systems and decision support applications. providing such automated triage services will help healthcare providers satisfy a larger number of patients and focus their valuable medical resources on telecare eligible patients at the same time. the optimisation of the medical resources will improve patient experience overall. a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia a novel coronavirus from patients with pneumonia in china distributed representations of words and phrases and their compositionality relation classification via convolutional deep neural network convolutional neural networks for sentence classification bidirectional recurrent neural networks long short-term memory finding structure in time learning phrase representations using rnn encoder-decoder for statistical machine translation natural language processing (almost) from scratch ontology learning from text: a survey of methods ontology learning from text: a look back and into the future a reference ontology for biomedical informatics: the foundational model of anatomy semiempirical molecular dynamics (semd) i: midpoint-based parallel sparse matrix-matrix multiplication algorithm for matrices with decay method for performing sparse matrix-matrix multiplication. us 20170147530 a1, united states patent and trademark office a review of relational machine learning for knowledge graphs relevance weighting of search terms aid, an associative interactive dictionary for online searching on term selection for query expansion an information-theoretic approach to automatic query expansion query expansion techniques for information retrieval: a survey. information processing & management deepwalk: online learning of social repreentations line: large-scale information network embedding node2vec: scalable feature learning for networks revisiting semi-supervised learning with graph embeddings patient risk assessment and warning symptom detection using deep attention-based neural networks key: cord-262100-z6uv32a0 authors: wang, yuanyuan; hu, zhishan; feng, yi; wilson, amanda; chen, runsen title: changes in network centrality of psychopathology symptoms between the covid-19 outbreak and after peak date: 2020-09-14 journal: mol psychiatry doi: 10.1038/s41380-020-00881-6 sha: doc_id: 262100 cord_uid: z6uv32a0 the current study investigated the mechanism and changes in psychopathology symptoms throughout the covid-19 outbreak and after peak. two studies were conducted separately in china during outbreak and the after peak stages, with 2540 participants were recruited from february 6 to 16, 2020, and 2543 participants were recruited from april 25 to may 5, 2020. the network models were created to explore the relationship between psychopathology symptoms both within and across anxiety and depression, with anxiety measured by the generalized anxiety disorder-7 and depression measured by the patient health questionnaire-9. symptom network analysis was conducted to evaluate network and bridge centrality, and the network properties were compared between the outbreak and after peak. noticeably, psychomotor symptoms such as impaired motor skills, restlessness, and inability to relax exhibited high centrality during the outbreak, which still relatively high but showed substantial remission during after peak stage (in terms of strength, betweenness, or bridge centrality). meanwhile, symptoms of irritability (strength, betweenness, or bridge centrality) and loss of energy (bridge centrality) played an important role in the network after the peak of the pandemic. this study provides novel insights into the changes in central features during the different covid-19 stages and highlights motor-related symptoms as bridge symptoms, which could activate the connection between anxiety and depression. the results revealed that restrictions on movement were associated with worsen in psychomotor symptoms, indicating that future psychological interventions should target motor-related symptoms as priority. the covid-19 pandemic has caused substantial threats to people's physical health and lives, as well as triggered psychological distresses such as anxiety and depression [1] . unlike previous infections, worldwide mass media reports have highlighted the unique threat of covid-19, increasing people's psychological distress and panic [2] . covid-19 is considered highly contagious and currently there is no targeted medical treatment available, instead reducing exposure to the virus is considered to be the best prevention strategy [2] . however, the negative effects of covid-19 on mental health could be exacerbated by prevention-related measures, such as social distancing and isolation, resulting in a continued fear and panic toward the virus [3] . therefore, timely mental health care has been required during this pandemic [4] . in order to provide the general public with appropriate mental health care, researchers have made an urgent call for guidance and practical evidence to inform the creation of both health and psychological interventions [5] . a number of recent studies have focused on mental health problems during covid-19, with the most frequently reported symptoms being depression and anxiety aspects [1, 6, 7] . a meta-analysis on the mental health within the general population during the covid-19 pandemic reported the prevalence of anxiety to be 31.9% (95% ci: 27.5-36.7) and the prevalence of depression as 33.7% (95% ci: 27.5-40.6) [8] . when understanding mental health problems, co-occurrence becomes a complex and principal issue in regards to treatment adherence and engagement in prevention measures [9] . considerations to better understand co-occurrence during the pandemic are required. depression and anxiety are commonly co-occur at high rates, with a co-occurrence of depression and anxiety resulting in more severe and chronic psychopathology [10, 11] . several theoretical models have been proposed to explain the co-occurrence of anxiety and depression; the diathesis-stress model proposes a simultaneously development of symptoms and left untreated anxiety could increase the risk of depressive disorders and vice versa [12] [13] [14] [15] . however, there is no universal agreement to explain the cooccurrence of anxiety and depression. in order to further investigate the relationship between anxiety and depression, the current study applied network analysis. to interpret the mechanisms of any underlying psychopathology and develop effective interventions, it is essential to characterize the interactions between the two different mental disorders. network models describe mental disorders using an interacting web of symptoms, which can offer new insight into co-occurrence [9, 16] . according to network theory, the symptoms of a mental disorder can lead to development of another disorder; the co-occurrence belongs to a dynamic network of symptoms that cause, sustain, and underlie the symptomology [17, 18] . bridge symptoms can be regarded as the symptoms that connect two mental health disorders, and the activation of the bridge symptoms increase the risk of symptoms transferring from one disorder to another [9] . thus, the identification of bridge symptoms between depression and anxiety could provide meaningful clinical implications to prevent cooccurrence. this could be done through applying targeted and prioritized treatment for bridge symptoms to control and prevent activation that can lead to the co-occurring symptoms between depression and anxiety. during the pandemic, there has been a dramatic decreases in individuals' social activities [2] . considering the preventative measures of quarantine, social distancing, and lockdown, people's mobile-related activities have been largely reduced. it is likely that motor-related symptoms could then be considered bridge symptoms between anxiety and depression. to understand how symptoms change over time, several studies have focused on psychologically related distresses during different covid-19 stages, with a lack of consensus within the studies' results. in a recent longitudinal study on mental health during covid-19, no significant changes in anxiety and depression were found in the general chinese population between the initial outbreak and the after peak period [6] . on the other hand, qiu et al. [1] conducted a national survey among chinese individuals and found that the distress caused by covid-19 decreased significantly over time among the general public. however, the existing studies did not investigate the mechanism and changes in anxiety and depressive symptoms throughout the covid-19 outbreak and the after peak using network analysis. a recently developed symptom network perspective has highlighted the importance of not only measuring whether symptoms have changed but measuring the interactions between individual symptoms [19] [20] [21] . using network analysis may then provide a more in-depth understanding on the dynamic changes between symptoms of depression and anxiety at different points throughout the pandemic. the researchers aimed to assess the interactions between anxiety and depressive symptom over the outbreak and peak of covid-19, and to identify the bridge symptoms (i.e., depressive symptoms with strong associations with anxiety symptoms) using network analysis. considering the covid-19-related prevention measures of social distancing and isolation, we hypothesized that motor-related symptoms would be the bridge symptoms between depression and anxiety. the current survey included a total of 5274 chinese participants who completed a surveyed via "wenjuanxing," a chinese online platform providing functions equivalent to qualtrics. the location was verified by participants' cellphone gps trackers. to avoid duplication of data, each ip address was only granted access once to complete the questionnaire. detailed data collection information, inclusion and exclusion criteria, and demographic information are described in supplementary information. a total of 5083 participants were included in the analysis. specifically, 2540 participants (mean age = 25.28 ± 8.07, education years = 15.93 ± 1.82) were surveyed during the outbreak stage from february 6 to 16, 2020 (fig. 1) . and, 2543 participants (mean age = 22.03 ± 6.30, education years = 15.97 ± 1.26) were surveyed during the after peak stage. the study was approved by the ethics committee of central university of finance and economics and the second xiangya hospital of central south university. the patient health questionnaire-9 (phq-9) depression symptoms were assessed via the nine-item phq-9 [22] . the items of phq-9 and their reference names are listed in table s1 . the scales for the questionnaire are in a four-point likert format where participants evaluate their symptoms on a scale from 0 (not at all) to 3 (nearly every day), with higher scores indicating severe symptoms. the validated chinese version uses a cutoff score of 5 to determine whether a participant had mild depression symptoms, and the same cutoff score was used for this study [22] [23] [24] . the cronbach's alpha was 0.915. anxiety symptoms were assessed using the seven-item gad-7 scale [25] . the items of gad-7 and their reference names are listed in table s1 . the scales consist of a fourpoint likert format, in which participants evaluate their symptoms on a scale from 0 (not at all) to 3 (nearly every day), with higher scores indicating severe symptoms. the validated chinese version uses a cutoff score of 5 to determine whether a participant has at least mild anxiety symptoms, and was also used to determine the cutoff score for this study [23, 26, 27] . the cronbach's alpha was 0.941. the changes of sum scores for depression and anxiety were compared, respectively, between the outbreak and after peak stages using two-tailed independent t-tests, with the significance level set as 0.05. the network analysis was then performed in the aspects of network estimation, network stability, and network differences [28] . in accordance with network parlance, the scores of the items were considered as nodes and the pair-wise correlations between these scores were considered as edges [18, [29] [30] [31] [32] . to estimate the symptom network illustrating the relationship between depression and anxiety symptoms, pair-wise pearson correlations were run and a sparse gaussian graphical model with the graphical lasso was performed to estimate the network [33] . the tuning parameter was decided upon using the extended bayesian information criterium [34] . within this procedure, symptom networks at outbreak and after peak stages were estimated. the r package "bootnet" was utilized to complete this analysis [35] . the network structure was characterized by network centrality indices, this is where each node is placed within a weighted network, i.e., strength, closeness, and betweenness [36, 37] . specifically, strength is the sum of edge weights directly connected to a node, which measures the importance of a symptom in the network. closeness is the inverse of the average shortest path length between a node and other nodes, it measures how close the symptom is linked to other symptoms. betweenness is the number of times that the shortest path between any two nodes passes through another node and measures the importance of the symptom in linking to other symptoms. the "centrality plot" function from "qgraph" package in r was used to complete this analysis [38] . the role of a symptom as a bridge between anxiety and depressive symptoms was also assessed. similar to the network centrality, the bridge centrality, which includes bridge strength, bridge closeness, and bridge betweenness, of each symptom was analyzed. the only difference between network and bridge centrality is that the associated two symptoms, as mentioned above, are from different disorders. the bridge centrality of the nodes measures the importance of a symptom in linking two mental health disorders. the complete this analysis the r package "networktools" [39] was used. after checking the stability of the network structure (see supplementary information), the symptom connections and the network properties, as mentioned above, were compared. the comparison was between the outbreak and the after peak stages to allow for any symptom network changes caused by the pandemic to be quantified. the differences were quantified using permutation tests with 1000 iterations [40, 41] using the r package "network comparison test" [42] . specifically, participants were randomly assigned into two group (within the outbreak group and the same within the after peak group). then the symptom networks were constructed, estimated, and compared using a bootstrap method of resampling by repeating 1000 times to get the null distribution of the network differences under the null hypothesis. the significance level was set as 0.05. in addition, the network differences in both edge and network properties, in global and local level, were compared. the global differences in edge weights were measured by the largest difference in paired edges between two networks. meanwhile, the local edge weight differences were also separately measured. in addition, the global difference in strength was measured by the difference between average strength. finally, the differences in local network properties were also measured separately. the severity of each disorder, between outbreak and after peak stages, was compared. it was found that participants at the after peak stage were more depressed than that at the outbreak stage (phq-9, m after peak = 4.72, m outbreak = 4.17, t 5075.5 = 4.0313, p < 0.001). however, the anxiety disorder scale scores (gad-7) showed no difference between these two stages (m after peak = 3.60, m outbreak = 3.57). using the cutoff score of 5 (at least experiencing mild depression and anxiety symptoms), after the peak stage, 42.94% of the participants showed depression symptoms, which is significantly higher (χ 2 = 24.29, p < 0.001) than that in outbreak stage (36.14%). meanwhile, we found more participants showed anxiety symptoms (χ 2 = 10.57, p = 0.001) after peak (36.41%), compared to the outbreak stage (32.05%). the estimated networks are displayed in fig. 1 . detailed edges weights are listed in tables s2 and s3. the symptom network at outbreak stage showed different patterns regarding the number and thickness of the edges. before characterizing the network properties and quantifying the property differences, the stability of the symptom networks during outbreak and after peak stages was evaluated by using the bootstrap method, results are displayed in figs. s1 and 2. these figures showed that most of the edges and centrality were stable. detailed results are provided in supplementary information. therefore, the network differences between the outbreak and after peak stages reflect solid changes of the psychological interaction patterns that were caused by the pandemic. the network differences in both edge and network properties were compared. no global differences were found between networks from outbreak and after peak stages. globally, according to the permutation test, the maximum difference (diff, contrast: after peak − outbreak, same below) between stages in any of the edge weights from both networks was not significant (the maximum difference in edge was between "afraid" and "inability to relax" symptoms from current networks, diff = −0.16, p = 0.20). meanwhile, the global strength difference between outbreak (global strength = 8.38) and after peak (global strength = 8.24) stages was also found as not significant (p = 0.70). however, local differences were found in multiple edges and nodes. locally, the networks at outbreak and after peak stages differed not only in symptom connections (edge weights), but also in network properties (network and bridge centrality). specifically, for the edge weights, the significant positive and negative correlations were visualized separately in fig. 3 (p < 0.05). at the after peak stage, insomnia symptom from the phq-9 showed stronger connections with impaired motor skills and changes in appetite symptoms from the gad-7 as well as with nervous symptoms from the phq-9. no decreased connections with other symptoms were shown. by contrast, the symptom of inability to relax from the gad-7 showed a decreased connection with symptoms of being afraid, restless, and irritable from the gad-7 and also with suicidal thoughts and guilty symptoms from the phq-9. there were no increased connections with other symptoms shown. it should also be noted that during the after peak stage, compared to the outbreak stage, suicidal thoughts showed a decreased connection with "inability to relax" and "guilty" symptoms, whereas suicidal thoughts showed an increased connection with the "too much worry" symptom. the decreased connection between feeling guilty and suicidal thoughts from the outbreak stage to the after peak stage is also illustrated in fig. s1 , in which the edge weights, no matter if from the current sample or bootstrapped sample, ranked at the top in the outbreak stage and dropped to number nine in the after peak stage. for the network properties, bar plots indicate the network and bridge centrality of each symptom in each stage as displayed in fig. 4 . during the outbreak, psychomotor symptoms such as impaired "motor skills, restless, and inability to relax" exhibited high network betweenness and bridge betweenness. while during the after peak stage, although these symptoms decreased, they were still relatively high when compared with other symptoms. these symptoms might not necessarily exhibit intensive connections with other symptoms. however, they stand between the associated symptoms, which may have played a key role as a mediator that regulated the connections between the symptoms in the network [43] . moreover, besides these symptoms, several other symptoms also showed increased network and bridge centrality during the after peak stage. in specific, using permutation tests, it was found that the "inability to relax" symptom showed a decreased strength at the after peak stage (diff = −0.16, p = 0.03) when compared to the outbreak stage. meanwhile, the "restlessness" symptom exhibited decreased betweenness (diff = −25, p = 0.04) and the "impaired motor sills symptom" showed decreased betweenness (diff = −26, p = 0.01), bridge closeness (diff = −0.021, p = 0.048), and bridge betweenness (diff = −27, p = 0.01). by contrast, the "irritable" symptom showed increased strength (diff = 0.22, p = 0.02), betweenness (diff = 14, p = 0.03), and bridge betweenness (diff = 14, p = 0.02) during the after peak stage, compared to the outbreak stage. meanwhile, the "loss of energy" symptom showed increased bridge closeness (diff = 0.016, p = 0.03) and bridge betweenness (diff = 11, p = 0.02). the novelty of the current study was to evaluate the psychopathological symptom changes between the outbreak fig. 3 edges exhibiting significant differences between outbreak and after peak stages. the green nodes denote the gad-7 items and the orange nodes denote the phq-9 items. meanwhile, the blue edges denote the increased correlations between items at the after peak stage when compared with those in the outbreak stage and the red edges denote the decreased ones. and after peak in china, which have significant implications for other countries that still have not reached their after peak. the current study identified the bridge symptoms and aimed to identify the risks of co-occurrence between anxiety and depressive symptoms during different phrases of covid-19 to prevent increasing psychological distress. the network differences and changes between outbreak and after peak stages showed the impact of the covid-19 pandemic on psychological interaction patterns. the prevalence of anxiety and depression in this study during outbreak was 32.05% and 36.14%, and during after peak phase was 36.41% and 42.94%. similar to the metaanalysis on depression and anxiety during the covid-19, over one-third of the population suffered from anxiety and depressive symptoms [8] . researchers have suggested that the mental health consequences of covid-19 could last over time and that mental health problems could peak later than the actual pandemic [3] . our results were consistent with the prediction and showed that after the covid-19 peak the prevalence of depression and anxiety increased. this could due to the far-reaching influences of covid-19, such as the induced economic uncertainty, the fear of economic crisis and recession, and increased unemployment [44, 45] . these aftereffects could all work toward increasing anxiety and depression after the actual pandemic peak. research has noted that different mental health problems have emerged during the covid-19 outbreak, which mainly included anxiety and depression [46] . previous research has examined the symptoms of anxiety and depression using network analysis in psychiatric patients and found that sad mood and worry were the most central symptoms in the network [28] . in the current study, during the outbreak stage psychomotor symptoms such as impaired motor skills, restlessness, and inability to relax were the most central symptoms in the network. during the after peak stage these symptoms showed a decreased centrality but were still relatively high when compared with other symptoms. in addition, the irritable symptom showed increased centrality during the after peak stage. that is, after the peak time, psychomotor centrality decreased, while the mental health problems were more severe due to the contributions from other non-psychomotor-related aspects. after the pandemic peak time, normal social activities started to resume. this could explain why people's physical-and motor-related activities began to show normality as the psychomotor-related symptoms would be eased. however, the mental health problems caused by the pandemic could have prolonged effects [3] and people might be anxious and depressed from other nonpsychomotor aspects. during the covid-19 period, there was a perceived decrease in physical-related activities [2] , which correspond with the central symptoms identified from the data. compared with the non-symptomatic group, depressed patients presented disturbances in psychomotor symptoms in terms of motor activities, body movement, and motor reaction time [47] [48] [49] . researchers have proposed that psychomotor symptoms may have unique significance in depression, which could explain the psychomotor manifestations and pathophysiologic significance of depression [47] . restless-agitation in anxiety is also related to psychomotor functions, in which the higher level of restlessagitation indicated more severe anxiety [25] . after assessing the interactions between anxiety and depressive symptoms, it was identified that the bridge symptoms during the outbreak also focused on psychomotor symptoms such as impaired motor skills, restlessness, and inability to relax. in particular, the impaired motor skill symptoms showed a significant decrease in bridge centrality during the after peak phase, although it was still relatively high when compared with other symptoms. meanwhile, it was also observed that the inability to relax showed decreased connections with being afraid, restlessness, suicidal thoughts, and feelings of guilt. in addition, during the after peak phase, other bridge symptoms such as irritable and loss of energy emerged, which showed higher bridge centrality than the outbreak stage. in a risky network, the connections among symptoms are tight and strong, and the activation of one symptoms could lead to others, resulting in more severe consequences [28, 30] . during the outbreak and after peak, the occurrence of either impaired motor skills with depression symptoms or restlessness with anxiety symptoms could increase the risk of activation for other mental disorders. this was different from a previous study conducted during the pre-pandemic period. previous network analysis has shown that the association of anxiety and depression can be attributed to the strong connection from anxious worrying to sleep problems and difficulty concentrating [50] . our results also indicated that during the after peak insomnia showed enhanced connections with appetite changes, impaired motor skills, and nervous symptoms. compared to the non-pandemic period, there have been a wide-scale lockdown and restrictions on transportation during the covid-19 pandemic. the beneficial effects of physical health on mental health have been welldocumented in research [51, 52] . covid-19 is having a negative impact on people's physical activity on a global level [53, 54] . recent covid-19 research in psychiatric patients also reported that poor physical health was related with higher levels of anxiety and depression [55] . this could explain why the impaired motor skills aspect and restlessness become the bridge symptoms between anxiety and depression. depression and anxiety are frequently co-occurring mental disorders, and previous research has indicated the likelihood of a causal relationship between these two mood disorders [50] . a cognitive neuroscience study using default model network (dmn) indicated that cortical areas of the dmn showed functional connectivity associated with anxiety and depression [56] . similar to previous studies, the current study cannot confirm the causal relation between anxiety and depression. however, the current network analysis can be utilized in clinical practice during the covid-19 period. a previous study suggested that interventions should focus on depression and anxiety symptoms which are most closely related to other symptoms, since those symptoms should theoretically decrease the associated risk [57] . moreover, symptoms with a high centrality may also have crucial roles in the network [58] . those core symptoms could have important roles in maintaining the psychopathology network and treating those symptoms could help to cure the psychopathology. that is, for treating covid-19-related mood problems, the study results suggest clinical practitioners to focus on the symptoms highlighted by our network analysis. researchers have expressed concern about the consequence of mental disorders resulting from the covid-19 pandemic [59] and mental health professionals have speculated a globe increase of mental disorders due to the impact of covid-19 [60, 61] . who has also mentioned that covid-19 related specific measures, such as self-isolation, quarantine, and social distancing, might increase loneliness and mood-related problems such as anxiety and depression in people [62] . our results showed that during the after peak phase, the impaired motor-skill-related symptoms were still prominent. it is hard to predict the duration of the covid-19 crisis, especially as cities such as leicester, united kingdom [63] are undergoing a second lockdown. it is possible that impaired motor-skill-related symptoms could persistent in people in the second lockdown control zones. during the covid-19 lockdown, physical health professionals have recommended people to stay active with home-based physical activities in order to maintain their health, engaging in activities such as aerobic exercise training and body weight training [53] . a healthy lifestyle and regular exercise are associated with an enhanced immune system [2] , which could help protect people from covid-19-related health problems. this study suggests that health professionals could provide tailored and practical suggestions for the general population by targeting mood symptoms through exercise as a prevention or as a treatment strategy. researchers have proposed to use mindfulness-based stress reduction practices to improve mental health during the covid-19 [64] [65] [66] . in the current literature, mindfulness-based interventions have shown effectiveness in reducing anxiety and depression [67, 68] . there are several limitations to the study that should be acknowledged. first, depression and anxiety were measured by self-reported questionnaires rather than systematic diagnosis. second, this network analysis on depression and anxiety focused specifically on the covid-19 pandemic and cannot be generalized to non-pandemic times. therefore, the central symptoms and bridge symptoms identified in the current study may not applicable during other periods. third, the age of the participants was relatively young. fourth, due to the cross-sectional design, causal relationship could not be established. future longitudinal studies are needed to investigate the causal relationship between anxiety and depression. finally, the study did not measure the changes in physical health and the degree of reduction in physical activities during covid-19. in conclusion, this is the first network analysis focusing on psychopathological symptoms during the covid-19 pandemic, which provides valuable insights to understand the interactions between depression and anxiety. the current findings indicated the central symptoms and bridge symptoms during the covid-19 outbreak and after peak stages in order to provide clinical suggestions for psychological interventions that target reducing the co-occurrence of symptoms between different mental health problems. author contributions rc, yw, zh, and yf designed the study. yf conducted the study. yf, and zh analyzed the data. yw, rc, zh, and aw drafted the paper. all authors read and approved the final paper. conflict of interest the authors declare that they have no conflict of interest. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. a nationwide survey of psychological distress among chinese people in the covid-19 epidemic: implications and policy recommendations using psychoneuroimmunity against covid-19 suicide risk and prevention during the covid-19 pandemic timely mental health care for the 2019 novel coronavirus outbreak is urgently needed medical journals and the 2019-ncov outbreak a longitudinal study on the mental health of general population during the covid-19 epidemic in china immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china prevalence of stress, anxiety, depression among the general population during the covid-19 pandemic: a systematic review and meta-analysis bridge centrality: a network approach to understanding comorbidity depression and generalized anxiety disorder: co-occurrence and longitudinal patterns in elderly patients the comorbidity of major depression and anxiety disorders: recognition and management in primary care pathways to anxiety-depression comorbidity: a longitudinal examination of childhood anxiety disorders the psychology of fear and stress. cambridge: cambridge university press tripartite model of anxiety and depression: psychometric evidence and taxonomic implications comorbidity of anxiety and depression in children and adolescents: 20 years after complex realities require complex theories: refining and extending the network approach to mental disorders what kinds of things are psychiatric disorders network analysis: an integrative approach to the structure of psychopathology psychometric perspectives on diagnostic systems assessment of symptom network density as a prognostic marker of treatment response in adolescent depression a network analysis of dsm-5 posttraumatic stress disorder symptoms and correlates in us military veterans the phq-9: validity of a brief depression severity measure the immediate impact of the 2019 novel coronavirus (covid-19) outbreak on subjective sleep status validity and utility of the patient health questionnaire (phq)-2 and phq-9 for screening and diagnosis of depression in rural chiapas, mexico: a cross-sectional study a brief measure for assessing generalized anxiety disorder: the gad-7 validation of the generalized anxiety disorder-7 (gad-7) and gad-2 in patients with migraine validity of the generalized anxiety disorder-7 scale in an acute psychiatric sample network analysis of depression and anxiety symptom relationships in a psychiatric sample the network structure of schizotypal personality traits association of symptom network structure with the course of depression models and methods in social network analysis the symptom network structure of depressive symptoms in late-life: results from a european population study sparse inverse covariance estimation with the graphical lasso a new method for constructing networks from binary data estimating psychological networks and their accuracy: a tutorial paper node centrality in weighted networks: generalizing degree and shortest paths cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder borsboom d. qgraph: network visualizations of relationships in psychometric data assorted tools for identifying important nodes in networks acute and chronic posttraumatic stress symptoms in the emergence of posttraumatic stress disorder:a network analysis symptoms of posttraumatic stress disorder in a clinical sample of refugees: a network analysis comparing network structures on three aspects: a permutation test the architecture of complex weighted networks covid-induced economic uncertainty the socio-economic implications of the coronavirus pandemic (covid-19): a review problems shared in psychiatry help-line of a teaching hospital in eastern nepal during covid-19 pandemic lockdown psychomotor symptoms of depression psychomotor symptoms in depression: a diagnostic, pathophysiological and therapeutic tool psychomotor disturbance in depression: defining the constructs perceived causal relations between anxiety, posttraumatic stress and depression: extension to moderation, mediation, and network analysis quality of life of women who practice dance: a systematic review protocol vigorous physical activity, mental health, perceived stress, and socializing among college students physical activity and coronavirus disease 2019 (covid-19): specific recommendations for home-based physical training sanchis-gomar f. health risks and potential remedies during prolonged lockdowns for coronavirus disease 2019 (covid-19) do psychiatric patients experience more psychiatric symptoms during covid-19 pandemic and lockdown? a case-control study with service and research implications for immunopsychiatry default mode network dissociation in depressive and anxiety states the core symptoms of bulimia nervosa, anxiety, and depression: a network analysis network destabilization and transition in depression: new methods for studying the dynamics of therapeutic change covid 19 and its mental health consequences changes in network centrality of psychopathology symptoms between the covid-19 outbreak and after peak progression of mental health services during the covid-19 outbreak in china patients with mental health disorders in the covid-19 epidemic leicester lockdown: streets deserted in city an e-mental health intervention to support burdened people in times of the covid-19 pandemic: cope it the benefits of meditation and mindfulness practices during times of crisis such as covid-19 social distancing in covid-19: what are the mental health implications? mindfulness-based stress reduction (mbsr) reduces anxiety, depression, and suicidal ideation in veterans the efficacy of mindfulness-based meditation therapy on anxiety, depression, and spirituality in japanese patients with cancer key: cord-012503-8rv2xof7 authors: levintow, sara n.; pence, brian w.; powers, kimberly a.; sripaipan, teerada; ha, tran viet; chu, viet anh; quan, vu minh; latkin, carl a.; go, vivian f. title: estimating the effect of depression on hiv transmission risk behaviors among people who inject drugs in vietnam: a causal approach date: 2020-08-24 journal: aids behav doi: 10.1007/s10461-020-03007-9 sha: doc_id: 12503 cord_uid: 8rv2xof7 the burden of depression and hiv is high among people who inject drugs (pwid), yet the effect of depression on transmission risk behaviors is not well understood in this population. using causal inference methods, we analyzed data from 455 pwid living with hiv in vietnam 2009–2013. study visits every 6 months over 2 years measured depressive symptoms in the past week and injecting and sexual behaviors in the prior 3 months. severe depressive symptoms (vs. mild/no symptoms) increased injection equipment sharing (risk difference [rd] = 3.9 percentage points, 95% ci −1.7, 9.6) but not condomless sex (rd = −1.8, 95% ci −6.4, 2.8) as reported 6 months later. the cross-sectional association with injection equipment sharing at the same visit (rd = 6.2, 95% ci 1.4, 11.0) was stronger than the longitudinal effect. interventions on depression among pwid may decrease sharing of injection equipment and the corresponding risk of hiv transmission. clinical trial registration clinicaltrials.gov nct01689545. electronic supplementary material: the online version of this article (10.1007/s10461-020-03007-9) contains supplementary material, which is available to authorized users. despite global progress in combating the hiv epidemic, people who inject drugs (pwid) remain disproportionately at risk of hiv infection in southeast and central asia and eastern europe [1] [2] [3] [4] [5] . sharing injection equipment is one of the most efficient means of hiv transmission [6, 7] , and in these regions, pwid have limited access to and suboptimal use of harm reduction services and antiretroviral therapy (art) [8, 9] . the persistence of injection drug use and viremia, without adequate preventive services, results in a high risk of hiv transmission to injecting or sexual partners [10] . the burden of depression is high among pwid and may further interfere with hiv prevention efforts. up to 50% of pwid suffer from severe depressive symptoms [11] [12] [13] [14] [15] , and the presence and severity of depressive symptoms are closely linked to frequency of injection and risk of relapse, suggesting a bidirectional relationship between depression and injection drug use [16] [17] [18] . comorbid depression consistently results in poor hiv treatment outcomes, such as lowering art use and viral suppression [19] [20] [21] [22] [23] [24] . the online version of this article (https ://doi.org/10.1007/s1046 1-020-03007 -9) contains supplementary material, which is available to authorized users. depression may be an important driver of continued hiv transmission among pwid if symptoms increase transmission risk behaviors (e.g., sharing injection drug use equipment, engaging in condomless sex) in the absence of viral suppression. however, while the deleterious effect of depression on hiv treatment outcomes is well established across populations, its effect on the injecting and sexual behaviors that can facilitate hiv transmission or acquisition is not well understood among pwid. although there is substantial evidence that depression increases sexual risk behaviors among men who have sex with men (msm) [25] [26] [27] [28] [29] , few studies have focused on pwid and assessed injecting behaviors. specifically, in vietnam, the focus of this study and a setting where the hiv epidemic is concentrated among men who inject drugs [30, 31] , there have been no prior studies of the relationship of depression with injecting and sexual behaviors. existing studies on depression and hiv transmission risk behaviors among pwid have suffered from several methodological limitations. to our knowledge, all previous studies that include pwid populations have assessed only correlations between depression and transmission risk behaviors, without inferring causality [32] [33] [34] [35] [36] [37] [38] [39] [40] . in these studies, depression and risk behaviors have typically been evaluated for the same time period (e.g., self-report covering the last month), without the ability to infer whether depression preceded risk behaviors or vice versa [35-37, 39, 40] . potential confounders of the relationship between depression and risk behaviors were also measured for the same retrospectively assessed time period. studies that used traditional statistical adjustment for these contemporaneous covariates [34, 38] may have induced bias if these variables acted as causal mediators rather than confounders [41] . in addition, although depression is known to be episodic [42] , prior analyses have primarily relied on a single assessment rather than accounting for changes in both depressive symptoms and time-varying confounders [33, 34, 38, 40] . possibly stemming from these methodological issues, existing evidence for an association between depression and transmission risk behaviors in pwid is inconsistent. while an early meta-analysis (that included studies among pwid) found little evidence for an association between depression and sexual risk behaviors [32] , more recent studies in pwid and msm populations have found higher sexual risk associated with depression [34, 35, 40] or a non-linear association [36] in which mild symptoms are most predictive of sexual risk. the few studies that have evaluated the association of depression with injecting risk behaviors among pwid have suggested that depressive symptoms were associated with greater injecting risk behaviors [35, [37] [38] [39] . we sought to overcome past methodological issues by using a causal approach to estimate the effect of depressive symptoms on hiv transmission risk behaviors among pwid. we used marginal structural models, a tool for causal inference that accounts for time-varying exposures and confounders [43] [44] [45] , with longitudinal data from male pwid living with hiv in vietnam. we hypothesized that depression would increase behaviors associated with risk of hiv transmission to injecting partners (sharing injection equipment) and sexual partners (condomless sex). by examining depression as a potential underlying cause of hiv transmission through these behavioral mechanisms, we sought to provide clearer evidence about the potential for interventions against depression to avert future hiv infections among pwid. we used longitudinal data from a randomized controlled trial of an hiv stigma and risk reduction intervention among pwid living with hiv in thai nguyen, vietnam from 2009 through 2013 [46] . thai nguyen is a province in northeastern vietnam with an estimated hiv prevalence of 34% among its approximately 6000 pwid [47] [48] [49] . participants were recruited via snowball sampling from the 32 thai nguyen sub-districts (of 180 total) with the most pwid. recruiters (former and current pwid) approached members of drug networks in private places to discuss study enrollment and then accompanied or referred interested participants to the study site for screening. at screening, all participants were tested for hiv using two rapid enzyme immunoassay tests run simultaneously (determine: abbot laboratories, abbott park, il and bioline: sd, toronto canada), with discordant results resolved with a third rapid assay (hiv rapid test: acon, san diego, ca). the trial enrolled 455 participants who met the following eligibility criteria: 1) hiv-positive according to study test results, 2) male (given that 97% of pwid in thai nguyen are male), 3) age ≥ 18 years, 4) had sex in the past 6 months, 5) injected drugs in the previous six months, and 6) planned to live in thai nguyen for the next 24 months (the duration of the trial). questionnaire and laboratory data were collected at study visits every 6 months during 24 months of follow-up. the questionnaire collected information on demographics, injection drug use and other substance use, sexual behavior, depressive symptoms, quality of life, pre-study hiv diagnoses (baseline only), and art use. blood specimens were collected to confirm hiv infection at baseline and measure cd4 cell count at baseline and over follow-up. the exposure of interest was depressive symptoms over the past week, as assessed by the 20-item center for epidemiologic studies depression scale (ces-d), which has been validated as a reliable measure of depressive symptoms in vietnam [50, 51] . consistent with past work, we defined severe depressive symptoms as ces-d scores ≥ 23, mild depressive symptoms as scores [16] [17] [18] [19] [20] [21] [22] , and no symptoms as scores < 16 [15, [50] [51] [52] . the transmission risk behavior outcomes were any sharing of injection equipment (needles, syringes, solutions, or distilled water) and any condomless sex with a female partner, reported for the prior 3 months. we also descriptively examined the numbers of injection equipment sharing and condomless sex acts in the prior 3 months reported at each visit. questionnaire and laboratory data included potential confounders of the depression-risk behavior relationship. time-fixed covariates, which were reported at baseline and assumed to be stable throughout the study period, were marital status, age, employment status, intervention arm, history of overdose, alcohol use, hiv diagnosis prior to enrollment, and previous art use. employment and alcohol use could, in theory, vary over time, but these variables remained fairly constant in our population, motivating our decision to treat them as time-fixed. time-varying covariates measured at one time point may affect subsequent depression and risk behaviors; they may also be influenced by depression and risk behaviors from a previous time point. thus, time-varying covariates may act as either confounders or mediators, depending on the time point assessed [41, 43] . for this analysis, time-varying covariates were cd4 cell count category (< 200, 200-499, ≥ 500 cells/μl), depressive symptoms at the visit prior to exposure measurement, and transmission risk behaviors at the visit prior to exposure measurement. in the main analysis, we used marginal structural models to estimate the average causal effect of severe depressive symptoms on the risks of any injection equipment sharing or any condomless sex (separately) in the period three to 6 months later, controlling for time-fixed and time-varying confounders. we evaluated each risk behavior outcome (reported with respect to the prior 3-month period) at the next 6-month visit in order to temporally separate it from the exposure of depressive symptoms (hereafter referred to as the "longitudinal effect"). in a second analysis, to facilitate comparison with prior research, we used marginal structural models to estimate the association between depressive symptoms and risk behaviors reported at the same visit, where temporal ordering could not be differentiated ("cross-sectional association"). we repeated both analyses using three levels of depressive symptoms (severe, mild, none) in addition to the binary categorization (severe, not severe). we used inverse probability weighted estimation of marginal structural models [43, 53] . weights were estimated from a propensity score model for the probability of severe depressive symptoms as a function of time-fixed and time-varying confounders. time-fixed confounders had a constant (baseline) value over all visits; time-varying confounders used the value from the visit immediately preceding the visit at which depressive symptoms were assessed. in the main analysis, the propensity score model was estimated using logistic regression to model the probability of severe (vs. mild or no) depressive symptoms. in a second set of analyses, we used ordinal logistic regression to separately model the three levels of depressive symptoms (severe vs. mild vs. none). propensity score model diagnostics assessed positivity for all confounderdefined subsets of the study population. the denominator of the weights was the predicted probability of depressive symptoms from the propensity score model, and weights were stabilized using the marginal probability of depressive symptoms in the numerator. application of the weights to the study population removes the association between depressive symptoms and potential confounding variables included in the propensity score model, permitting estimation of a causal effect under key assumptions [53, 54] (see discussion). in the weighted study population, we estimated the risk difference (rd) for the risk behavior outcomes using generalized estimating equations (binomial regression models with an identity link) to account for repeated observations on participants [55] [56] [57] . for the longitudinal analysis, this weighted rd can be interpreted as the causal effect of depressive symptoms on the risk behavior outcome: that is, the difference in risk of the behavior in the period three to 6 months later if all participants had depressive symptoms compared with the risk if they all did not have depressive symptoms. to account for missing data due to missed study visits, we used multiple imputation by chained equations (mice) [58, 59] , imputing and analyzing 50 datasets. we included participants who were incarcerated or died during the study period in the main analysis up until the start of the 6-month follow-up interval during which incarceration or death occurred, censoring them after their final visit preceding death or incarceration. in sensitivity analyses, we instead used the imputed risk behavior outcome for that 6-month interval (and censored them at the start of the following interval), given the possibility of engaging in unmeasured risk behaviors prior to incarceration or death. for all estimates, our interpretation focuses on the point estimate and confidence interval, rather than statistical significance [60] . analyses were conducted using r version 3.4.3 [61] . this study was approved by the ethical review committees at all participating institutions. written informed consent was obtained from all participants. as required by inclusion criteria, all 455 participants were male, hiv-positive, and reported being sexually active and using injection drugs at baseline. the median age of participants was 35 years (interquartile range [iqr]: 30, 39), and half were married or cohabitating (47%) ( table 1 ). onethird had a high school education (34%), and the majority were employed full-time (69%). most participants were newly hiv-diagnosed at baseline (74%), while 15% had been previously diagnosed and were not taking art, and 11% reported being previously diagnosed and currently using art. the median cd4 cell count was 241 cells/µl (iqr: 126, 370). general health was rated as poor by 30%. nearly half reported injecting heroin daily (45%), 18% had a history of overdose, and 67% reported current alcohol use. participants completed between zero and four follow-up study visits (median = 4, iqr: 2, 4) at 6-month intervals over 24 months, with 87% completing at least one follow-up visit. at baseline, 44% of participants reported severe depressive symptoms (ces-d ≥ 23), 25% had mild symptoms (16 ≤ ces-d ≤ 22), and 30% had no symptoms (ces-d < 16). one quarter of participants reported sex without a condom in the prior 3 months (24%), with a median of 10 condomless sex acts reported for that period (iqr: 5, 20) . most participants reported sharing injection drug use equipment with injecting partners over the past 3 months (73%); these participants reported a median of 21 sharing acts during that period (iqr: 7, 52). after the baseline visit-when all participants received risk reduction counseling and the majority became newly hiv-diagnosed-sharing injection equipment and condomless sex decreased across trial arms (previously reported in [46] ). however, among the 397 participants attending ≥ 1 follow-up visit, 21% reported sharing injection equipment at ≥ 1 visit, and 7% reported condomless sex at ≥ 1 visit. the severity of depressive symptoms varied over time (supplemental fig. 1 ) with 59% of those attending ≥ 1 follow-up visit reporting severe depressive symptoms at least once. the percentage of participants experiencing competing events increased over time, with 8% incarcerated and 23% deceased at 24 months. in our main analysis, we estimated that severe depressive symptoms (compared to no or mild symptoms) increased the risk of sharing injection equipment by 3.9 percentage points (rd = 3.9%, 95% ci −1.7%, 9.6%) and decreased the risk of condomless sex by 1.8 percentage points (rd = −1.8%, 95% ci −6.4%, 2.8%) in the period three to 6 months later (table 2, fig. 1 ). in the crosssectional analyses, the association between severe depressive symptoms and contemporaneous injection equipment sharing (rd = 6.2%, 95% ci 1.4%, 11.0%) was stronger than the estimated longitudinal effect, while the association with condomless sex was attenuated (rd = −0.7%, 95% ci −4.5%, 3.0%). in analyses using three levels of depressive symptoms, there were small decreases in the risk of condomless sex as depressive symptoms increased, although all confidence intervals overlapped substantially ( table 2 , fig. 2 ). for injection equipment sharing, patterns of risk corresponding to the three levels of depressive symptoms differed between the longitudinal effect and the cross-sectional association. in longitudinal analyses, we observed a u-shaped relationship in which the risk of injection equipment sharing in the period three to 6 months later was 12.8% (95% ci 8.1%, 17.6%) among those with no depressive symptoms, 9.2% (95% ci 5.3%, 13.2%) among those with mild symptoms, and 13.8% (95% ci 9.1%, 18.5%) among those with severe symptoms. in contrast, in the cross-sectional analysis, we observed a monotonic increasing relationship in which those with no depressive symptoms had the lowest risk of 8.5% (95% ci 5.3%, 11.8%) while those with mild symptoms had a risk of 15.5% (95% ci 11.1%, 20.0%) and those with severe symptoms had a risk of 17.4% (95% ci 13.1%, 21.8%). we did not find appreciable differences in sensitivity analyses that varied censoring time for participants who were incarcerated or deceased (supplemental fig. 2 ). using longitudinal data and methods for causal inference, we found that severe depressive symptoms increased the risk of sharing injection equipment but not the risk of condomless sex among pwid. to overcome past methodological issues, we used marginal structural models to capture the episodic nature of depression, enforce temporal ordering of depression and transmission risk behaviors, and control time-varying confounding in the analysis. by focusing on pwid living with hiv in vietnam, a population at high risk of ongoing hiv transmission, we aimed to better understand depression as an underlying cause of behaviors associated with transmission. in our main analysis of injection equipment sharing in the period three to 6 months after assessment of depression, we found a rd of 3.9% (95% ci −1.7%, 9.6%), comparing participants with severe depressive symptoms to those with mild or no depressive symptoms. this longitudinal effect was only slightly weaker than the corresponding cross-sectional association (rd = 6.2%, 95% ci 1.4%, 11.0%) found in the analysis that did not enforce temporality. the 95% ci of the longitudinal effect (−1.7%, 9.6%) shows that a risk difference ranging from a 1.7 percentage point decrease, a small negative association, to a 9.6 percentage point increase, a substantial positive association, is compatible with the data. given that the overall risk of injection equipment sharing was 10% across follow-up visits, the point estimate of a 3.9% point increase is substantively meaningful. previous research has suggested a possible non-linear relationship between the severity of depressive symptoms and occurrence of sexual risk behaviors, although this literature has focused on msm, not pwid, and findings have been mixed. some studies have found that mild depressive symptoms are associated with higher levels of sexual risk behavior but decreasing risk with severe depressive symptoms [25, 36] ; others have observed increasing risk with increasing severity of depressive symptoms [26] [27] [28] . in contrast, our analysis of condomless sex according to three levels of depressive symptoms suggested slight decreases in condomless sex with increasing severity of depressive symptoms, consistent with our main analysis. participants with depressive symptoms -regardless of severity -may be experiencing fatigue, social isolation, and loss of interest in sex, thereby reducing the risk of engaging in this behavior [62] . although all participants reported sex in the 6 months prior to baseline (due to trial eligibility criteria), a loss of interest in sex over 24 months of follow-up, particularly among participants with depressive symptoms, may have contributed to our findings. in contrast to condomless sex, we observed possible nonlinearities in the relationship between depressive symptom severity and risk of sharing injection equipment, which have not been observed previously. prior studies have found an increasing risk of injecting risk behavior with increasing depressive symptom severity [38] or have not differentiated between mild and severe symptoms [35, 37, 39] . we found monotonically increasing risk with increasing depressive symptoms in our cross-sectional analysis, and a u-shaped risk in our longitudinal analysis, where those with mild depressive symptoms had the lowest risk. interestingly, the u-shaped relationship we observed for longitudinal injecting risk is the inverse of some previous findings on sexual risk among msm (where those with mild depressive symptoms had the highest risk) [36] . this may be due to mild depressive symptoms manifesting differently for injecting behavior compared to sexual behavior and inherent differences between pwid and msm populations. depressive symptoms could lead to cognitive distortions, maladaptive coping, and loss of risk aversion [63] [64] [65] , and such symptoms may need to become severe in order to be expressed behaviorally as increased frequency of injection drug use (to treat severe symptoms) and consequently, greater sharing of equipment. although various relationships between depression and hiv transmission risk behaviors have been studied previously, the unique contributions of this study are its focus on pwid living with hiv, a population for whom there is limited data on depression and risk behaviors, and its methodological rigor in inferring causality rather than correlation. our modeling approach controlled time-varying confounding and incorporated the episodic nature of depressive symptoms by using longitudinal data from five study visits over 2 years. given that the longitudinal effect enforced temporal ordering of depressive symptoms prior to risk behaviors, we believe that it more closely reflects the causal effect than does the cross-sectional association. however, it is important to consider the trade-off between temporal ordering and etiologic relevance in the context of data limitations particular to this study. separating the measurement of depressive symptoms and risk behaviors by 6 months (with a 3-month "blackout period" in between) was necessitated by the parent trial's data structure. this incomplete interval coverage could have attenuated effect estimates relative to what they might have been if the entire interval were included (that is, if depressive symptoms were more likely to influence risk behaviors in the first 3 months of the follow-up interval). a shorter time interval with more complete data coverage may allow better capture of the effect of episodic depressive symptoms on subsequent risk behavior. inferring causality relies on several key assumptions, which must be evaluated carefully in light of the limitations of this observational study [53, 54] . the assumption of no unmeasured confounding holds that there are no systematic differences between participants with and without depression beyond any differences in variables controlled for in the analysis. although we controlled for a variety of confounders, it is possible that unmeasured confounding biased estimates of the effect of depression on risk behaviors. we also assumed positivity (i.e., participants with and without depressive symptoms were in all confounder-defined subsets of the population) and that models were correctly specified without measurement error for covariates. importantly, this study's ascertainment of depression relied on ces-d score categories, and the ces-d is not diagnostic of clinical depression. however, we used a conservative cut-point for severe depressive symptoms with high reliability and validity [50, 51] . there may also have been under-ascertainment of risk behaviors due to social desirability and recall bias. however, participants reported high levels of drug use and had been recruited by former drug users (aware of their injection drug use), indicating a willingness to disclose sensitive behaviors. finally, the consistency assumption holds that there is no meaningful variability in treatment relevant to its effect on the outcome. here, we did not model a specific treatment on depression, and results should only be interpreted as the hypothetical effect of eliminating severe depressive symptoms without specifying the treatment used for elimination. our conclusions are specific to this study population, which was not randomly sampled and may not be representative of all pwid living with hiv. while men who inject drugs drive the hiv epidemic in vietnam, our findings may not be applicable to other groups, such as women or pwid in other regions. however, our findings may be broadly generalizable to other asian and european countries where the hiv epidemic is concentrated among similar groups. we also note that the sample size of this hard-to-reach population was relatively small, which limited our statistical power to detect small differences in risk between depression groups. importantly, the risk behavior outcome in our study does not allow direct prediction of forward hiv transmission risk, as we did not take into account viral suppression status, the frequency of risk acts, or partner susceptibility to hiv. these determinants of transmission will be incorporated into a future mathematical modeling analysis that will explicitly estimate forward transmission events from this study population. we found that severe depressive symptoms may perpetuate the risk of sharing injection equipment among pwid living with hiv in vietnam. during the study period (2009) (2010) (2011) (2012) (2013) , there was very limited access to mental health services for people living with depression in vietnam [66] . however, in recent years, mental health services have become a national health priority, and there is growing attention and funding for increasing local services and availability of depression treatment [66, 67] . screening and treating depressive symptoms among pwid presents an opportunity not only to improve mental health and drug abuse outcomes but also to reduce behaviors associated with hiv transmission risk. funding doctoral training support for sara n. levintow was provided by nida (r36 da045569), niaid (t32 ai070114-10), and viiv healthcare (pre-doctoral fellowship). the parent trial for this study was funded by nida (r01 da022962-01). the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. this content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health. conflicts of interest none. ethical approval this research was approved by the ethical review committees at the thai nguyen center for preventive medicine, the johns hopkins bloomberg school of public health, and the university of north carolina at chapel hill gillings school of global public health. all procedures performed were in accordance with the 1964 helsinki declaration and its later amendments or comparable ethical standards. informed consent written informed consent was obtained from all participants. global epidemiology of injecting drug use and hiv among people who inject drugs: a systematic review hiv prevention, treatment, and care services for people who inject drugs: a systematic review of global, regional, and national coverage the global hiv epidemics among people who inject drugs the hiv epidemic in eastern europe and central asia drug use as a driver of hiv risks estimating per-act hiv transmission risk a probability model for estimating the force of transmission of hiv infection and its application scaling up hiv prevention efforts targeting people who inject drugs in central asia: a review of key challenges and ways forward global, regional, and country-level coverage of interventions to prevent and manage hiv and hepatitis c among people who inject drugs: a systematic review the perfect storm: incarceration and the high-risk environment perpetuating transmission of hiv, hepatitis c virus, and tuberculosis in eastern europe and central asia prevalence of depressive symptoms and associated factors among people who inject drugs in china factors associated with symptoms of depression among injection drug users receiving antiretroviral treatment in indonesia depression and clinical progression in hiv-infected drug users treated with highly active antiretroviral therapy frequency of and risk factors for depression among participants in the swiss hiv cohort study (shcs) prevalence and predictors of depressive symptoms among hiv-positive men who inject drugs in vietnam longitudinal predictors of depressive symptoms among low income injection drug users depression as an antecedent of frequency of intravenous drug use in an urban, nontreatment sample depression severity and drug injection hiv risk behaviors interrelation between psychiatric disorders and the prevention and treatment of hiv infection psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the united states role of depression, stress, and trauma in hiv disease progression depression in hiv infected patients: a review psychiatric illness and virologic response in patients initiating highly active antiretroviral therapy mortality under plausible interventions on antiretroviral treatment and depression in hivinfected women: an application of the parametric g-formula risk factors for hiv infection among men who have sex with men depression, compulsive sexual behavior, and sexual risk-taking among urban young gay and bisexual men: the p18 cohort study depression and oral ftc/tdf pre-exposure prophylaxis (prep) among men and transgender women who have sex with men (msm/tgw) depression, substance use and hiv risk in a probability sample of men who have sex with men a pilot study examining depressive symptoms, internet use, and sexual risk behaviour among asian men who have sex with men mortality and hiv transmission among male vietnamese injection drug users regional differences between people who inject drugs in an hiv prevention trial integrating treatment and prevention (hptn 074): a baseline analysis are negative affective states associated with hiv sexual risk behaviors? a meta-analytic review health psychol correlates of depression among hiv-positive women and men who inject drugs depression and sexual risk behaviours among people who inject drugs: a gender-based analysis people who inject drugs and have mood disorders-a brief assessment of health risk behaviors moderate levels of depression predict sexual transmission risk in hiv-infected msm: a longitudinal analysis of data from six sites involved in a prevention for positives study psychiatric correlates of injection risk behavior among young people who inject drugs association of depression, anxiety, and suicidal ideation with high-risk behaviors among men who inject drugs in delhi intimate relationships and patterns of drug and sexual risk behaviors among people who inject drugs in kazakhstan: a latent class analysis associations of depression and anxiety symptoms with sexual behaviour in women and heterosexual men attending sexual health clinics: a cross-sectional study the control of confounding by intermediate variables measuring depression over time or not? lack of unidimensionality and longitudinal measurement invariance in four common rating scales of depression marginal structural models and causal inference in epidemiology effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models marginal structural models for analyzing causal effects of time-dependent treatments: an application in perinatal epidemiology efficacy of a multi-level intervention to reduce injecting and sexual risk behaviors among hiv-infected people who inject drugs in vietnam: a four-arm randomized controlled trial ministry of health of vietnam. results from the hiv/sti integrated biological and behavioral surveillance (ibbs) in vietnam, round ii socialist republic of viet nam. vietnam aids response progress report 2014, following up the 2011 political declaration on hiv/ aids, reporting period thai nguyen provincial aids center and the division of social evils control and prevention, department of labor a self-report depression scale for research in the general population screening value of the center for epidemiologic studies-depression scale among people living with hiv/aids in ho chi minh city, vietnam: a validation study changes in depressive symptoms and correlates in hiv people at an hoa clinic in ho chi minh city vietnam constructing inverse probability weights for marginal structural models estimating causal effects from epidemiological data the r package geepack for generalized estimating equations estimating equations for association structures yet another package for generalized estimating equations. r-news multiple imputation for nonresponse in surveys mice: multivariate imputation by chained equations in r scientists rise up against statistical significance r: a language and environment for statistical computing depressive symptoms, social support, and personal health behaviors in young men and women sex, drugs and escape: a psychological model of hiv-risk sexual behaviours co-occurrence of treatment nonadherence and continued hiv transmission risk behaviors: implications for positive prevention interventions testing a social-cognitive model of hiv transmission risk behaviors in hiv-infected msm with and without depression mental health in vietnam: burden of disease and availability of services barriers and facilitators to the integration of depression services in primary care in vietnam: a mixed methods study key: cord-032382-5tp9i9vh authors: hackert, volker h.; dukers-muijrers, nicole h. t. m.; hoebe, christian j. p. a. title: signs and symptoms do not predict, but may help rule out acute q fever in favour of other respiratory tract infections, and reduce antibiotics overuse in primary care date: 2020-09-21 journal: bmc infect dis doi: 10.1186/s12879-020-05400-0 sha: doc_id: 32382 cord_uid: 5tp9i9vh background: from early 2009, the dutch region of south limburg experienced a massive outbreak of q fever, overlapping with the influenza a(h1n1)pdm09 pandemic during the second half of the year and affecting approximately 2.9% of a 300,000 population. acute q fever shares clinical features with other respiratory conditions. most symptomatic acute infections are characterized by mild symptoms, or an isolated febrile syndrome. pneumonia was present in a majority of hospitalized patients during the dutch 2007–2010 q fever epidemic. early empiric doxycycline, guided by signs and symptoms and patient history, should not be delayed awaiting laboratory confirmation, as it may shorten disease and prevent progression to focalized persistent q fever. we assessed signs’ and symptoms’ association with acute q fever to guide early empiric treatment in primary care patients. methods: in response to the outbreak, regional primary care physicians and hospital-based medical specialists tested a total of 1218 subjects for q fever. testing activity was bimodal, a first “wave” lasting from march to december 2009, followed by a second “wave” which lasted into 2010 and coincided with peak pandemic influenza activity. we approached all 253 notified acute q fever cases and a random sample of 457 q fever negative individuals for signs and symptoms of disease. using data from 140/229(61.1%) q fever positive and 194/391(49.6%) q fever negative respondents from wave 1, we built symptom-based models predictive of q-fever outcome, validated against subsets of data from wave 1 and wave 2. results: our models had poor to moderate auc scores (0.68 to 0.72%), with low positive (4.6–8.3%), but high negative predictive values (91.7–99.5%). male sex, fever, and pneumonia were strong positive predictors, while cough was a strong negative predictor of acute q fever in these models. conclusion: whereas signs and symptoms of disease do not appear to predict acute q fever, they may help rule it out in favour of other respiratory conditions, prompting a delayed or non-prescribing approach instead of early empiric doxycycline in primary care patients with non-severe presentations. signs and symptoms thus may help reduce the overuse of antibiotics in primary care during and following outbreaks of q fever. from march 2009, south limburg, the southernmost region of the netherlands, experienced a massive outbreak of human q fever related to an abortion storm on a local dairy-goat farm. laboratory-confirmed symptomatic human q-fever cases were first reported in april, peaked in may, and then steadily declined over subsequent months. culling of infected goats took place around the turn of the year. by april 2010, no more new cases were reported to the regional public health service (phs), and the number of notified human cases reported to the regional phs had totalled 253, whereas the number of infections was estimated to run into thousands [1] . a majority of acute q fever infections are understood to be asymptomatic or only mildly symptomatic. symptomatic patients usually present with a febrile syndrome or flu-like illness frequently said to be associated with myalgia and headache. during the dutch q fever epidemic, which lasted from 2007 to 2010, pneumonia was present in as many as 86% of hospitalized patients. although most cases of acute q fever are self-limiting, early antibiotic treatment with doxycycline within the first days of symptoms may shorten duration of disease, and may prevent progression to persistent focalized infection, commonly referred to as chronic q fever, in cases with underlying risk factors, including vascular and valvular anomalies [2, 3] . in patients with known valvular heart disease, combining doxycycline with hydroxychloroquine has been shown to prevent progression to q fever endocarditis [4, 5] . definitive diagnosis usually relies on laboratory testing. while polymerase chain reaction (pcr) may provide timely outcomes, serological assays still are the mainstay of laboratory testing, resulting in diagnostic delay and foregone or inappropriate treatment [2] . during the dutch epidemic of q fever, general practitioners (gp's) with experience in treating q fever patients tended to start empiric antibiotic therapy ahead of laboratory confirmation, which had a median delay of 20 days from onset of illness in 2009 [6, 7] . while doxycycline was the most commonly prescribed initial antibiotic, a substantial proportion of subjects were treated with a penicillin, which is considered to be ineffective in q fever [8] . a complicating factor in the diagnostic workup of cases was the influenza a(h1n1)pdm09 pandemic which overlapped with the regional outbreak for several months during the second half of the year. several studies have assessed the diagnostic potential of signs and symptoms in respiratory disease, including influenza and q fever [9] [10] [11] [12] . however, evidence regarding the predictive usefulness of signs and symptoms in patients with suspected q fever is scarce, and has been limited to hospital settings. a dutch study performed during the 2007-2010 q fever epidemic in the netherlands, for example, found that signs and symptoms did not differentiate between acute q fever and other respiratory infections in hospitalized patients [13] . however, it is the primary care setting where signs and symptoms of disease are essential in the initial diagnostic workup and in guiding early clinical decision-making. our study, which used data from a cohort of subjects a majority of whom were tested by general practitioners, aimed to assess whether signs and symptoms could support decision-making in primary care. specifically, we assessed whether signs and symptoms could accurately identify acute q fever in suspect cases prior to laboratory confirmation, or help rule out the diagnosis in favour of other respiratory infections where, depending on national guidelines, treatment with amoxicillin as a first-line antibiotic or a delayed or non-prescribing approach would be considered more appropriate. the study area was the catchment area of one of the largest dutch general hospitals, located in south limburg, netherlands (346 km 2 , 12 municipalities, 308,000 inhabitants). in march 2009, the regional food and consumer product safety authority notified the south limburg phs of a large dairy-goat farm where 220 out of 450 pregnant goats had aborted due to laboratory-confirmed q fever. the study period was defined by the time of veterinary notification (march 2009) and the time when the outbreak source had been eliminated through culling of infected goats and vaccination of remaining goat populations, and new community cases were no longer reported (april 2010). we performed a retrospective case-control study assessing the association of acute q fever case status with signs and symptoms of disease in a sample of questionnaire respondents from the cohort of all individuals tested for acute q fever by gp's or hospital-based medical specialists in the period from march 2009 through april 2010 (n = 1218). medical specialists requesting tests were from a variety of fields, including internal medicine, infectious disease, or respiratory medicine. all notifiable community cases (n = 253) were reported to the regional phs by the affiliated regional testing laboratory. disease onset in community cases was physicianreported. the testing laboratory also provided data on all 965 non-notifiable q fever negative individuals tested in the study period, including date of birth, gender, zip code as a proxy for residential address, name and address of gp, testing dates, and testing results. promptly following notification, all notified community cases were approached with a questionnaire assessing the presence or absence of individual presenting signs and symptoms of disease preceding testing, underlying medical conditions, and risk exposure activities, among others. response in this group was 64.4%(163/253). among the 965 subjects who had tested negative (non-notifiable controls), a random selection of 457 individuals were approached with the same questionnaire via their gp's (response: 67.2%(307/457)). the entire cohort of subjects was tested for igg-and igmtype antibodies to phase-i and phase-ii c. burnetii antigen by serion elisa classic, according to manufacturer's instructions (serion elisa classic, institut virion\serion gmbh, würzburg, germany). elisa-positive specimens were subjected to confirmation by indirect immunofluorescent antibody assay (ifa) (c. burnetii ifa igm/igg test kit, fuller laboratories, fullerton, california). pcr was routinely performed on all elisa-negative samples. the presence of phase-ii igm antibodies to c. burnetii (absorbance > 10% above extinction of the cut-off control) in a single serum sample, confirmed by ifa, or the presence of c. burnetii dna in pcr (cycle threshold ≤36) was considered diagnostic of acute q fever [14] [15] [16] . overall, 20.8% (253/1218) of all patients tested were confirmed with a diagnosis of acute q fever by serology or pcr. testing activity followed a bimodal distribution over time. a larger first testing wave from march to december 2009 (wave 1) was followed by a second smaller one from december 2009 through april 2010 (wave 2) (fig. 1) . the larger first wave, including subjects tested from week 13 (march 2009) until week 49 (december 2009), contained 72% of all tested patients, with a q fever positive rate of 26%, thus yielding 91% of all notifiable patients with a laboratory-confirmed diagnosis of acute q fever in the study period. by contrast, the second wave, although it counted more than a quarter of all tested patients, had a positive rate of only 7% and identified just 9% of all notified patients. characteristics of tested subjects are summarized in table 1 . statistical analyses were performed using spss statistics 21.0 (ibm corporation, new york, usa). for derivation and validation of our symptom-based prediction, we fig. 1 weekly counts of all individuals tested for q-fever by south limburg gp's and hospital-based medical specialists (n = 1218), along with weekly counts of notified q-fever cases (by gp-reported week of disease onset, n = 253) used questionnaire data from all adult questionnaire recipients with a complete questionnaire response tested during wave 1, i.e., all questionnaire recipients from the age of 20 years who had been tested in the weeks before week 49 and had answered all questions about presenting signs and symptoms of disease which preceded testing. of all 873 patients tested during wave 1, 620 (71.0%) had received the questionnaire, with response from 341 questionnaire recipients (response rate 55.0%), and a complete response from 334 recipients (complete response rate 53.9%). children and adolescents under the age of 20 were excluded since the association of signs and symptoms with q fever in this age group are known to be less clear-cut than in adults [17, 18] . a holdout sample of all subjects tested during wave 2 (i.e., the immediate post-outbreak phase) with a complete questionnaire response was used for additional validation of the models derived from our wave 1 data. of all 345 patients tested during wave 2, 119 (34.5%) had received the questionnaire, with response from 113 questionnaire recipients (response rate 95.0%), and complete response from 109 recipients (complete response rate 91.6%). characteristics of questionnaire respondents are summarized in table 2 . we first assessed association of q fever status with sex, age, smoking habits, test ordered by gp versus (hospital-based) medical specialist, and presence or absence of individual presenting signs and symptoms of disease in all 334 complete questionnaire respondents tested during wave 1, using univariable logistic regression. for a full list of signs and symptoms assessed by our questionnaire refer to table 3 . as a next step, we assessed associations with q fever status, entering the full set of variables into stepwise backward multivariable logistic regression, a procedure that eliminates statistically non-significant variables along the way. variables that were statistically significantly (p < 0.10) associated with q fever outcome in univariable or multivariable regression were selected for inclusion in our prediction models (refer to next paragraph). sex, age, active smoking habits, and test ordered by gp versus medical specialist were selected as potential predictors regardless of their association with outcome in univariable or multivariable regression in the steps described above. distance of residential address from the outbreak farm was not included as a candidate predictor, since this information would usually be unavailable to physicians at the time when patients present to their office, or may be unknown altogether in situations where no outbreak source has (yet) been identified. the entire dataset of 334 complete questionnaire respondents tested during wave 1 was randomly split into four subsets, each including roughly 25% of respondents. one subset was set aside for validation (henceforth referred to as the validation subset), while data of the remaining three subsets combined (including roughly 75% of the 334 respondents, henceforth referred to as the prediction subset) were used for derivation of our prediction model. to build the prediction model, we used the prediction subset, entering all variables selected according to the procedure described in the previous paragraph into backward stepwise logistic regression. coefficients obtained from the variables that were statistically significantly associated with q fever outcome (p < 0.10) were used to calculate a sum score. predictive performance of the model was then assessed by applying the score to the validation subset to determine area under the curve (auc) of the receiver operator curve (roc), sensitivity and specificity (based on cut-points specific to the model, calculated according to the youden index), and the model's positive (ppv) and negative predictive value (npv) (based on an estimated regional seroprevalence of 2.9%, derived from comparison of two regional population samples, one pre-outbreak dating from 2008, and the second one post-outbreak dating from 2010) [1, 19] . for additional validation, the same score was applied to the immediate post-outbreak holdout sample from wave 2, again using auc to assess predictive performance of the model. the entire process was repeated for the remaining three subsets, resulting in four prediction models, each applied once to its specific validation subset from wave 1, and once to the holdout sample from wave 2. finally, we compared models in terms of their auc's of the roc, assessing statistical differences between auc's using a bivariate approach [20, 21] . uni-and multivariable associations of acute q fever outcome with potential predictors univariable associations of q fever status with sex, age, smoking habits, test ordered by gp versus (hospital-based) medical specialist, and presence or absence of individual presenting signs and symptoms of disease in all 334 complete questionnaire respondents (q fever positive n = 140, q fever negative n = 194) tested during wave 1, based on univariable logistic regression, are summarized in table 3 . statistically significant multivariable associations for the same set of 334 complete questionnaire respondents are summarized in table 4 , eliminating non-significant associations through backward stepwise logistic regression. prediction models derived from the four prediction subsets (model 1 through 4) table 5 shows sets of statistically significant predictors, referred to as model 1 through 4, derived from backward stepwise logistic regression for the four prediction subsets including roughly 75% of the 334 respondents each. coefficient, p value, standard error (se), and odds ratio (or) are included for each predictor, in addition to relevant model statistics. predictive performance of model 1 through 4 figure 2 summarizes performance characteristics of the four prediction models, based on each model's coefficient score applied to the corresponding validation subset from wave 1 (left column), and to the holdout sample from wave 2 (right column). auc's ranged from 0.671 to 0.784 from least to best performing model, generally considered to be poor to moderate in terms of predictive accuracy. sensitivity of the models ranged between 55.6 and 92.3%, with specificities between 42.4 and 80.5%, ppv's between 4.6 and 8.3%, and npv's between 91.7 and 99.5%. the difference between model performance in terms of auc was statistically significant between the leastand best-performing model applied to their corresponding validation subsets (model 1 versus model 2, p = 0.02), but not between the least-and best-performing model applied to the holdout sample (model 4 versus model 3, p = 0.73). comparing performance of each model on the validation subset versus the holdout sample (rows in fig. 2 ) showed no statistically significant differences either. given the poor to moderate performance of our prediction models, our study suggests that signs and symptoms of disease do not accurately predict acute human q fever in gp patients, confirming findings from a dutch study in hospitalized patients [13] . however, signs and symptoms may be useful in ruling out acute q fever in favour of other acute lower respiratory tract infections. this is especially relevant in cases where pneumonia is not suspected and a non-prescribing or delayed prescribing approach would seem more appropriate, helping reduce the overuse of antibiotics. in the cohort of patients tested in our region, this would have been particularly relevant in the immediate post-outbreak phase where the number of tests for acute human q fever remained high but the proportion of seropositive cases was very low (7%), and prevalence of pneumonia was also low (12%). even during the outbreak phase, only 26.2% of tested individuals were q fever positive, and ruling out acute q fever by symptoms would likely have contributed to a reduction in antibiotic overuse. male sex, fever, and pneumonia were positive predictors of acute q fever across all four of our models, in accordance with other studies [2, 22] . cough was a negative predictor in three models, suggesting that cough as a symptom may be useful in ruling out q fever in suspected cases. cough is considered a common symptom in upper respiratory tract infections. its presence, according to our findings, may point to respiratory conditions other than q fever [23] . specifically, cough has been described as a symptom suggestive of influenza, rather than, for example, common cold [9] . overall, in our sample cough was the most prevalent symptomsecond only to flu-like illnessin questionnaire respondents from the second wave, both in q fever positive and q fever negative subjects. this, combined with the low rate of q fever positive findings during the second wave, may suggest that the rise in q fever testing activity by gp's and medical specialists during the second half of 2009 and the early months of 2010 mayat least to some degreehave resulted from patients presenting with respiratory symptoms due to increasing pandemic influenza a(h1n1)pdm09 activity in that period. moreover, due to long persistence of anti-coxiella phase ii igm following infection, some of the subjects who tested positive during the second wave may have been misclassified as acute q fever. while abdominal pain was a negative predictor of acute q fever across all four models, gastrointestinal symptoms such as abdominal pain and diarrhoea were much less prevalent than cough in both q fever positive and q fever negative subjects from both waves, and the nature of the observed negative association of abdominal pain with q fever remains unclear. studies on the gastrointestinal symptoms in patients with influenza report prevalence rates ranging from 0.6 to 6.6% for influenza a(h1n1) infections, and 9.8 to 57.5% for influenza a(h1n1)pdm09 infections, suggesting a possible association of gastrointestinal symptoms in our study with the 2009 swine flu [24] . use of signs and symptoms of disease to rule out acute q fever would be most appropriate in patients with nonsevere lower respiratory tract infections, i.e., in cases where pneumonia is not suspected clinically. in such cases, use of antibiotics has been shown to provide little benefit in primary care, both overall and in patients aged 60 years and above, but may cause slight harms [25, 26] . nevertheless, inappropriate use of antibiotics remains common in this population, as a study performed in 14, 987 outpatients was recently able to show [27] . in a subgroup of 3306 patients with laboratory-confirmed influenza, in whom no pneumonia had been diagnosed, 945 (29%) were prescribed an antibiotic. given the low yield of q fever positives in wave 2 of our study, we assume that q fever testing during wave 2 was in large part instigated by patients presenting with unspecific, but most likely influenza-related, symptoms. although we have no data on rates of antibiotic prescriptions in this group, the percentage of subjects receiving inappropriate empiric doxycycline or other antibiotics may have been even higher than in aforementioned study. therefore, under circumstances where outbreaks of q fever overlap with other respiratory conditions, symptom-based prediction may deliver the greatest gain in terms of reducing antibiotic overuse. in cases with clinical suspicion of pneumonia, however, the benefit of antibiotics would outweigh potential harms. for instance, several national guidelines recommend doxycycline as a second or first line drug for empiric treatment of community-acquired pneumonia (cap), where it is generally considered to be safe and effective [28] [29] [30] [31] [32] . in cases of lower respiratory tract infections where acute q fever is included in the differential diagnosis and pneumonia is suspected, use of doxycycline would thus seem an appropriate choice in an outpatient setting. the combination of doxycycline and hydroxychloroquine should be considered in patients with known valvular heart disease to prevent evolution to q fever endocarditis (but is not recommended in patients with increased risk of acute q fever endocarditis as revealed by high igg anticardiolipin levels included in routine testing in some countries) [4, 5, 33] . local antimicrobial resistance patterns are an important consideration in the choice of empirical treatment. while doxycycline is generally considered to be highly effective against atypical pathogens, including c. burnetii, doxycycline resistance is becoming more common in streptococcus pneumoniae, particularly in isolates with reduced penicillin susceptibility. although overall frequency of doxycycline resistance in s. pneumoniae in 2004 was 24%, rates vary widely geographically and over time, ranging from 2% to more than 20%, and more than 60% in penicillin-resistant strains, potentially limiting the use of doxycycline for more severe pneumococcal infections [34] [35] [36] [37] . in our study, the prevalence of pneumonia in subjects tested during wave 1 was 23% overall, but 36% in q fever positive subjects, which is higher than the 27% rate found in q fever positive patients from a large 26-year cohort of patients with q fever from the french national reference center for q fever [38] . nevertheless, a huge majority of patients in our study had no suspicion of pneumonia and would have had potential benefit from symptom-based exclusion of q fever. predictive values are greatly impacted by prevalence of the disease in the base population. positive predictive values (ppv) tend to be low in situations where prevalence in the base population is low, as was the case in our study, where post-outbreak seroprevalence of prior exposure to c. burnetii in the base population was estimated a mere 2.9% [1] . with ppv ranging between 4.6 and 8.3%, mirrored by low areas under the receiver (see figure on previous page.) fig. 2 predictive performance of the four prediction models tested on their corresponding validation subsets from wave 1 (left column) and the holdout sample from wave 2 (right column). (legend). 1 at cut-point calculated according to youden index 2 based on cut-point calculated according to youden index and an estimated regional prevalence of 2.9% operator curves, our models had no use as a diagnostic tool for acute q fever. conversely, negative predictive values (npv) tend to be high under circumstances of low disease prevalence. with npv ranging between 91.7 to 99.5%, our models were able to rule out the presence of acute q fever with a relatively high degree of confidence. nevertheless, decisions favouring a delayed or non-prescribing approach should ideally be corroborated by information from patient history, including self-reported exposures to farms, farm animals and farm animal products, and other clinical findings supporting such approach. in other contexts, for example in a well-circumscribed population of patients with high-risk exposure to a known source, prevalence may be (much) higher, with resulting decline in npv. to the best of our knowledge, ours is the first study to use post-outbreak data to validate prediction models for acute q fever derived from outbreak data, thus enhancing the generalisability and robustness of our findings. moreover, our study is first to assess the predictive potential of signs and symptoms for the diagnosis of acute q fever in a large population of subjects most of whom were primary care patients. other studies attempting to predict q fever by signs and symptoms, including a retrospective case-control study from the netherlands, were performed in hospital settings. the dutch study reported that clinical signs and symptoms were not helpful in differentiating adult hospital-referred patients with acute q fever from a hospital-referred control group [13] . a second study aimed to predict q fever in patients presenting with community-acquired pneumonia to the hospital. the only symptom independently associated with q fever in this study was headache. the prognostic score derived from multivariable logistic regression included male sex, age 30-60 years, a low leukocyte count and a high c-reactive protein (crp) level, along with headache, as predictors of q fever pneumonia [12] . a third study attempted to predict acute q fever in febrile patients from rural kenya, based on parameters including a range of clinical signs and symptoms. the study identified acute lower respiratory infection, abdominal pain, diarrhoea and a history of fever lasting > 14 days as independent significant positive predictors of acute q fever. a prediction score derived from a modelling approach similar to ours was reported to reliably identify acute q fever in febrile patients with undifferentiated illness [11] . our study had a number of limitations. selection of subjects for inclusion in our study was based on laboratory q fever testing outcomes rather than random sampling, with a potential for selection bias, e.g., due to variations in diagnostic strategies between individual physicians. laboratory confirmed cases of acute q fever and patients who were q fever negative were both selected based on signs and symptoms leading to addition of q fever in the differential diagnosis, possibly resulting in some weakening of the association under study. our laboratory data were strictly limited to outcomes of q fever testing, precluding us from assessing signs and symptoms in relation to possible alternative outcomes. as mentioned above, misclassification of positive laboratory results as acute q fever infection cannot be entirely ruled out, since phase-ii igm antibodies to c. burnetii, which at the time of the outbreak were considered to be reliable markers of acute q fever infection, have been shown to persist for longer periods in individual patients, thus complicating the differentiation between past q fever infections and acute respiratory infections with different aetiologies [39] . validation and testing of our models were performed on samples from the same base population, potentially compromising generalisability of our findings. the lack of external validation of our models, however, may have partly been offset by the fact that we performed validation against a holdout sample, i.e., data from the second wave of q fever testing. testing during the second wave took place in what may be described as an immediate post-outbreak transition period where q fever was increasingly replaced by other aetiologies of clinical respiratory disease, thus distinguishing the population of individuals tested during the second wave from those included in the first wave. splitting our first-wave dataset for internal validation may have resulted in loss of power, and may have contributed to discrepancies between our four models in terms of predictors included in each model. nevertheless, all four models showed poor to moderate performance in terms of auc, but performed equally well in terms of their negative predictive value, suggesting that signs and symptoms of disease may be useful for symptom-based exclusion of acute q fever. whereas the youden index is a commonly used method for cut-point selection in roc analysis, there are several other approaches, whose application may have led to different results [40] . our study suggests that signs and symptoms of disease, considered in combination with age, sex and active smoking habits, do not accurately predict q fever. however, presence of cough and gastrointestinal symptoms may point to different, possibly viral respiratory aetiologies, and help rule out acute fever in the absence suspected pneumonia and fever. in these cases, physicians in primary care may favour a delayed or non-prescribing approach if no known risk factors for progression to persistent focalized (or chronic) q fever (e.g., heart valve or vascular anomalies) are present. a history of exposure to farms, single-point source outbreak with high attack rates and massive numbers of undetected infections across an entire region from q fever to coxiella burnetii infection: a paradigm change identification of risk factors for chronic q fever, the netherlands risks factors and prevention of q fever endocarditis evolution from acute q fever to endocarditis is associated with underlying valvulopathy and age and can be prevented by prolonged antibiotic treatment general practitioners aware of q-fever three years of q fever in the netherlands: faster diagnosis antibiotic therapy for acute q fever in the netherlands in 2007 and 2008 and its relation to hospitalization clinical signs and symptoms predicting influenza infection symptomatic predictors of influenza virus positivity in children during the influenza season febrile patients admitted to remote hospitals in northeastern kenya: seroprevalence, risk factors and a clinical prediction tool for q-fever q fever pneumonia in french guiana: prevalence, risk factors, and prognostic score differentiation of acute q fever from other infections in patients presenting to hospitals, the netherlands evaluation of a diagnostic algorithm for acute q fever in an outbreak setting real-time pcr with serum samples is indispensable for early diagnosis of acute q fever interlaboratory evaluation of different extraction and real-time pcr methods for detection of coxiella burnetii dna in serum coxiella burnetii infection is lower in children than in adults after community exposure: overlooked cause of infrequent q fever reporting in the young q fever in children index for rating diagnostic tests the meaning and use of the area under a receiver operating characteristic (roc) curve a method of comparing the areas under receiver operating characteristic curves derived from the same cases the use of a geographic information system to identify a dairy goat farm as the most likely source of an urban q-fever outbreak duration of cough in acute upper respiratory tract infections prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? amoxicillin for acute lower respiratory tract infection in primary care: subgroup analysis by bacterial and viral aetiology amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: a 12-country, randomised, placebo-controlled trial outpatient antibiotic prescribing for acute respiratory infections during influenza seasons bts guidelines for the management of community acquired pneumonia in adults: update diagnosis and treatment of adults with community-acquired pneumonia recommendations and guidelines for the treatment of pneumonia in taiwan british thoracic society community acquired pneumonia guideline and the nice pneumonia guideline: how they fit together nice guidelines to family doctors on diagnosis of pneumonia antiphospholipid antibody syndrome with valvular vegetations in acute q fever antimicrobial susceptibility/ resistance of streptococcus pneumoniae distribution of serotypes and patterns of antimicrobial resistance among commensal streptococcus pneumoniae in nine european countries in: mandell, douglas, and bennett's principles and practice of infectious diseases kucers the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs clinical features and complications of coxiella burnetii infections from the french national reference center for q fever evaluation of commonly used serological tests for detection of coxiella burnetii antibodies in well-defined acute and follow-up sera defining an optimal cut-point value in roc analysis: an alternative approach lyophilization to improve the sensitivity of qpcr for bacterial dna detection in serum: the q fever paradigm publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank sander van kuijk, clinical epidemiologist at the department of clinical epidemiology and medical technology assessment at maastricht university / mumc+, for statistical advice, review of our manuscript, and valuable suggestions for improvement. we also thank public health nurses rick boesten, elleke leclercq, and hans frantzen, and communicable disease consultant henriëtte ter waarbeek of phs south limburg for their contribution to data logistics. we wish to thank medical microbiologist frans stals, zuyderland medical centre, for providing laboratory data. farm animals or farm animal products may increase the likelihood of acute q fever. it should be noted that pcr testing, whose sensitivity may be enhanced by lyophilisation, may shorten diagnostic delay and support early decision-making [41] . we recommend further validation of our findings in different larger independent cohorts. authors' contributions vh conceptualised and designed the study, collected, analysed and interpreted the patient data, and wrote the manuscript. nd and ch were major contributors in designing and conceptualising the study, and in writing the manuscript. all authors read and approved the final manuscript. this work was supported by the netherlands organization for health research and development (zonmw) (grant number 50-50405-98-133). the funder had no role in no role in the design of the study and collection, analysis, or interpretation of data nor in writing the manuscript. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. this study was ethically approved by the medical ethics committee of the maastricht university medical centre (number 104034). no administrative permissions were required to access the raw data used in this study. all data were de-identified prior to analysis. not applicable. the authors declare that they have no competing interests.received: 23 march 2020 accepted: 6 september 2020 key: cord-017862-9fkjjmvf authors: smith, roger p. title: respiratory disorders date: 2007 journal: primary care in obstetrics and gynecology doi: 10.1007/978-0-387-32328-2_19 sha: doc_id: 17862 cord_uid: 9fkjjmvf like it or not, patients with respiratory complaints are a part of our practice. the common cold is often referred to as the most frequent illness occurring in humans: over 40% of americans suffer from a “cold” each year, accounting for more lost productivity than any other illness. pharyngitis affects almost 30 million patients annually, with over 10% of all school-aged children seeking medical care each year. seventeen million patients a year are diagnosed with asthma, with more females than males among adult-onset patients. whether it is the reason for our patient’s visit or an incidental complaint, we are involved with the diagnosis and management of these problems. like it or not, patients with respiratory complaints are a part of our practice. the common cold is often referred to as the most frequent illness occurring in humans: over 40% of americans suffer from a "cold" each year, accounting for more lost productivity than any other illness. pharyngitis affects almost 30 million patients annually, with over 10% of all school-aged children seeking medical care each year. seventeen million patients a year are diagnosed with asthma, with more females than males among adult-onset patients. whether it is the reason for our patient's visit or an incidental complaint, we are involved with the diagnosis and management of these problems. sinusitis affects roughly 35 million people in the united states annually. the accumulation of purulent material in infl amed paranasal sinuses results in a feeling of fullness and pressure in and over the involved sinuses. these symptoms are worse with posture changes, bending, or with air travel-anything that alters pressure inside the sinuses. nasal congestion and a purulent, blood-tinged discharge, general malaise, low-grade fever, and sore throat are common. these patients will have tenderness over the involved sinuses and edematous or thickened mucosa may be noted on physical examination. these fi ndings help to differentiate sinusitis from the more common cold. the most common cause of sinusitis is bacterial infection with haemophilus infl uenzae, pneumococci, or streptococci. viral and fungal infections may occur, but are less common. upper respiratory infections, allergy, or air travel often precede the development of sinusitis, and secondary infection from a tooth abscess or from swimming in contaminated water may also create a sinus infection. affecting roughly 41% of people per year, the symptoms of the common cold are familiar. the sneezing, runny nose, and malaise usually lasts 6-10 days, but may range from 2 to 26 days. coryza (rhinorrhea and sneezing) is present in 50-66% of patients, and almost 50% of patients experience pharyngitis with a cold. hoarseness and cough develop in 25-50% of patients. between 25% and 45% of patients experience headache, muscular aches, lethargy, and malaise, though only 15-30% actually develop fever or chills. surprisingly, up to 25% of patients infected with the usual cold viruses will not develop symptoms. the patient's symptoms generally begin with the loss of a sense of well-being, scratchy eyes, and discomfort in the nose or back of the throat ( fig. 19.1 ). this is soon followed by sneezing and nasal obstruction with a clear, watery discharge. systemic symptoms, which reach their peak in the fi rst 2-3 days, resolve fi rst, followed by a change in nasal discharge to a cloudy or yellow, thick character. a sore throat, cough, or hoarseness may persist up to 10 days. transmission of the causative virus is usually by personal contact; infected droplets of respiratory discharge are spread by coughing and sneezing, and by transfer from the hands to the eyes, nose, or face. experimental evidence suggests that small doses of virus (1-30 particles) are suffi cient to produce infection. healthy people with normal immune systems are highly susceptible to cold virus infection once the virus enters the nose. in volunteer studies, approximately 95% of normal adults became infected when virus was dropped into the nose. cold viruses are carried to the back of the throat by ciliary action where they are deposited in the area of the adenoids, where the viruses attach. from the time a cold virus enters the nose, it takes 8-12 hours for the viral reproductive cycle to be completed and for new cold virus to be released in nasal secretions. cold symptoms can begin shortly after virus is fi rst produced in the nose (10-12 hours). the time from the beginning of the infection to the peak of symptoms is typically 36-72 hours. there are over 100 serotypes of rhinoviruses that may cause the common cold. these account for about 15-40% of infections. additional viral agents include coronaviruses (10-20% of cases), infl uenza types a, b, and c (1-5%), parainfl uenza (1-5%), respiratory syncytial virus (1-5%), adenoviruses (1-5%), and others. no specifi c agent is known in 30-50% of cases, though it is presumed to be viral. any exposure to an infected person places you at risk for infection. consequently, anything that brings larger numbers of people together, such as daycare, schools, or the work place, increases the chances of infection. the secondary attach rates in families is approximately 25%. cold weather, fatigue, and loss of sleep do not appear to alter the risk of infection, though colds are most prevalent in the winter months. careful hand washing may reduce the risk, especially among those chronically exposed (e.g., health care workers). data regarding the protective effects of large doses of vitamin c are inconclusive. only 12-25% of all "sore throats" seen by physicians have a true pharyngitis-most are simple viral upper respiratory infections such as the common cold. of greatest priority is the identifi cation and treatment of those with group a streptococcal infections so as to reduce the potential for rheumatic sequelae. despite roughly 30 million cases annually, the incidence of rheumatic fever has declined to approximately 64 cases per 100,000. streptococcal pharyngitis has its greatest incidence between the ages of 5 and 18 years, but is still common in patients seen in a gynecology offi ce setting. (see fig. 19 .2 for a decision tree for sore throats.) a sore throat, tonsillar enlargement (often with exudates), soft palate petechiae, and cervical adenopathy characterize true pharyngitis. hoarseness and lower respiratory symptoms should be absent. streptococcal pharyngitis usually runs a 5-7 day course, with a peak fever at 2-3 days. this time course and the presence of a moderate to high fever help to differentiate true pharyngitis from the common cold. spontaneous resolution of symptoms generally occurs, but rheumatic complications are still possible. viral agents, including rhinovirus, adenovirus, and parainfl uenza viruses, cause most pharyngitis. neisseria gonorrhoeae, corynebacterium diphtheriae, and h. infl uenzae may also cause bacterial pharyngitis. the same factors that increase the risk of the common cold (close quarters, unhygienic practices) also increase the risk of pharyngitis. viral infections with infl uenza a or b, parainfl uenza, or adenovirus, or bacterial infections by β-hemolytic streptococcus or streptococcus pneumoniae are the most common etiology for laryngitis. excessive or improper voice use (strain) or aspiration may also result in loss of voice. an upper respiratory tract infection, bronchitis, or pneumonia often precedes laryngitis. environmental causes such as smoking or being in an environment with second-hand tobacco smoke can also cause laryngitis. in the industrial or school environment, exposure to irritating chemicals can also lead to similar symptoms. the peak incidence of laryngitis parallels epidemics of the individual viruses (winter). this subacute viral illness is noteworthy for its barking cough, biphasic stridor, and risk of airway obstruction. while more common in children (the most common cause of stridor in children), the potential for serious complications (e.g., acute obstruction) makes it an illness that should be familiar to gynecologists. patients with laryngotracheobronchitis often have had an upper respiratory prodromal infection in the last 1-7 days. fatigue, malaise, low-grade to moderate fever, and a normal voice characterize the patient's symptoms. the uncomplicated disease usually wanes in 3-5 days but may persist for as many as 10 days. most cases of laryngotracheobronchitis are caused by viral infection (parainfl uenza, infl uenza a, and others). recurrent upper respiratory infections increase the risk of developing laryngotracheobronchitis. as the infection extends to the proximal trachea, diffuse infl ammation with exudate and edema of the subglottic area causes narrowing of the airway. the cricoid ring of the trachea (in the immediate subglottic area) is the narrowest portion of the airway. a small amount of edema in this region can cause signifi cant airway obstruction. (the resistance to fl ow through a tube is inversely proportional to the fourth power of the radius.) air fl owing through this narrowed subglottic area causes the characteristic stridor. with over 10 million new cases diagnosed each year, asthma affects up to one in fi ve children in the united states-more than 4.8 million children under the age of 18. direct health care costs for asthma (adults and children) in the united states total more than $9.8 billion annually; indirect costs (lost productivity) add another $2.8 billion for a total of $12.6 billion. inpatient hospital services represented the largest single direct medical expenditure, over $4.2 billion. the prevalence of asthma increased 75% from 1980 to 1994, and currently affects more than 17 million americans. researchers have yet to pinpoint the cause for the increase in asthma. allergic rhinitis is considered a risk factor in developing asthma, as up to 78% of people with asthma also have allergic rhinitis. while it is tempting to think of asthma as a childhood condition that is not seen in a gynecologic practice, half of all asthma cases occur in patients over the age of 10, and more women than men make up this adult onset group. asthma is a chronic infl ammatory disorder involving constriction of the muscles lining the bronchial airways. physical symptoms of asthma include coughing, wheezing, tightness of the chest, and shortness of breath. narrowing of both the large and small airways results in the wheezing, cough, and dyspnea typical of this condition. hyperresonance and decreased breath sounds are found on clinical examination. allergy, exposure to smoke or other pollutants, viral infections, exercise, or even aspirin intake may induce these episodic attacks. while there is a familial association of reactive airway disease, no known genetic pattern exists. other triggers that may play a signifi cant role in provoking asthma attacks are shown in table 19 .1. asthmatic patients who become pregnant can expect their condition to remain the same or improve (75% of cases). in about 25% of cases, asthma worsens during pregnancy. more common in adults than its viral cousin, bacterial pneumonia has an annual incidence of approximately 20 per 1000 population. of these, approximately 60% are community acquired and 40% are acquired in a hospital or nursing home setting. alcoholics, the debilitated, postoperative patients, patients with respiratory diseases or viral infections, and those who have weakened immune systems are at greater risk. the cardinal signs of bacterial pneumonia are a cough, fever and chills, chest pain, and a thick dark or bloody (rusty) sputum. malaise, myalgia, and abdominal, shoulder, or pleuritic pain may also be present. rales and rhonchi, decreased breath sounds, and vocal fremitus may be found on examination. the tissue of part of a lobe of the lung, an entire lobe, or even most of the lung becomes completely fi lled with liquid (consolidation). the infection may quickly spread through the bloodstream, resulting in septicemia or bacterial seeding to other sites. hematogenous spread or direct inhalation of the organism (s. pneumoniae, h. infl uenzae, staphylococcus aureus, legionella pneumophila, and allergens such as pollens, molds, animal dander, dust mites, and cockroaches irritants such as strong odors and sprays, chemicals, air pollutants, tobacco smoke, and cold air viral or sinus infections including colds, pneumonia, and sinusitis exercise, especially in cold, dry air gastroesophageal refl ux disease (gerd), a condition in which stomach acid fl ows back up the esophagus medication and foods emotional anxiety others) is the most common source of infection for most patients. s. pneumoniae is the most frequent cause of bacterial pneumonia and is the one form of pneumonia for which a vaccine is available. anything that diminishes the host's defenses increases the risk of becoming ill. alcoholism and smoking, immunosuppression and aids, chronic disease, malnutrition, and advanced age are all associated with an increased risk. groups for whom vaccination should be recommended are shown in table 19 .2. viral pneumonia has signs and symptoms similar to those of bacterial pneumonia, with fever, chills, and a productive cough the predominant symptoms. as with bacterial infections, a preceding upper respiratory tract infection is common. rales, rhonchi, and altered breath sounds are typical fi ndings on examination. while 90% of childhood pneumonia is viral, only between 1% and 5% of adult pneumonias are caused by viral infections. infl uenza a and b, as well as parainfl uenza (1, 2, 3, and 4), and respiratory syncytial virus may also be common agents. varicella, herpes simplex, and rubeola are atypical causative organisms but account for signifi cant morbidity when they are the causative agents. infection with the infl uenza virus may be severe and occasionally fatal. the virus invades the lungs and multiplies, but there are almost no physical signs of lung tissue becoming fi lled with fl uid. fatalities are most common among those who have preexisting heart or lung disease or are pregnant. because of its somewhat different symptoms and physical signs, and because the course of the illness differed from classic pneumococcal pneumonia, mycoplasma pneumonia was once believed to be caused by one or more undiscovered viruses and was called "primary atypical pneumonia." mycoplasmas generally cause a mild and widespread pneumonia that can affect all age groups, occurring most frequently in older children and young adults. the death rate is low, even in untreated cases. little separates mycoplasma pneumonia from viral pneumonia except for the presence of cold agglutinins. a prodromal period of mild sore throat, those with chronic illnesses such as lung disease, heart disease, kidney disorders, sickle cell anemia, or diabetes those recovering from severe illness those in nursing homes or other chronic care facilities age 65 or older low-grade fever, and malaise generally precedes the development of paroxysmal cough and blood-streaked sputum. confi ned living spaces (such as military bases, college campuses, and hospitals) increase the risk of mycoplasma epidemics. immunocompromised patients are also at higher risk for infection. pneumocystis carinii pneumonia is caused by an organism believed to be a fungus and is frequently the fi rst sign of illness in many persons with aids. this often insidious infection is seen almost exclusively in immunocompromised individuals. weakness, fatigue, malaise, fever and chills, and mild dyspnea on exertion are typical. a mild nonproductive cough or a cough productive of only scant amounts of clear sputum is common. the clinical signs and symptoms present most often establish the diagnosis of sinusitis. sinus x-rays will show cloudiness and air-fl uid levels with thickened mucosa in the affected sinuses, but are not required for diagnosis in most cases. computed tomography and magnetic resonance imaging are not indicated in these patients. transillumination of the affected sinuses will reveal opacity. a mildly elevated white blood cell count may be found and appropriate cultures (especially in chronic sufferers) may be of help, and can help to separate cases of viral and allergic rhinitis from those of bacterial infection. the possibility of a foreign body must always be considered. the diagnosis of the common cold is made on clinical grounds with testing rarely indicated and useful only when other conditions are suspected. viral culture or isolation is not practical and should not be undertaken. infl uenza, rubeola and rubella, mycoplasma pneumonia, group a β-hemolytic streptococcal infections, and allergic rhinitis may all be confused with the common cold and should be considered when appropriate. in addition to the patient's symptoms, a throat culture (on blood agar) or a rapid screening test for streptococcus is indicated because history and physical examination are only 50% accurate in establishing the diagnosis. because of a sensitivity of 80% and specifi city of 95% for most rapid screening tests, a followup culture is indicated even if the rapid test is used for the initial screening. a fever of greater than 39.2°c (102.5°f), white blood count of greater than 12,000, or a scarlet fever rash (punctate erythematous macules with reddened fl exor creases and circumoral pallor) is suggestive of a streptococcal infection and requires more aggressive evaluation and treatment. a gray pseudomem-brane suggests the presence of diphtheria and vesicles should suggest herpes stomatitis as alternate diagnoses. the diagnosis of laryngitis is made primarily on the patient's symptoms. the hallmarks of laryngitis are hoarseness, abnormal sounding voice, or loss of voice. feelings of throat tickling or rawness, coupled with a frequent urge to clear the throat, are also common. like the cough of the common cold, laryngitis may continue after the acute infection is over. this can be recognized by noting that the fever and ill feeling have resolved, but the hoarseness continues for several days to a week or longer. direct or indirect laryngoscopy is diagnostic but generally beyond the interest of most gynecologists. laryngotracheobronchitis must be differentiated from epiglottitis, foreign body aspiration, diphtheria, and simple upper respiratory infections. x-rays of the neck (pa and lateral) will show a characteristic narrowing in the subglottic region with a normal epiglottis (an inverted v-shaped "steeple" or "pencil" sign). direct laryngoscopy is often required to establish the fi nal diagnosis. early in the course of the disease leukopenia may be present with leukocytosis occurring in later, more severe cases. because hypoxia may be insidious and occurs in up to 80% of children with laryngotracheobronchitis, pulse oximetry should be considered. even in adults, the condition of the patient can change rapidly, necessitating early consultation and aggressive management. allergists follow the national guidelines for the diagnosis and management of asthma (national asthma education and prevention program, national institutes of health, 1997) to diagnosis and establish treatment plans for patients with asthma and other allergic diseases. the diagnosis of asthma is made mainly on the basis of the recurrent clinical pattern. allergy testing, spirometry, and chest x-ray may support or clarify the diagnosis. unusual conditions such as recurrent pulmonary emboli and cystic fi brosis, or more common processes such as congestive heart failure and tuberculosis, must all be considered. special attention should be paid to the nose and sinuses for evidence of chronic infection. a spirometer may be used to objectively measure the amount of air inhaled and exhaled and to determine the level of airway obstruction, though the simple bedside test of asking the patient to blow out a match held at arm's length can provide a quick assessment of forced expiratory volume (fev 1 ). frequently, the criteria for diagnosis have been fever, cough, and development of purulent sputum, in combination with radiologic evidence of a new or progressive pulmonary infi ltrate, a suggestive gram stain, and cultures of sputum, tracheal aspirate, pleural fl uid, or blood. unfortunately, symptoms, elevated white blood count with left shift, hemoconcentration, hyponatremia, and transaminase elevations are all nonspecifi c signs of bacterial pneumonia. the onset of bacterial pneumonia can vary from gradual to sudden. in the most severe cases, the patient may experience shaking chills, chattering teeth, severe chest pain, and a cough that produces rust-colored or greenish mucus. the patient's temperature may rise as high as 105°f. the patient sweats profusely, and breathing and pulse rate increase rapidly. lips and nail beds may demonstrate hypoxia and confusion or delirium may be present. the chest x-ray will show air bronchograms and consolidation, with pleural effusion common. blood cultures will be positive in 20-30% of patients with community-acquired infections. bronchoscopic cultures with greater than 10,000 organisms are diagnostic, but beyond the capability of most gynecologists. induced sputum for culture and gram stain may be helpful, but are less reliable. the initial symptoms of viral pneumonia are the same as infl uenza symptoms: fever, a dry cough, headache, muscle pain, and weakness. within 12-36 hours, there is increasing breathlessness; the cough becomes worse and produces a small amount of mucus. there is a high fever and there may be hypoxia and cyanosis. in extreme cases, the patient has a desperate need for air and extreme breathlessness. exclusion of the more common bacterial pneumonia and the addition of viral culture or fl uorescent antigen studies establish the diagnosis of viral pneumonia. the most prominent symptom of mycoplasma pneumonia is a cough that tends to come in violent attacks, but produces only sparse whitish mucus. chills and fever are early symptoms, and some patients experience nausea or vomiting. patients may experience profound weakness that lasts for a long time. the presence of cold agglutinins in a titer of 1 : 64 or greater, or with a fourfold rise in titers, is found in 50% of infections. cultures for mycoplasma take 7-10 days, so are of little use in making the acute diagnosis. suspicion greatly aids the diagnosis. chest x-ray shows bilateral interstitial or perihilar infi ltrates in 75% of cases, though a normal chest x-ray may be present. serum lactate dehydrogenase (ldh) is often elevated (average 340 iu) and cd4 cell counts are generally depressed (<200) in hiv-infected patients. outpatient care for patients with sinusitis is appropriate except when there is involvement of the frontal or sphenoid sinuses. for simple cases involving the other sinuses, steam inhalation will provide some comfort and promote drainage. irrigation with saline may be recommended, but is seldom required. amoxicillin (500 mg three times a day) or trimethoprim-sulfamethoxazole twice a day for 14-21 days will generally provide good coverage for the most common causative organisms. recent data suggest that treatment courses of as little as 3 days may be suffi cient in uncomplicated cases. with proper antibiotic treatment, over 90% of cases of acute bacterial sinusitis are cured. if response is not forthcoming, a switch to an antibiotic with activity against βlactamase-producing bacteria is prudent. cases of acute bacterial sinusitis that do not clear after a few months of appropriate medical treatment may require sinus surgery. analgesics, vasoconstrictors to relieve fullness, and antihistamines may all be used as needed. patients should be advised to avoid alcohol and caffeine because both may result in swelling of the sinus membranes. though rare, sinusitis may lead to meningitis, extradural, subdural, or brain abscesses, osteomyelitis, or septic cavernous sinus thrombosis. patients with chronic or recurrent sinusitis may require surgical drainage. common sense and supportive therapies are all that are required for most patients suffering from the common cold. rest, fl uids (including fruit juices), smoking cessation, and humidifi cation may all be of some help. the best strategy for treating a cold is to start treatment as soon as there is the recognition that a cold is beginning and to continue treatment on a regular basis until it appears that the cold is over (3-7 days). analgesics, oral decongestants (pseudoephedrine, phenylephrine, and phenylpropanolamine), antitussives (dextromethorphan, codeine) combined with mucolytics (guaifenesin), antihistamines, and topical decongestants (oxymetazoline) may all provide some relief. early studies of the fi rst generation antihistamines for the treatment of colds gave negative results because of inadequate precision in symptom recording. subsequent studies have demonstrated that fi rst generation antihistamines are quite effective in reducing the sneezing and runny nose of colds. the use of topical decongestants should be limited to 3-4 days to avoid rebound hyperemia and congestion. decongestants taken by mouth have less powerful and immediate activity but cause fewer problems with the cycles of recurrent nasal obstruction than topical preparations. there is some evidence that supplemental vitamin c may reduce the duration of disability. the use of zinc gluconate lozenges has been shown to reduce the duration of symptoms but they must be used frequently and are often associated with nausea. the use of zinc (gluconate) lozenges has been shown to reduce the duration of symptoms by roughly one-half if used early in the course of the infection. in clinical trials, doses of 13-15 mg every 2 hours while symptoms persist have been used. studies using intranasal ipratropium bromide (atrovent) three times daily have demonstrated a reduction in rhinorrhea and sneezing. efforts to either treat or prevent the common cold with echinacea preparations have had variable success when subjected to randomized trials. the use of antibiotics has only a limited role in the treatment of the common cold and should be discouraged. when a common cold has lasted for 7-10 days and is no better or worse, acute bacterial sinusitis may have developed and additional medical care may be required. for this reason, antibiotics may be indicated when symptoms continue unabated for more than 10 days. after this time, the probability of a secondary bacterial infection increases to roughly 80%. erythromycin, amoxicillin, and sulfi soxazoletrimethoprim are reasonable empiric choices at this point. symptomatic treatments for pharyngitis include salt-water gargles, acetaminophen, dyclonine lozenges, and use of a cool mist humidifi er. smoking cessation and voice rest are always indicated. when a streptococcal infection is suspected (i.e., when a high fever is present), treatment with penicillin, penicillin vk (250 mg three times daily), erythromycin ethylsuccinate (300-400 mg three times daily), or cephalexin (250 mg three times daily) should be started and continued for a full 10 days. azithromycin is also effective, with its higher cost partially offset by the shorter (5 day) course of therapy. patients are considered noninfectious after 24 hours of antibiotic coverage. complications from pharyngitis are rare and are generally restricted to the bacterial forms. the greatest concern is the development of rheumatic fever and its sequellae. poststreptococcal glomerulonephritis, peritonsillar abscess, otitis media, and systemic infections are also possible complications. usually, laryngitis is self-limiting. however, children's croup or acute epiglottitis can present like laryngitis. the primary treatment of laryngitis is voice rest, humidity (steam or cool mist), increased fl uids, antipyretics, and analgesics (table 19 .3). smoking should be stopped. penicillin g (250 mg every 6 hours for 10-12 days) is indicated when streptococcal or pneumococcal infections are suspected. indications for further investigation or that a change in therapy is needed are shown in table 19 .4. in mild cases, outpatient treatment with humidifi cation, fl uids, rest, and analgesics may suffi ce. dexamethasone has been shown to reduce symptoms in patients with moderate-to-severe croup and is frequently used in children. because of the possibility of acute airway obstruction, more severe cases require hospitalization and intensive monitoring by those familiar with the disease. although there is no cure for asthma, there are effective treatment methods. successful management of asthma consists of four components: (1) patient education, (2) reduction of environmental triggers (allergens), (3) measurement and monitoring of pulmonary function, and (4) pharmacologic intervention. medication therapies are designed to minimize the airway infl ammation component of asthma as well as to treat airway narrowing. environmental control measures are implemented to avoid or eliminate factors that induce or trigger asthma fl are-ups. immunotherapy may also be considered if allergies are known to be an asthma trigger, a condition that is most common in children. the treatment of asthma is based on fi ve major classes of drugs: antiinfl ammatory agents (cromoglycate and nedocromil), steroids (beclomethasone, prednisone), β-agonists (albuterol, terbutaline), methylxanthines (theophylline), and anticholinergics (atropine, ipratropium bromide). a sixth class has gained favor recently: antileukotrienes or leukotriene modifi ers. suck on cough drops, a throat lozenge, or hard candy stop smoking avoid places where cigarettes are smoked use a humidifi er (cool mist ultrasonic humidifi ers are preferred-these are more expensive than the usual vaporizer, but are safer and more effective); you can also try standing in a hot shower use aspirin, ibuprofen, or acetaminophen for temperature, muscle discomfort, and pain; do not give aspirin to anyone less than 19 years of age-it can trigger an attack of reyes syndrome gargle with warm salt solution (1/2 tsp salt in 1 cup of water) speak softly, but do not whisper; use a notebook and pencil to communicate drink warm liquids like hot tang or honey and lemon diffi culty breathing fever over 101°f diffi culty swallowing deep cough or, in a young child, a cough like the bark of a seal (suggestive of laryngotracheobronchitis) brown, green, or yellow sputum hoarseness that persists for 1 month or more inability to carry on normal activities symptoms of gasping or drooling leukotrienes are responsible for the contraction of the airway smooth muscle, increasing leakage of fl uid from cells in the lung, and further promoting infl ammation by attracting other infl ammatory cells into the airways. recently, new antileukotriene medications have been introduced to fi ght the infl ammatory response typical of allergic disease. these drugs are generally limited to the treatment of chronic asthma, though recent data have demonstrated that antileukotriene therapy can be benefi cial for many patients with less chronic asthma. it is likely that these newer medications will eventually have an increased role in asthma care as more studies are conducted. comanagement with both the patient and an asthma specialist is essential when the disease is advanced. mild cases of asthma (brief wheezing one to two times per week) are often managed by intermittent use of β-agonists or theophylline. bronchodilators are generally used as "rescue medications" to relieve coughing, wheezing, shortness of breath, and diffi culty in breathing. those patients with weekly symptoms that interfere with sleep, exercise, or work require a regular maintenance schedule with cromolyn qid or nedocromil bid, with inhaled steroids as an adjunct. theophylline is added when symptoms worsen. salmeterol is a long-acting bronchodilator that, along with an antiinfl ammatory medication, is used for maintenance in the long-term control of asthma symptoms. both patients and physicians must be aware of several potential pitfalls in management: not recommended are mist therapy, fl uid loading, breathing exercises, or intermittent positive-pressure breathing (ippb) therapy. erythromycin and ciprofl oxacin can slow theophylline clearance resulting in increased levels of as much as 15-20% and possible toxicity. in addition to common sense support measures, antimicrobial therapy for the most likely organisms is required. for community acquired infections, empiric treatment with erythromycin (500 iv every 6 hours) provides good coverage, including coverage for mycoplasma and legionella. for patients with nosocomial infections, third-generation cephalosporins (cefotaxime, ceftizoxime) plus vancomycin are recommended. in otherwise healthy adults, improvement should occur in 1-3 days. despite clinical improvement, it may take quite some time for the chest x-ray to clear, necessitating repeated studies for up to 6 weeks. mortality rates for bacterial pneumonia still runs about 5%. this rate rises when the pneumonia is associated with debilitating processes such as alcoholism and aids. for these high-risk patients, consideration should be given to prophylaxis with polyvalent pneumococcal and infl uenza vaccinations (table 19 .2). general supportive measures such as analgesics, antitussives, and antipyretics are appropriate. amantadine (100 mg q 12 h) is effective for treating infections with infl uenza a, but not against infl uenza b infections. symptoms should resolve in several days to a week. it should be noted that amantadine should be used with caution in patients with liver disease or epilepsy, and in those with a history of psychotic illness. rest, fl uids, and analgesics are appropriate initial therapy. antibiotic treatment with either tetracycline or erythromycin (500 mg every 6 hours for 7 days) provides good coverage. azithromycin, given as 500 mg the fi rst day, then 250 mg for days 2 through 5, may also be effective. antibiotics such as penicillin are not effective against mycoplasma pneumoniae. symptoms often take more than 2 weeks to resolve. a false-positive vdrl may be found in patients with mycoplasma pneumonia. trimethoprim/sulfamethoxazole (10-20 mg/kg/day of trimethoprim component divided every 6 hours for 21 days) with adjunctive corticosteroid therapy (prednisone) is standard, though a high percentage of aids patients will develop intolerance to trimethoprim/sulfamethoxazole. trimethoprim/sulfamethoxazole has been used in pregnancy for both treatment and prophylaxis. pneumocystis carinii pneumonia can be successfully treated in many cases. it may recur a few months later, but treatment can help to prevent or delay its recurrence. mortality for fi rst episode infections is now about 10-15%, down from as high as 30-40% previously. approximately 10% of patients develop respiratory failure and more than 85% of these succumb. a 23-year-old g2p2002 patient calls your offi ce complaining of a "sinus infection" and requesting that a prescription for antibiotics be called to a local pharmacy. she reports congestion, a nasal discharge that has become thick and purulent and she has had a low-grade fever. her symptoms began about 5 days ago. how should you proceed at this point? this is a typical presentation for the common cold-the symptoms, their progression and the request for antibiotic therapy are all typical. unless there is a history of previous sinus infections, or a reason to suspect that this patient is at high risk for an atypical infection or complication (e.g., immunocompromise), an offi ce visit, additional testing, or anything other than symptomatic interventions are not warranted. arroll b, kenealy t. antibiotics for the common cold. cochrane database syst rev 2000;(2):cd000247. future directions for research on diseases of the lung echinacea for upper respiratory infection cost burden of viral respiratory infections: issues for formulary decision makers towards excellence in asthma management (team): a population diseasemanagement model forecasted state-specifi c estimates of self-reported asthma prevalence-1998 management of acute bacterial rhinosinusitis vitamin c for preventing and treating the common cold anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma: systematic review of current evidence rhinovirus respiratory infections and asthma evaluation of echinacea for treatment of the common cold respiratory viral infections in adults a randomized controlled trial of the effect of fl uid extract of echinacea purpurea on the incidence and severity of colds and respiratory infections clinical signifi cance and pathogenesis of viral respiratory infections viral respiratory infection therapy: historical perspectives and current trials effi cacy and safety of a fi xed combination phytomedicine in the treatment of the common cold (acute viral respiratory tract infection): results of a randomised, double blind, placebo controlled, multicentre study the diagnosis and treatment of cough antivirals for the common cold gastroesophageal refl ux disease-state of the art pharmacologic management of common lower respiratory tract disorders in women the effi cacy of echinacea compound herbal tea preparation on the severity and duration of upper respiratory and fl u symptoms: a randomized, double-blind placebo-controlled study h1-antihistamines in asthma zinc for the common cold beat the winter bugs. how to hold your own against colds and fl u echinacea root extracts for the prevention of upper respiratory tract infections: a doubleblind, placebo-controlled randomized trial use of cough and cold preparations during breastfeeding epidemiology of viral respiratory infections zinc gluconate lozenges for treating the common cold. a randomized, double-blind, placebocontrolled study infl uenza-associated morbidity and mortality in young and middle-aged women highlights from the annual scientifi c assembly: patient-centered approaches to asthma management: strategies for treatment and management of asthma zinc lozenges for treatment of common colds drugs in pregnancy. respiratory disease recommendations of prophylaxis against pcp for adults and adolescents with human immunodefi ciency virus continuous vs intermittent beta-agonists in the treatment of acute adult asthma: a systematic review with meta-analysis heated, humidifi ed air for the common cold antibiotics for acute bronchitis nasal decongestants for the common cold the role of respiratory viruses in acute and chronic asthma the common cold at the turn of the millennium acute upper airway infections key: cord-021905-fjcks7w4 authors: win, patrick h.; hussain, iftikhar title: asthma triggers: what really matters? date: 2009-05-22 journal: clinical asthma doi: 10.1016/b978-032304289-5.10017-7 sha: doc_id: 21905 cord_uid: fjcks7w4 nan in the preceding chapters, authors have discussed the various important aspects of the clinical asthma assessment. as is the case with assessing level of control, severity, and inflammation, identifying triggers for asthma is an integral part of the initial evaluation of newly diagnosed asthmatic individuals. furthermore, reviewing potential asthma triggers at each follow-up visit helps educate asthma patients. this education is a preventative first step in identifying and modifying risk factors that are responsible for poor quality of life, unnecessary morbidity, and mortality. in this, the final chapter of section iii, we will review our current concepts of asthma triggers and their role in the assessment and management of asthma. we hope to organize the classification of asthma triggers, and provide quick reference tables to simplify the initial assessment and follow-up management of asthmatics. by the end of this chapter, you will be "armed" with the information to rapidly assess, educate, and intervene upon the asthma triggers that really matter. what is an asthma trigger? asthma triggers are any condition or stimuli that cause inflammation or hyperresponsiveness of the airways that result in the symptoms of asthma: wheezing, shortness of breath, chest tightness, and/or coughing. given the heterogeneity of asthma phenotypes, it is important to understand that triggers will vary among patients. so focusing on the relevant triggers for each patient is of utmost importance. while some asthmatic individuals are atopic, others are not. accordingly, while allergen avoidance may vastly help the so-called "extrinsic" asthmatic individual by preventing morbidity and exacerbations, exposure to aeroallergens may not be detrimental to the nonatopic, "intrinsic" asthmatic individual (box 17-1). furthermore, even within the group of atopic asthmatic individuals, some will be sensitized to seasonal allergens (trees, grasses, or weeds), while others will be triggered by perennial allergens (cat, dog, or dust mites). given we have little, precious time at every patient encounter, it is imperative that we have a systematic approach to assessing and intervening upon asthma triggers targeted to the individual patient (box 17-2). accordingly, asthma triggers can be conveniently placed into groups by etiology: allergens, irritants, medications, weather changes, infections, emotions, gastroesophageal reflux, foods, and exercise (table 17 -1). in genetically predisposed individuals, allergen exposure may lead to sensitization resulting in the formation of allergen-specific immunoglobulin e (ige) by b lymphocytes. this process of allergen sensitization is uncommon within the first year of life, as formation of ige to specific aeroallergens does not commonly occur before the age of 2 to 3. in these individuals, the combination of allergen sensitization to common aeroallergens (table 17 -2) and reexposure to these allergens can trigger symptoms of asthma. subsequent allergen exposure through the respiratory tract results in t h 2-type lymphocyte recruitment, mast cell activation through ige, and clinicians must take time to carefully identify potential asthma triggers at the time of initial evaluation and at each follow-up visit to minimize unnecessary morbidity from asthma. just as asthma phenotypes vary among patients, so too do their specific triggers. thus, care must be individualized and reviewed regularly as triggers can change over time. new-onset, uncontrolled asthma may be a sign of a new asthma trigger previously not identified. after asthma triggers are identified and confirmed with testing (if necessary), every effort should be made to avoid or eliminate these specific triggers of asthma symptoms (with the exception of exercise). opportunities to minimize infectious triggers must always be taken. this should include influenza and pneumococcal vaccinations. aeroallergen: any airborne substance that can result in an ige-mediated allergic response. typically these include tree, grass, and weed pollen; mold spores; and perennial allergens like cat and dog dander, dust mite, and cockroach. asthma trigger: any condition or stimuli that cause inflammation or hyperresponsiveness of the airways that results in wheezing, shortness of breath, chest tightness, and/or coughing. atopy: the genetic predisposition to develop any of the classic allergic diseases (atopic dermatitis, allergic rhinitis, and asthma). atopy involves the capacity to produce specific-ige in response to common environmental allergens such as house-dust mites, foods, and tree and grass pollen. irritant: any substance, chemical, or physical factor that triggers asthma symptoms by nonspecific mechanisms resulting in increased bronchial hyperreactivity. examples include smoke and cold air. samter's triad: a medical condition consisting of asthma, aspirin sensitivity, and nasal polyposis. this triad is typically identified in patients in their 20s and 30s and may not include other atopic diseases. it is also commonly known as aspirin-sensitive asthma, aspirin triad, and aspirin-induced asthma and rhinitis (aiar). eosinophil influx. the ensuing inflammation from this milieu of cells and cellular mediators is thought to be responsible for not only acute asthma exacerbations, but also chronic inflammation. allergen sensitivity is commonly diagnosed by a combination of history and positive epicutaneous skin ( fig. 17-1) and/or intradermal testing ( fig. 17-2) , and in some cases, in vitro testing such as allergen-specific radioallergosorbent testing or newer technologies. after the diagnosis is made, health care providers should strive to identify the allergic triggers of asthma, treat comorbid underlying disease (e.g., rhinitis) with appropriate medications, and implement environmental controls to eliminate or minimize exposure to these factors. seasonal allergens from trees, grasses, and weeds are predominantly derived from air/wind-borne pollen. even though whole pollen grains are quite large, plants can extrude allergen-containing particles that are less than 10 μm in size through the pores in their outer covering. this relatively small size likely facilitates entry into the lower airways, and results in the aforementioned allergic cascade with subsequent inflammation. the presence and time of release of these airborne allergens vary according to location and climate. generally speaking, tree pollen is released first, in the springtime; grasses come later in the spring and early summer; and weed pollen arrives in late summer and early fall lasting until the first frost. accordingly, pollen-allergic patients can have significant asthma exacerbations during their specific pollen season or seasons. exposure to seasonal pollens is classically box 17-2 assessment considered an outdoor exposure, with peak outdoor pollen concentrations occurring in the morning. unfortunately, during the grass pollen season, pollen can be found indoors at high levels in bedding, furniture, and carpeting. this is facilitated by leaving home windows open and using window and attic fans to cool the inside environment. to minimize morbidity, asthma patients should be educated about their specific pollen sensitivities and corresponding "high-risk" seasons, as avoidance is the best way for patients to reduce risk of asthma flare. decreasing exposure and, in turn, asthma exacerbations can be facilitated by remaining indoors, closing windows, avoiding the use of cooling fans, and using car and home air-conditioning as much as possible. this is particularly important in the early morning, the time of peak airborne pollen concentration. early morning outdoor exercise should be strictly avoided, as the combination of peak pollen counts and cardiovascular exercise with increased oxygen demand, increased respiratory rate, and larger tidal volumes can be a dangerous combination. recognizing that complete avoidance is not always feasible, using locally available pollen counts to help inform patients of potential high-exposure days can be quite helpful in reducing allergen exposure. perennial allergens that trigger asthma include domesticated animals, house-dust mites, and cockroaches. cat and dog exposures are among the most common causes of perennial asthma triggers; however, all warm-blooded feathered or furry animals, including hamsters, rabbits, guinea pigs, and birds can produce allergen. exposure to these allergens, in turn, may induce ige-mediated reactions and asthma exacerbations. pet allergens are ubiquitous in our environment as 30% to 40% of american homes have pets, and even trace amounts of cat or dog allergen can be found in virtually any home (>90%, even in homes without cats or dogs). acute symptoms may develop in cat-or dog-sensitive asthmatic patients within minutes after entering a home where these animals reside. cat allergen, mainly fel d 1, is a 17-kda heterodimer comprising two disulfide-linked peptide chains. fel d 1 is produced in the sebaceous glands and is typically spread via contact with cat saliva, dander, and urine. common allergens are present in all breeds of cat (including lions, tigers, and hairless cats), but males produce more allergen than females. cat allergen can be very small (<3 to 4 μm), and the distribution in the household air at any time is highly variable. cat allergen is also very light and sticky, so it becomes airborne easily and can accumulate on household furniture, carpeting, and walls. these unique characteristics allow it to remain suspended in the air for long periods and to be inhaled deeply into the lungs, possibly accounting for its greater potential to trigger asthma symptoms than other aeroallergens. the level of cat allergen that is required to induce asthma symptoms is not well defined, so strict avoidance and proper cleaning after an animal has been removed from the household are key to preventing morbidity. cat allergen levels drop slowly after animal removal, so brief trials of cat avoidance are useless. in fact, it takes approximately 5 months for cat allergen to drop to levels similar to those found in homes without cats, and 4 to 6 months after the animal has been removed for asthma patients to achieve any improvement in symptoms. unfortunately, the clothes of cat owners constitute the vehicle of passive transport of fel d 1 to cat-free environments, so recontamination to some extent is unavoidable. in contrast to cat allergen, where the major antigenic component has been identified, dog allergen appears to be more heterogeneous, containing many varied allergens (primarily can f 1 and can f 2). contrary to popular belief, it is impossible to generalize certain dog breeds as either "nonallergenic" or "hypoallergenic." in fact, all dogs have common allergens, but there may be differences in an individual's response to a particular dog breed or possibly even an individual dog of a specific breed. despite this, even though many patients claim that "my pet has never bothered me," patients are notoriously poor at perceiving asthma symptoms when they have chronic, continuous exposure to allergens to which they have become sensitized. this is likely due to, at least in part, their emotional attachment to their animal. the best "treatment" for all animal allergies is strict avoidance, including removal of the animal that is triggering symptoms of asthma from the home. when animal removal is not possible, confining the pet to carpet-free areas, outside the bedroom, may be beneficial. these measures, combined with the use of a hepa (high-efficiency particulate air) or electrostatic air filter may provide additional benefit in "light" allergen removal (e.g., cat and dog allergen). weekly or biweekly washing of pets, by a family member or individual other than the asthmatic patient, may also help to decrease allergen exposure and symptoms. interestingly, dog, but not cat, ownership during infancy has been shown to reduce the development of allergic sensitization, and absolute number of pets, and not the type of furred pet, might also reduce future risk. the two species of house-dust mite, dermatophagoides pteronyssinus and dermatophagoides farinae, are the most important mite allergens in north america. house-dust mites are microscopic (approximately 0.3 mm long), sightless, eight-legged acarids that feed on sloughed human skin. the most allergenic parts of the house-dust mite are its body parts and fecal matter. one ounce of house dust can contain approximately 40,000 dust mites. thus a bed, a common site of house dust mites, may contain approximately 2 million dust mites. in contrast to pet allergy, dust mite-sensitive asthmatic patients are rarely aware of symptoms immediately, even when levels of dust mite allergen in a home are high. studies indicate that the critical level of house-dust mites that poses a risk factor for asthma ranges from 100 to 500 mites per gram of house dust (about 2 to 10 μg of der p 1), while acutely ill mite-sensitive asthmatic patients usually reside in homes with more than 500 mites per gram of house dust (>10 μg of der p 1). house-dust mite levels vary with humidity, temperature, season, and type of home furnishings. the most important factor influencing growth of house-dust mites is humidity. asthmatic patients who are mite-sensitive and live in environments with suitable sites for mite growth (e.g., wall-to-wall or bedroom carpeting and upholstered or overstuffed furniture) are at greater risk in more humid climates. house-dust mites optimally reproduce in bedding and carpeting where the relative humidity in the home is higher than 50%. accordingly, improper setting of the central air humidifier (commonly part of a home's central heating and air-conditioning unit) may worsen asthma control; while dehumidifiers set to keep humidity levels lower than 50% may be beneficial in reducing asthma symptoms from house-dust mite exposure. although using other environmental control measures to minimize dust mite exposure are generally endorsed by allergists as a preventative first step to reduce asthma flares, studies examining their use are conflicting and have provided much controversy. some studies using relatively basic dust mite control measures have shown no effect on asthma symptoms or reduction in mite growth; whereas other studies that use methods of extensive cleaning and dust mite proofing (e.g., mattress and pillow covers) to minimize mite exposure have been associated with a reduction in asthmatic symptoms, medication use, and morbidity. furthermore, some studies have shown that patients exposed to lower levels of house-dust mites not only have decreased asthma symptoms and medication use, but also have improvement in nonspecific bronchial hyperresponsiveness. having said this, the cochrane library meta-analysis on house-dust mite control measures for asthma, including 49 trials that examined the use of physical, chemical, and combination methods to reduce house-dust mite exposure, showed no benefit/effect on frequently reported outcomes (am peak flow, asthma symptom scores, and medication use). the reviewers mention that many of the trials included in this analysis were of poor quality, making their conclusions difficult to interpret. if environmental control measures are suggested, the bedroom is the most important room to target, as most of our day in the home (approximately 8 to 10 hours during the night for sleep) is spent there. other areas of the home, such as the living or family room that contains overstuffed furniture or carpeting, must be considered as potential sites of significant house-dust mite exposure. proposed environmental controls to be considered include replacing wall-to-wall carpeting with hardwood or vinyl flooring, encasing bedding in dust-mite impermeable material, frequent dusting (with mask or by an unaffected individual), replacing upholstered/overstuffed furniture with leather furniture, replacing fabric curtains with blinds, washing bedding weekly in hot water (60° c or 130° f), washing and high-heat drying or freezing of stuffed toys, reducing humidity to less than 50%, frequent vacuuming (with hepa filter and doublethickness bags) by an individual not sensitive to dust mites (or with mask), and using acaricides and/or tannic acid to mitigate house-dust mite infestation. cockroach has also been identified as a major allergen capable of triggering asthma exacerbations. the ability of cockroach allergen to stimulate the formation of specific ige antibodies has been demonstrated by end point skin test titration and radioallergosorbent testing. furthermore, a causal relationship between bronchospasm and sensitivity to cockroach allergen has been proved in bronchial provocation studies. positive skin tests to cockroach allergen are reportedly present in 20% to 53% of allergic patients and as high as 49% to 61% of asthmatic patients. although there are about 50 species of cockroaches that live in the united states, only 3 have been shown to induce allergen-specific ige: the american, german, and asian/oriental cockroaches. cockroach allergen usually is found in kitchen cabinets and kitchen floor dust, as they usually hide out in cabinets and behind refrigerators. a study in urban asthmatic patients has shown that cockroach sensitivity may be as important a risk factor for inner-city asthmatic individuals as house-dust mite allergy. because elimination of cockroach infestation requires aggressive, repeated extermination efforts with irritant chemicals (deltamethrin powder or cypermethrin), it is best performed by professional exterminators. cockroach baits and gels (fipronil and hydramethylnon) can be purchased at local superstores. these are generally safer and relatively nontoxic to mammals (pets and children), but may not be as effective in cases of severe infestation. other partially effective measures include restricting havens by caulking and sealing cracks in plaster work and flooring, controlling dampness, reducing the availability of food, and restricting access to the dwelling (sealing sources of entry around doors). molds and fungi are aeroallergens that can trigger significant asthma symptoms in both a seasonal and perennial fashion. unlike pollens, molds have ill-defined seasonal peaks and nadirs for airborne mold spore levels. only in the northernmost areas of the united states are there consistent seasonal increases in mold counts. in this region, mold counts increase starting in may or june and decrease by october or november, having peaked in july or august. in the south, airborne molds are present throughout the winter, with a peak in summer or early fall. clinically, molds are divided into two groups: outdoor and indoor. the two most common outdoor molds are alternaria and cladosporium. other common outdoor molds include fusarium, spondylocladium, and helminthosporium. these outdoor or field molds grow in soil, on plants, and in decaying vegetation such as cut grass or raked leaves. mold levels are affected by temperature, wind, rainfall, and humidity. rain or high humidity levels will lower mold spore counts temporarily, but afterwards, counts rise rapidly. generally, a late summer-autumn peak is seen for common fungal spores. similar to the aforementioned avoidance measures for pollen-sensitive asthmatic individuals, asthma symptoms from exposure to mold spores may be minimized by staying indoors as much as possible (especially during peak spore concentrations) and keeping home and automobile windows closed. the importance of minimizing mold exposure in mold-sensitive asthmatic individuals cannot be overemphasized. it is clear, from the observation of "new orleans asthma" and other recently described cases of mold-induced asthma, that inhalation of large quantities of mold spores can produce severe, life-threatening asthma exacerbations in mold-sensitive patients. although it is unclear what etiological factors are responsible for these cases of severe mold-sensitive asthma flares, it is hypothesized that because mold spores are smaller than pollen, they are more likely to enter and inflame the lower airways. the two most important indoor molds are aspergillus and penicillium (also known as mildew). the amount of indoor mold in any dwelling depends on several important factors: age and composition of the structure, type of heating and cooling system, and use of humidifiers. dark and humid (often poorly ventilated) basements are ideal sites for mold growth. the next most common sites of mold growth are the bathroom and the kitchen. in tropical and subtropical climates, fungi may grow on the walls of the house as a result of water seepage and humidity. to avoid this, the walls can be tiled or cleaned as necessary. home heating, cooling, and humidification systems are also potential sources of fungal growth, although air-conditioning generally reduces indoor humidity and hence discourages mold growth. most fungal spores in an indoor environment are nonviable spores that will be found in house-dust reservoirs such as carpeting, bedding, and furniture. implementing the same precautions used to reduce levels of dust mites is the best way to eliminate mold spores from the home. levels of viable indoor mold spores can be reduced by removing or cleaning mold-laden objects. levels may also be reduced by use of dehumidifiers (set humidity level < 50%) in the basement and air-conditioners in the bedroom or family room. air-conditioners and dehumidifiers reduce humidity and filter large fungal spores, lowering the mold and yeast count indoors, although their benefit in reducing asthma symptoms is controversial. home humidifiers should be used with caution and cleaned frequently because of the potential for mold and actinomyces growth. bathrooms and kitchens should be well ventilated. electronic air filters also lower the level of mold spores within a dwelling. when the major source of molds within a home is a wet or damp cellar, the basement should be kept free of carpeting, immediately dried out after a rainstorm, and, whenever possible, protected with a drain tile and sump pump. nonallergenic indoor triggers (table 17 -3) of asthmatic symptoms are a heterogeneous group of irritants that affect bronchial hyperreactivity in a non-ige-dependent fashion. as with all other asthma triggers, each should be identified and meticulously eliminated or avoided. active and passive tobacco cigarette smoke, consisting of very small, light particles that remain airborne for long periods, is a high-risk trigger for all asthmatic individuals. studies have demonstrated that children may be at increased risk of developing asthma and allergic sensitization when exposed to passive smoke. other studies in children show worsening asthma symptom severity, higher medication requirements, more frequent emergency department visits, and increased airway responsiveness when exposed to passive maternal tobacco smoke. active cigarette smoking not only has direct, deleterious effects on the lung parenchyma, it also reduces the efficacy of inhaled and systemic corticosteroids. thus, smoking cessation must be a primary objective for the patient, friends, and family members of asthmatic patients. other forms of smoke, such as that of wood-burning stoves, also have negative effects on the lower respiratory tract. additional airborne irritants, fumes, and strong odors (e.g., chalk dust, talcum powder, paint fumes, insecticides, household cleaning sprays, polishes, cooking oil fumes, perfumes, and cosmetics) may initiate or exacerbate asthmatic symptoms in some patients. other indoor pollutants include carbon monoxide, formaldehyde, nitric oxide, nitrogen oxides, and bacterial endotoxin. in all of these cases, adequate ventilation plays a pivotal role in successful prevention of asthma symptoms, as air stagnation has been shown to be a surrogate marker for the accumulation of indoor pollutants. other important preventative avoidance measures include household cleaning and proper maintenance of gas appliances. nonallergic outdoor irritants (see table 17 -3) that trigger asthma are also exceedingly common and important to identify and eliminate. studies have implicated several outdoor pollutants as potential triggers of asthma symptoms. air pollutants such as ozone, nitrogen oxides, acidic aerosols, and particulate matter can lead to asthma symptoms and frank exacerbations. other important outdoor asthma triggers include exposure to vehicle traffic (especially diesel exhaust), which might exacerbate preexisting allergic conditions by enhancing airway responses to allergen, a potential compounding effect. on occasion, weather and atmospheric conditions create brief periods of intense air pollution in a defined geographic area. at these and other times and in areas of high outdoor pollution, patients with asthma should avoid unnecessary outdoor physical activity (especially exercise) and try to stay indoors in a clean environment. as with pollen and aeroallergens, air-conditioning and filters may be helpful in preventing unnecessary morbidity. when working outdoors in polluted areas is unavoidable, taking a preventative, short-acting inhaled bronchodilator beforehand may prevent acute asthma symptoms. if prolonged outdoor polluted conditions are likely to persist, it is a good idea to tell patients to leave the polluted area before mild symptoms spiral into an acute asthma flare. hundreds of substances have been identified as occupational irritants or allergens that can trigger asthma symptoms. one can access a fairly comprehensive list of potential occupational asthma triggers at http://asmanet.com. an overview of these triggers and occupational asthma is covered in chapter 42. levels of exposure above which sensitization occurs have been proposed for many chemicals, so primary prevention is possible with proper precautionary measures. however, once a patient has been sensitized, the level of exposure necessary to induce symptoms may be very low, and resulting exacerbations may become progressively severe on reexposure. attempts to reduce occupational exposure have been successful, especially in the industrial setting, where potent sensitizers have been replaced by less allergenic or sensitizing substances. for example, primary prevention of latex allergy has been very successful. this has been accomplished by producing powder-free, lower allergen-content gloves. in cases where prevention is not possible, the early identification of occupational sensitizers and the removal of affected patients from these environments are critical to the successful management of occupational asthma. numerous medications (table 17 -4) have been implicated in triggering asthma symptoms. the most common offenders include nonsteroidal anti-inflammatory drugs (nsaids) and b-blockers. approximately 5% to 10% of adult asthmatic patients will have an acute worsening of asthma symptoms after ingesting nsaids. samters triad or "the aspirin triad" can be identified in some adult asthmatic patients. the response to aspirin or other nsaids typically begins within smoke (tobacco, wood-burning stove) strong odors (perfumes and cosmetics) particulates (chalk dust, talcum powder) fumes (household cleaning products, insecticides, paints, chemicals, cooking) smoke (wood/tree, refuse and chemical fires) exhaust (diesel fumes) other (ozone, chemicals) an hour of aspirin ingestion and may be associated with profound rhinorrhea, lacrimation, and, potentially, severe bronchospasm. patients sensitive to aspirin usually are reactive to all other nsaids (e.g., ibuprofen, naproxen), and variations in the frequency and severity of adverse responses appear to depend on the potency of each drug within this class of compounds to inhibit the activity of the cox-1 enzyme. sensitivity to nsaids is not ige-mediated and involves the modulation of eicosanoid production. nsaids likely act by reducing the formation of prostaglandins that help maintain normal airway function while increasing the formation of asthma-provoking eicosanoids, including hydroxyeicosatetraenoic acids and cysteinyl leukotrienes. thus, if aspirin-sensitive asthmatic individuals require treatment with an nsaid, the use of a selective cox-2 inhibitor is a viable treatment option, especially when combined with an inhibitor of leukotriene synthesis or leukotriene receptor antagonist. in addition, there is evidence that mast cell activation occurs, and its mediators can be detected in nasal secretions during an episode of aspirin-induced asthma. this syndrome should be of concern in any asthmatic patient with nasal polyposis, chronic sinusitis, and eosinophilia, although nasal polyposis and sinusitis may precede the onset of recognized nsaid-sensitivity by years. b-blockers administered either orally or via eye drops (for hypertension or glaucoma, respectively) may exacerbate asthma symptoms via bronchospasm. as a general rule, these medications should be not be used by asthmatic individuals, as other classes of drugs may be used to successfully treat these underlying comorbidities. if b-blockers are used, close medical supervision is essential to prevent unnecessary morbidity. as is the case with all of the aforementioned asthma triggers, avoidance is the treatment of choice. weather and atmospheric changes also commonly trigger asthma symptoms. classically, cold dry air can induce bronchoconstriction in asthmatic individuals. atmospheric conditions that typically trigger asthma symptoms include changes in temperature and humidity, barometric pressure, or gusts of wind. perhaps of greater importance than these changes are the effects these atmospheric changes have on seasonal and perennial allergens. for example, pollen and mold counts have seasonal patterns and release of these allergens is highly dependent upon "proper" environmental conditions to allow successful release and plant pollination/procreation. as aforementioned, it is well recognized that exposure to molds or pollens during a particular season can induce asthmatic attacks in sensitized (allergic) individuals, so any atmospheric change (seasonal change or sudden gust of wind) that increases exposure to these allergens is potentially detrimental to allergensensitized asthmatic individuals. furthermore, with seasonal changes (particularly the fall and winter) also comes an increased exposure to viruses like rhinovirus and influenza that commonly precipitate asthma attacks. respiratory viral and bacterial infections (table 17 -5) are a major cause of morbidity and mortality in people with asthma. respiratory viruses trigger acute exacerbation of asthma in children and adults. these infections frequently result in outpatient visits and hospitalizations. additionally, these infections make asthmatic individuals more sensitive to other asthma triggers. typical respiratory tract infections that cause airway inflammation and trigger asthma include the "common cold" and flu, bronchitis, ear infections, sinusitis, and pneumonia. asthma attacks that occur in conjunction with an upper or lower respiratory tract infection may be more severe than exacerbations that occur without concomitant infection. the most common respiratory viruses are the rhinovirus ("common cold" virus), respiratory syncytial virus (rsv), and certain influenza viruses. these viruses are present in most patients hospitalized with life-threatening asthma exacerbations and acute non-life-threatening asthma flares. asthmatic individuals are not more susceptible to upper respiratory tract rhinovirus infections than healthy, nonasthmatic individuals, but they do suffer more severe consequences of lower respiratory tract infections. recent epidemiologic studies suggest that viruses provoke asthma attacks by additive or synergistic interactions with allergens or irritants like air pollutants. an impaired antiviral immunity to rhinovirus may rhinovirus (1-100+ serotypes; causes "common cold," bronchitis and bronchiolitis) coronavirus (2299e and oc43 serotypes; causes "common cold") influenza (a, b, and c serotypes; causes "common cold," pneumonia and bronchitis) parainfluenza (1, 2, 3, and 4 serotypes; causes "common cold," laryngotracheobronchitis, and bronchiolitis) respiratory syncytial virus (a and b serotypes; causes "common cold," pneumonia, bronchitis, and bronchiolitis) adenovirus (1-4 serotypes; causes "common cold," pneumonia, bronchitis and bronchiolitis) metapneumovirus (bronchiolitis) streptococcus pneumoniae (sinusitis and pneumonia) haemophilus influenzae and parainfluenzae (sinusitis and pneumonia) moraxella catarrhalis (sinusitis and pneumonia) staphylococcus aureus (pneumonia) klebsiella pneumoniae (pneumonia) atypical (chlamydia pneumoniae and mycoplasma pneumoniae causing pneumonia) lead to impaired viral clearance and, in turn, prolonged symptoms. viral respiratory tract infections exacerbate asthma by recruiting t h 2-type cells into the lungs. currently, we have no specific antiviral strategies for preventing the exacerbation of asthma by respiratory viral infection; however, clinical trials of potential antiviral agents are ongoing. indirect prevention strategies focus on reducing overall airway inflammation to reduce the severity of the host response to respiratory viral infections. although many bacterial infections are known to cause asthma exacerbations in susceptible individuals, recent attention has been focused on lower respiratory tract infections with atypical bacteria. mycoplasma pneumoniae and chlamydia pneumoniae are thought to be common triggers of asthma. whether these bacteria are the inciting agents for the onset of disease or acute exacerbations has yet to be definitively determined; however, there are also data supporting the notion that infection with atypical bacteria may be a contributing factor to difficult-to-treat asthma. strenuous physical exercise can also trigger asthma attacks. exercise can cause asthma symptoms to flare, especially when asthma is not well controlled. mouth breathing; exercising in cold, dry air; or prolonged, strenuous activities such as medium-to long-distance running can increase the likelihood of exercise-induced bronchospasm-an obstruction of transient airflow that usually occurs 5 to 15 minutes after the onset of physical exertion. although exercise can trigger asthma in certain people, it is one trigger that should not be avoided. exercise strengthens the cardiovascular system and may lessen the sensitivity to asthma triggers. to minimize the effects of this trigger, asthmatic individuals should start any new exercise regime slowly, gradually building strength and endurance, and warm up gradually at the beginning of each exercise session. avoiding exercise outdoors in extremely cold weather or during peak pollen seasons is also a prudent measure. asthma and gastroesophageal reflux disease (gerd) are common medical conditions that often coexist. studies have shown conflicting results on whether lower esophageal acidification can act as a trigger for asthma. in fact, asthma might precipitate gerd symptoms; thus, a temporal association between the two does not establish that gerd triggers asthma. randomized trials investigating different treatment modalities for gerd in asthma have been conducted to determine whether treatment of gerd improves asthma symptoms and outcomes. a meta-analysis of randomized controlled trials concluded that therapy for gerd, including acid-suppressive treatment with a proton-pump or histamine-2 receptor antagonists, does not consistently improve lung function, asthma symptoms, nocturnal asthma, or lessen the use of asthma medications. littner and colleagues showed that in adult patients with moderate-to-severe persistent asthma and symptoms of acid reflux, treatment with 30 mg of lansoprazole twice daily for 24 weeks did not improve asthma symptoms, pulmonary function, or reduce albuterol use. however, this dose significantly reduced asthma exacerbations and improved quality of life, particularly in those patients receiving more than one asthma-controller medication. with all of this being considered, untreated gerd symptoms may affect airway reactivity in patients with asthma. thus, treating patients for symptoms of gerd with concomitant asthma has become standard practice and should be considered. exposure to food allergens and additives (see fig. 17 -3) can cause a variety of symptoms. it is widely believed that allergic reactions to foods are common asthma triggers, but definitive evidence to support this concept is lacking. despite this lack of data, some asthmatic individuals report worsening asthma symptoms after ingesting specific foods and food additives. food additives that have been implicated include salicylates, food preservatives, monosodium glutamate, and some food-coloring agents. sodium metabisulfite, a preservative in many beverages (including beer and wine) and foods, is thought to release sufficient sulfur dioxide to provoke bronchoconstriction. for some people, eating a particular food (common culprits include milk, eggs, peanuts, tree nuts, soy, wheat, fish, and shellfish) can trigger asthma symptoms. this constellation of food sensitivity and worsening asthma symptoms tends to correlate with a more severe course of disease. patients with food allergies and underlying asthma experience more severe reactions to food allergens than do patients without asthma, because their reactions are more likely to involve life-threatening respiratory symptoms. allergic reactions that involve respiratory symptoms are almost always more severe than reactions that do not involve the respiratory tract. particularly susceptible food-sensitive asthmatic individuals have been reported to react to merely inhalation without ingestion; however, isolated symptoms of rhinitis or asthma without concomitant cutaneous or gastrointestinal symptoms are rare. nevertheless, if any type of food triggers an asthma attack, the best treatment is strict avoidance. although asthma is not a psychological condition, emotional or nervous stress can trigger asthma symptoms. stress alone cannot provoke asthma; however, if accompanied by anxiety, stress can cause fatigue, potentiating coughing, shortness of breath, and wheezing. a strong feeling or emotional behavior, such as laughing or crying, may trigger asthma symptoms because of the accompanying change in breathing patterns. as with any other chronic health condition, proper rest, nutrition, and exercise are important to overall wellbeing and can help in managing asthma. effective control of asthma depends on identification and alleviation of exacerbating factors. triggers of asthma frequently include ongoing exposure to allergens and irritants, medications, weather and atmospheric changes, upper and lower respiratory tract infections, uncontrolled gastroesophageal reflux disease, foods and food additives, and emotional stress and anxiety (fig. 17-3) . it is of paramount importance to recognize contributing factors early, and eliminate exposure to prevent unnecessary morbidity and mortality. a key theme to this chapter has been avoidance, which in many cases is quite difficult; but by following a systematic method for identifying and removing potential triggers from the asthmatic individual's environment, the goal of optimum asthma control can be accomplished with a combined, concerted effort on the part of the physician and patient. attaining optimal asthma control: a practice parameter global initiative for asthma (gina): global strategy for asthma management and prevention national institutes of health, national heart, lung, and blood institute house dust mite control measures for asthma asthma: factors underlying inception, exacerbation, and disease progression effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children practice parameter for the diagnosis and management of asthma key: cord-265563-1k8v0luz authors: sperlich, johannes m.; grimbacher, bodo; workman, sarita; haque, tanzina; seneviratne, suranjith l.; burns, siobhan o.; reiser, veronika; vach, werner; hurst, john r.; lowe, david m. title: respiratory infections and antibiotic usage in common variable immunodeficiency date: 2017-07-19 journal: j allergy clin immunol pract doi: 10.1016/j.jaip.2017.05.024 sha: doc_id: 265563 cord_uid: 1k8v0luz background: patients with common variable immunodeficiency (cvid) suffer frequent respiratory tract infections despite immunoglobulin replacement and are prescribed significant quantities of antibiotics. the clinical and microbiological nature of these exacerbations, the symptomatic triggers to take antibiotics, and the response to treatment have not been previously investigated. objectives: to describe the nature, frequency, treatment, and clinical course of respiratory tract exacerbations in patients with cvid and to describe pathogens isolated during respiratory tract exacerbations. methods: we performed a prospective diary card exercise in 69 patients with cvid recruited from a primary immunodeficiency clinic in the united kingdom, generating 6210 days of symptom data. we collected microbiology (sputum microscopy and culture, atypical bacterial pcr, and mycobacterial culture) and virology (nasopharyngeal swab multiplex pcr) samples from symptomatic patients with cvid. results: there were 170 symptomatic exacerbations and 76 exacerbations treated by antibiotics. the strongest symptomatic predictors for commencing antibiotics were cough, shortness of breath, and purulent sputum. there was a median delay of 5 days from the onset of symptoms to commencing antibiotics. episodes characterized by purulent sputum responded more quickly to antibiotics, whereas sore throat and upper respiratory tract symptoms responded less quickly. a pathogenic virus was isolated in 56% of respiratory exacerbations and a potentially pathogenic bacteria in 33%. conclusions: patients with cvid delay and avoid treatment of symptomatic respiratory exacerbations, which could result in structural lung damage. however, viruses are commonly represented and illnesses dominated by upper respiratory tract symptoms respond poorly to antibiotics, suggesting that antibiotic usage could be better targeted. abbreviations used copd-chronic obstructive pulmonary disease cvid-common variable immunodeficiency hr-hazard ratio iqr-interquartile range oat-oral antibiotic therapy or-odds ratio sgrq-st george's respiratory questionnaire te-treated exacerbation tse-treated symptomatic exacerbation use-untreated symptomatic exacerbation between 1 in 10,000 and 1 in 50,000, it is the most common symptomatic primary immunodeficiency. [1] [2] [3] [4] despite adequate immunoglobulin replacement, recurrent respiratory tract infections are the commonest clinical feature in cvid 2, 5 and can result in progressive bronchiectasis. [6] [7] [8] [9] respiratory tract infections were thought to be caused largely by encapsulated bacteria. 6, 10 however, recent evidence shows that there may be a significant contribution from viral infections. 11, 12 despite the high incidence of respiratory tract infections and their negative influence on quality of life in primary antibody deficiency syndromes, 13 the nature of symptoms during these episodes remains unknown. patients are often prescribed antibiotics to mitigate respiratory tract infections, both as "rescue" courses to promptly self-administer for acute events and as prophylaxis to reduce infection frequency. however, the symptomatic triggers for taking breakthrough antibiotics and the clinical response to these treatments are not known. in this prospective study, we sought to answer these questions by systematically recording daily symptoms and treatment in a cohort of patients with cvid over a winter period. in a parallel analysis, we also explored bacterial and viral pathogens encountered during acute respiratory symptoms in patients with cvid. patients were recruited from the joint immunology-respiratory service at the royal free hospital, london. patients had a diagnosis of cvid made by a clinical immunologist following the definitions of the pan-american group for immunodeficiency and the european society for immunodeficiencies. 14 all were receiving immunoglobulin replacement and were under regular (at least 6-monthly) clinical review. the only exclusion criterion was inability to provide informed consent. all participants provided written informed consent (rec 04/q0501/119). for this observational, prospective cohort study, patients completed daily checkbox symptom diaries for 90 days between december 2014 and february 2015, covering the uk winter season. participants were asked to report new or increased respiratory symptoms from a predefined list (table i) . chronic or stable symptoms were not to be reported. definitions of symptoms and instructions for diary completion were clearly explained; further details are provided in this article's online repository at www.jaciinpractice.org. we have previously used such methodology in other chronic respiratory diseases. 15 participating patients were also asked to complete the st george's respiratory questionnaire (sgrq), a validated measure of respiratory health status scored between 0 (best) and 100 (worst) quality of life. 16 simultaneously, but independently from the described study, we conducted a cross-sectional study in which patients experiencing acute respiratory symptoms provided samples (nasopharyngeal swabs and spontaneously expectorated sputum) for bacterial and viral testing. sputum was considered purulent when more than 10 granulocytes per hpf were found. samples were either collected by clinic staff or, after careful instruction on sampling, submitted directly from patients by mail. figure 1 shows the 2 investigations undertaken on the cohorts. for preanalysis, we grouped clinically related symptoms as presented in table i . for calculation of total symptom count, each symptom was counted individually for each patient and each day. cumulative total symptom count is the sum over all days of an exacerbation period. we used 2 definitions of exacerbation, based either on symptoms or health care utilization. similar methodology has been reported and validated in chronic obstructive pulmonary disease (copd). 17 for the first definition, we identified a symptomatic exacerbation as an event of 2 or more new symptoms lasting for 2 or more consecutive days as recorded by the patient in their diary, whether or not they received additional treatment. the start of a symptomatic exacerbation episode was the first day of 2 or more new symptoms lasting for 2 or more consecutive days. the end of the episode was the last consecutive day with 2 or more symptoms (allowing symptoms to change over time). if oral antibiotic therapy (oat) was used during a symptomatic exacerbation episode, this was considered a treated symptomatic exacerbation (tse). if not, it was an untreated symptomatic exacerbation (use). we defined a health care utilization exacerbation as use of oat for worsening respiratory symptoms. we call this a treated exacerbation (te) event, and if it coincided with diary-defined symptoms it would be a tse. the episode was considered to last from the first day on which a symptom occurred until recovery, defined as the last day of any symptom that was present when oat was started. additional details regarding exacerbation and variable statistical analysis was performed using stata version 14.0 (statacorp lp, college station, tex). continuous variables are presented as median and first and third quartiles or by mean and sd as appropriate. for categorical and binary variables, we present frequencies. missing data were not imputed. results were considered statistically significant at a p value of less than .05. data were analyzed with logistic regression for trigger symptom analysis, cox regression for antibiotic response analysis, pearson correlation, wilcoxon rank sum test, and t tests as indicated. further details are provided in this article's online repository at www.jaci-inpractice.org. a multiplex real-time pcr (rt-pcr) for adenovirus, coronavirus (hku, nl63, oc43, and 229e), enterovirus, human metapneumovirus, influenza virus (a and b), parainfluenza virus (1, 2, 3, and 4), parechovirus, respiratory syncytial virus, and rhinovirus was performed in the national health service virology laboratories at the royal free hospital. sputum samples were examined by microscopy and culture for bacteria and mycobacteria plus in-house multiplex rt-pcr for chlamydia pneumoniae, legionella pneumophila, and mycoplasma pneumoniae. further details are provided in this article's online repository at www.jaci-inpractice.org. we included multiple samples from a single patient if separated by at least 2 weeks and the patient was asymptomatic between episodes. airway colonization by pathogenic bacteria was diagnosed when the same organism had been isolated more than twice within the 2 years before our study. a total of 134 patients with cvid were given a diary. out of these, 69 (51%) patients returned a diary after completion of the study period, providing 6210 days of data ( figure 1 ). demographic and clinical characteristics of included patients are presented in table ii . patients who completed a diary were older [1] [2] [3] [4] ; p ¼ .01) than those who did not. during the study period, there were 170 symptomatic exacerbation events (mean, 0.82 per patient month). of these events, 75 (mean, 0.36 per patient month) were treated by oat but 95 (mean, 0.46 per patient month) were not. nine patients had no symptomatic exacerbations during the period. published literature suggests that 106 courses of antibiotics were prescribed per 1000 men and 155 per 1000 women for respiratory tract infections by general practitioners in the united kingdom in 2014. 18 this corresponds to 2.3 courses of antibiotics in total (0.01 per patient month) prescribed to a group similar to our cohort in the general population during 3 months. tse episodes were more severe than use in terms of cumulative total symptom count (median [iqr], 40 vs 12 symptoms; p < .001) and episode duration (median duration, 10 vs 4 days; hazard ratio [hr], 0.54; p < .001). a total of 76 tes were covered within our study period. one te did not meet the criteria of tse. the median (iqr) duration of te episodes was 14 (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) days; median (iqr) time from the start of symptoms until oat was 5 (2-7) days; and median (iqr) time until recovery was 6.5 (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) days. the median (iqr) duration of therapy was 14 (7) (8) (9) (10) (11) (12) (13) (14) days. a detailed description of symptom prevalence is shown in figure 2 . as treatment, patients used co-amoxiclav for 23 exacerbations (30%), amoxicillin for 20 exacerbations (26%), doxycycline for 12 exacerbations (16%), ciprofloxacin for 10 exacerbations (13%), clarithromycin for 7 exacerbations (9%), and azithromycin, erythromycin, flucloxacillin, and levofloxacin for 1 exacerbation each (1%). cough, shortness of breath, and purulent sputum are the strongest triggers for patients to initiate antibiotic therapy we compared 76 days on which oat was started with 5370 days without oat. the 764 days comprising the remainder of the antibiotic courses were ignored. in univariate analysis, all symptoms were positively and significantly associated with start of oat. cough (odds ratio [ ct, x-ray computed tomography. note. p values were calculated using the wilcoxon rank sum test for continuous variables and the fisher exact test for categorical variables. *serum igg level measured immediately before the next immunoglobulin replacement is administered. †bronchiectasis severity index, ranging from 0 (best) to 25 (worst), is a validated multicomponent score in bronchiectasis that predicts the future risk of exacerbations, hospitalizations, and mortality. zfev 1 predicted is the proportion of actual fev 1 vs predicted fev 1 in accordance with the european respiratory society guidelines of 1993. xthe sgrq is a validated measure of respiratory health status scored between 0 (best) and 100 (worst) quality of life. in univariate analysis, time since start of symptoms was not positively associated with start of oat, and instead patients started oat at a fairly constant rate over the first 12 days of symptoms ( figure 3 , b). there was, however, a significant positive association between total symptom count and start of oat (or, 2.19; 95% ci, 1.96-2.43), suggesting an approximate doubling of the odds to start oat for each additional symptom. the mean number of symptoms on days on which oat was started was 4.97 ae 1.94 versus 0.86 ae 1.55 symptoms on days when antibiotics were not taken (p < .001). exacerbations characterized by purulent sputum respond rapidly to antibiotics, whereas those characterized by upper respiratory tract symptoms and sore throat respond more slowly median (iqr) time until recovery after start of oat in all tes was 6.5 (5-14) days ( figure 4 , a). in 56% of tes, time until recovery was 7 days or less; in 81% it was 14 days or less. in univariate analysis, time until recovery was longer in the presence of upper respiratory tract symptoms (median, 8 vs 5 days; hr, 0.50; p ¼ .03; figure 4 , b), sore throat (12 vs 6 days; hr, 0.54; p ¼ .007; figure 4 , c), or white sputum (12 vs 6 days; hr, 0.63; p ¼ .03) on the day before commencing oat. however, time until recovery was shorter in exacerbations in which purulent sputum was present (6 vs 13 days; hr, 1.98; p ¼ .02; figure 4 , d). in multivariate analysis, upper respiratory tract symptoms, sore throat, and purulent sputum were significant independent predictors for response to oat (figure 4, e) . there was no statistically significant correlation between time until starting oat and time until recovery nor between total symptom count on the day before oat was started and subsequent time until recovery. however, a longer time until starting oat was associated with a longer episode duration (hr, 0.92; p < .001). patients taking prophylactic antibiotics have more untreated exacerbations and wait longer from the onset of symptoms to initiate breakthrough antibiotics we proceeded to investigate whether the frequency and nature of exacerbations were affected by antibiotic prophylaxis or by the presence of bronchiectasis. the mean numbers of symptomatic exacerbations (total, treated, and untreated) were analyzed with t tests and interaction was tested with 2 (prophylactic antibiotics) by 2 (bronchiectasis) analyses of variance. there were more symptomatic exacerbation events in patients on prophylactic antibiotics than in patients not on prophylaxis ( the higher numbers of symptomatic exacerbations and uses in patients on prophylactic antibiotics did not depend on the presence or absence of bronchiectasis. we observed a mean difference of 0.93 in the number of symptomatic exacerbations between patients on and off prophylaxis in those with bronchiectasis and of 1.61 in those without. for uses, the differences in regarding the impact of antibiotic prophylaxis on exacerbation severity, there was no significant difference in episode duration or cumulative total symptom count during symptomatic exacerbations between patients on or off prophylactic antibiotics. patients taking prophylactic antibiotics waited longer before starting oat for breakthrough infections (median, 6 vs 3 . e, forest plot displays hrs for time until recovery after start of oat depending on the presence of specific symptoms. a multivariate cox model was used for all symptoms that proved to be significant in univariate analysis (only multivariate data are shown for these variables). hr reflects the "risk" for earlier complete symptomatic remission over time. isv, increased sputum volume; sob, shortness of breath. j allergy clin immunol pract volume 6, number 1 days; hr, 0.55; p ¼ .03). however, time until recovery after commencing oat was not significantly different between patients on or off prophylactic antibiotics. there were no significant differences between patients with and those without bronchiectasis in exacerbation severity, time until oat, and time until recovery. prospective symptoms correlate modestly with cross-sectional analysis of quality of life there was moderate correlation between the sgrq total score and the number of days on which new cough (r ¼ 0.29; p ¼ .02), sore throat (r ¼ 0.29; p ¼ .02), shortness of breath (r ¼ 0.38; p ¼ .002), and wheeze (r 0.32; p ¼ .01) were present. the cumulative total symptom count or cumulative number of days of symptomatic exacerbation episodes over the study period also correlated with sgrq symptom score (r ¼ 0.36; p ¼ .004) and sgrq total score (r ¼ 0.28; p ¼ .03). a total of 54 nasopharyngeal swabs were obtained from 41 patients with acute respiratory symptoms. viruses were detected in 30 (56%) exacerbations ( figure 5 ). rhinovirus was the most common virus detected (in 18 [33%] exacerbations), including 2 (4%) co-infections with respiratory syncytial virus, 2 (4%) co-infections with adenovirus, and 1 (2%) co-infection with human metapneumovirus. a total of 43 spontaneously expectorated sputum samples were obtained from 34 patients with acute respiratory symptoms. pathogenic bacteria were isolated in 14 (33%) exacerbations ( figure 5 ). the most common bacteria were haemophilus influenzae in 8 (19%), streptococcus pneumoniae in 2 (5%), and pseudomonas aeruginosa in 2 (5%) exacerbations. two patients accounting for 4 exacerbations were colonized with h. influenzae as defined earlier. all samples were negative for mycobacterial culture and pcr for atypical pneumonia organisms. there was bacterial and viral co-infection in 25% of exacerbations; in 27.5% no pathogen was found. microscopic evidence of purulence as measured by more than 10 granulocytes per hpf was found on microscopy in 41% of exacerbations positive for a pathogenic virus (whether or not patients produced sputum), in 69% of exacerbations positive for a pathogenic virus where contemporaneous sputum was collected, and in 64% of exacerbations positive for pathogenic bacteria. this is the first prospective cohort study describing symptoms and treatment of respiratory tract infection in cvid. we discovered a clinically important delay in commencing antibiotic therapy and that many symptoms are untreated, especially in patients taking prophylactic antibiotics. episodes characterized by purulent sputum respond more quickly to antibiotics, whereas sore throat and upper respiratory tract symptoms respond less quickly; perhaps correspondingly, in many respiratory exacerbations we detected a pathogenic virus. patients with cvid are frequently prescribed antibiotics and educated to promptly take them if they suffer "breakthrough" infections. however, their actual behaviors in relation to this therapy have not previously been documented. here, across 6210 days of data, we discovered that individual "warning" symptoms (cough, shortness of breath, and purulent sputum) are the most important triggers for patients to start oat. time since start of symptoms is a less important trigger, and the proportion of patients starting therapy each day is fairly constant across the first 12 days of symptoms. consequently, and despite the fact that all patients should have antibiotics available for immediate usage, there is a median delay of 5 days in starting oat. we are investigating whether delays to commencing treatment are explained more by patient choice or by access to health care. a longer time to commencing therapy did not adversely impact subsequent response to antibiotics (measured by time until recovery), but inevitably increased the total length of an infectious episode. because infections in cvid can lead to structural lung damage, 2,13 this delay may be clinically significant. similarly, many exacerbations (95 across the study period) were untreated and may not have been reported without prospective data collection. indeed, it is well documented that uses often go unreported in copd, 19 with up to 3 times more exacerbations collected by symptom diaries than by interview; patients with copd also treat only half of all exacerbations recorded in diaries. 20 response to oat, judged by time until recovery, did not correlate with delay to commencing therapy or total symptom count, but depended on individual symptoms. there was a slower response in patients with upper respiratory tract symptoms and sore throat, which we hypothesize may be explained by a purely viral etiology for some of these episodes. conversely, exacerbations with purulent sputum resolved more quickly on antibiotics, perhaps indicating a dominant bacterial component. the number of uses, and delay to commencing oat, was higher in patients on prophylactic antibiotics. this could imply a reluctance to start oat in this group because of over-reliance on prophylaxis or as an increased tolerance of symptoms (generally prophylaxis is instituted only in patients with a background of high incidence of exacerbations). we found no difference in severity or duration of individual symptomatic exacerbations with or without prophylaxis; this could indicate effectiveness of prophylaxis, but conversely there is no evidence that prophylaxis attenuates the severity of breakthrough exacerbations. there was a modest correlation between some acute symptoms reported in diaries and the sgrq, which measures the impact of symptoms on health-related quality of life. 16 cumulative total symptom count and cumulative number of days of symptomatic exacerbation over the study period also correlated with sgrq scores, confirming that symptomatic exacerbations have a significant impact on patients. however, our study design included only new or worsening symptoms rather than chronic symptoms, which presumably explains only a moderate correlation between diary-derived parameters and sgrq scores. in our analysis of pathogens isolated during symptomatic exacerbations, we detected a virus in 56% of patients' samples. this is similar to other reports; for example, kainulainen et al 11 reported positive viral pcr in 54% of 65 exacerbations in 12 patients. bacterial pathogens, most commonly encapsulated organisms, were found in 33% of symptomatic exacerbations. interestingly, in exacerbations positive for a pathogenic virus but in which the patient also expectorated sputum, there was evidence of purulence as measured by high microscopic granulocyte count in 69% of samples. although this may be partly explained by underlying bronchiectasis in some patients, we frequently observed co-infection with bacteria. although this may represent simply colonizing bacteria in the presence of an acute viral exacerbation, there is evidence from copd that rhinovirus infections adversely affect microbiome and the prevalence of pathogenic bacteria. 21, 22 our earlier results suggest that new or worsening purulent sputum predicts rapid response to antibiotic therapy, regardless of the organism isolated. further research is required to investigate how the pathogens identified here influence the balance of other organisms in the respiratory tract and thereby the response to antibiotic therapy. however, our current recommendation would be to promptly treat exacerbations characterized by purulent sputum irrespective of virology results, not least because neutrophil elastase is significantly implicated in bronchiectasis pathogenesis. 22, 23 our study has some limitations. it was performed at a single tertiary care center during the winter, when respiratory tract infections are more frequent. 24, 25 the true incidence of symptomatic exacerbations and antibiotic use throughout the year thus cannot be extrapolated. we cannot exclude that factors particular to our geographic location and particular to the brief study period have influenced our results. no pathogen (gray) was found in 24 (44%) exacerbations. a pathogenic virus was found in 30 (56%) exacerbations. rhinovirus was found in 18 (33%) exacerbations, including 2 co-infections with adenovirus (adeno), 2 with respiratory syncytial virus (rsv), and 1 with human metapneumovirus (hmpv). b, bacterial culture was performed on spontaneously expectorated sputum in 43 symptomatic respiratory exacerbations in patients with cvid. no pathogen (gray) was found in 29 (67%) exacerbations. a pathogenic bacterium was found in 14 (33%) exacerbations. pseudomonas aeruginosa was isolated in 3 (7%) exacerbations; among those was 1 co-infection with streptococcus pneumoniae. two patients (accounting for 4 exacerbations) were probably colonized with haemophilus influenzae. j allergy clin immunol pract volume 6, number 1 because of its design, this study lacks a healthy control group. we therefore cannot discuss differences in quality or quantity of exacerbations between cvid and nonimmunocompromised patients, but available data from other sources 18 suggest that the usage of antibiotics in our cohort is many times higher than in the general population. we have data only from patients who agreed to complete a diary (69 patients) and not the entire cvid cohort (134 patients). this may result in a selection bias, especially because these patients are older and have more clinically severe bronchiectasis. although exacerbations did not differ in number or severity between patients with or without bronchiectasis, generalizability may be affected by variation in the prevalence of bronchiectasis throughout centers. 2 the symptomatic definition of a respiratory exacerbation in cvid is not standardized and we therefore operated with a simplified definition, which has been validated in copd. 17 although patients were carefully instructed to record only new or worse symptoms, we cannot exclude the possibility that some reported chronic morbidity. we note that the mean number of "new" symptoms even on days without antibiotic therapy was 0.86; however, this includes the period before and after antibiotic therapy in exacerbations and may also reflect a genuinely high frequency of acute symptoms. because many patients resided at a significant distance from the hospital, we were unable to perform microbiology and virology tests on diary-defined exacerbations and thus performed 2 parallel studies ( figure 1 ). we have demonstrated that respiratory exacerbations are extremely common in cvid, but that patients delay starting antibiotics and ignore symptoms. although viruses were identified commonly, patients should nevertheless be educated to take antibiotics promptly if they develop purulent sputum. for this observational, prospective cohort study, patients completed daily checkbox symptom diaries for 90 days between december 2014 and february 2015. participants were asked to report new or increased respiratory symptoms from a predefined list ( figure e1 ). chronic or stable symptoms were not to be reported. patients reported daily the use of oat to treat breakthrough infections and once a month the use of prophylactic antibiotics. patients discontinued prophylactic antibiotics if they started oat for breakthrough infections. participating patients were also asked to complete the sgrq, a validated measure of respiratory health status scored between 0 (best) and 100 (worst) quality of life and on which 4 points is considered the minimum clinically important difference. e1 the sgrq was conducted at the end of the study period so that its 3-month recall period covered the period during which the diary was competed. baseline information on spirometry, computed chest tomography, previous bacterial isolates on sputum culture, medical research council breathlessness score, and smoking status was collected from medical records and the departmental database. from these data, we calculated the bronchiectasis severity index, a validated multicomponent score in bronchiectasis that predicts the future risk of exacerbations, hospitalizations, and mortality. e2 simultaneously, we conducted an observational cross-sectional study in which patients experiencing acute respiratory symptoms provided samples for bacterial and viral testing. a total of 54 nasopharyngeal swabs were collected from 41 patients if patients were able to tolerate the procedure. a total of 43 spontaneously expectorated sputum samples were obtained from 34 patients if patients were able to produce a sufficient quantity of sputum. these samples were either collected by clinic staff or, after careful instruction on sampling, submitted directly from patients by mail. patients were recruited from outpatient clinics at the royal free hospital, london. all patients with a diagnosis of cvid and with written informed consent were included in the study (134 patients). there were no other exclusion criteria. we sent a copy of the diary and instructions to all 134 patients. an example is shown in figure e1 . patients who decided to participate had at least 3 follow-up contacts during the study period via telephone, via post, or at clinical visits to provide counseling on the diary and to improve adherence. a total of 69 (51%) patients returned a fully completed diary. at scheduled or ad-hoc visits to our outpatient clinics, patients in the cohort of consented patients with cvid were also asked to provide a microbiological sample at times of acute exacerbation. in all, 41 (31%) patients provided samples. for preanalysis, we grouped clinically related symptoms as presented in table i . blocked nose, nasal discharge, and sinus pain were combined as "upper respiratory tract symptoms." yellow and green sputum were combined as "purulent sputum," whereas any reported increase in sputum volume was analyzed as a single parameter. for the calculation of total symptom count, each symptom was counted individually, giving a theoretical range up to 9 total symptoms on each day. for the purpose of analysis of exacerbations, we distinguish exacerbation "events" from exacerbation "episodes." events are occurrences at one time point, whereas episodes are time periods with a defined start and ending. each exacerbation event was associated with an exacerbation episode. for events, we calculate incidence rates, association with other parameters, and time to events. for episodes, we calculate time-dependent characteristics such as duration and total symptom count, and we plot symptoms prevalence over time. we used 2 different definitions of exacerbation ( figure e2 ), based either on symptoms or health care utilization. for the first definition, we identified a symptomatic exacerbation event as 2 or more new symptoms lasting for 2 or more consecutive days as recorded by the patient in their diary, whether or not they received additional treatment for that. each symptomatic exacerbation event was associated with a symptomatic exacerbation episode. the start of a symptomatic exacerbation episode was the first day of 2 or more new symptoms lasting for 2 or more consecutive days. the end of a symptomatic exacerbation episode was defined as the last consecutive day with 2 or more symptoms, allowing symptoms to change over time. the duration of an episode is thus given as the time between the first day on which at least 2 symptoms occurred until the last day on which 2 or more symptoms were present. if oat was used during a symptomatic exacerbation episode, this was considered a tse. if not, it was a use. on the basis of treatment only, we defined a health care utilization exacerbation as use of oat for worsening of respiratory symptoms. we call this a te, and if this event coincided with diary-defined symptoms it would be a tse. in our study, 1 te did not fulfill the criteria of a tse. in analogy to the definition of symptomatic exacerbation episodes, each te event was associated with a te episode. each te episode lasted from the first day on which a symptom occurred until the last day a symptom was still present out of all symptoms present on the day oat was started. time until oat was defined as the period between the first day of symptom occurrence and the first day of oat. time until recovery was defined as the period between the day oat was started and the day all symptoms ended. together, time until oat and time until recovery represent te duration. if a te was only partially covered within the study period, we used censored data for time until oat and time until recovery. statistical analysis was performed using stata version 14.0 (statacorp lp, college station, tex). we summarized continuous variables by median and iqr or by mean and sds as appropriate. for categorical and binary variables, we present frequencies. results were considered to be statistically significant at a p value of less than .05. missing data were not imputed. six patients in the diary group did not complete the sgrq. data for these patients were ignored for the quality-of-life analysis. because of missing data, we were unable to calculate the bronchiectasis severity index for 19 patients (7 in the diary group). computed tomography scans were not available for 11 patients (5 in the diary group). data on lung function were missing for 13 patients (3 in the diary group). trigger symptom analysis and antibiotic response analysis. when analyzing which symptoms trigger patients to start antibiotic treatment, only days without oat and the first day after starting oat were included in analysis. all other days in a consecutive course of oat were ignored. first, to examine the association of each symptom separately with the start of oat we calculated ors and cis for each symptom in univariate analysis. next, we included all symptoms that proved to be significant in univariate analysis in a logistic regression model to analyze their effect adjusted for the other symptoms. similarly, ors were calculated to test the association between total symptom count or time since start of symptoms and the start of oat. the time since start of symptoms is defined as the number of days for which 2 or more symptoms have been present. to assess response to oat we analyzed the time until recovery after the start of oat and the cumulative total symptom count after the start of oat. the cumulative total symptom count is the sum of all symptoms on all days from start of oat until the last day a symptom was still present. because the results using either parameter were similar, we report time until recovery only. to analyze the predictive value of each symptom for the response to oat separately, we first used univariate cox regression models. next, we used a multivariate cox regression model for all symptoms that proved to be significant predictors in the univariate setting to examine their effect adjusted for the other symptoms. to analyze the predictive value of time until oat and total symptom count on the day before start of oat for the response to oat, we used univariate cox models. exacerbation severity analysis. as indicators for exacerbation severity, we used exacerbation duration and cumulative total symptom count over the exacerbation episode. cumulative total symptom count is defined as the sum of all symptoms over the duration of an exacerbation episode. we used cox models to compare durations and wilcoxon rank sum tests to compare cumulative total symptom counts. bronchiectasis and prophylactic antibiotics analysis. to analyze the impact of prophylactic antibiotics and bronchiectasis, we compared patients on or off prophylactic antibiotics and with or without radiological evidence of bronchiectasis in regard to number of exacerbations, exacerbation severity in symptomatic exacerbations, time until oat, and time until recovery. we used t tests to compare means of the number of symptomatic exacerbations, the number of tses, and the number of uses. the significance of the difference in the difference between mean values was assessed by an interaction test in a 2-way anova. time until oat, time until recovery, and episode duration in symptomatic exacerbations were compared using univariate cox regression models. quality-of-life analysis. the sgrq is a validated and widely used measurement of respiratory health based on a 3-month recall period. e1 its total score is a continuous variable ranging from 0 to 100, where 0 indicates low and 100 indicates high impairment of respiratory health. e1 on the basis of our diary data, we calculated the number of days on which a specific symptom was present over the entire study period of 90 days, the cumulative total symptom count summing up the total symptom count over the entire study figure e1. example of a section of the symptom diary. check marks (o) indicate presence of the respective symptom or oat. dashes (-) indicate absence of specific symptom or oat. participants recorded their sputum color as absent/unchanged (-), white (w), yellow (y), or green (g). sputum volume was recorded as absent/unchanged (-), increase equivalent in volume to a teaspoon (ts), egg cup (eg), or cup (c). participants were asked to record new or increased symptoms only. indicate oatwas not used, and "-/o" indicates either use or nonuse. use is defined as an event with a total symptom count (tsc) equal or greater than 2 for 2 or more consecutive days in absence of oat during the episode. tse is defined as an event with a total symptom count equal or greater than 2 for 2 or more consecutive days and use of oat during the episode. te is defined as use of oat. the start of a te episode is defined as the first day a symptom occurs and which is still present on the day oat is started. the end of a te episode is defined as the last day a symptom is present and which is also present on the day oat is started. time until oat is defined as the period between te start and oat start. time until recovery is defined as the period between oat start and te end. primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency clinical picture and treatment of 2212 patients with common variable immunodeficiency update in understanding common variable immunodeficiency disorders (cvids) and the management of patients with these conditions primary immunodeficiency diseases. report of an iuis scientific committee common variable immunodeficiency: clinical and immunological features of 248 patients primary hypogammaglobulinaemia: a survey of clinical manifestations and complications long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency but cvid is not cvid common variable immune deficiency (cvid), what do we know in 2011? lung disease in primary antibody deficiency infections in 252 patients with common variable immunodeficiency recurrent and persistent respiratory tract viral infections in patients with primary hypogammaglobulinemia immune deficiency: changing spectrum of pathogens activity, severity and impact of respiratory disease in primary antibody deficiency syndromes representing pagid (pan-american group for immunodeficiency) and esid (european society for immunodeficiencies) lung function, symptoms and inflammation during exacerbations of non-cystic fibrosis bronchiectasis: a prospective observational cohort study validation of the st. george's respiratory questionnaire in bronchiectasis time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease safety of reduced antibiotic prescribing for self limiting respiratory tract infections in primary care: cohort study using electronic health records underreporting exacerbation of chronic obstructive pulmonary disease in a longitudinal cohort reported and unreported exacerbations of copd: analysis by diary cards outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease neutrophil fates in bronchiectasis and alpha-1 antitrypsin deficiency a winter's tale: coming to terms with winter respiratory diseases. london: health protection agency effect of temperature on lung function and symptoms in chronic obstructive pulmonary disease validation of the st. george's respiratory questionnaire in bronchiectasis the bronchiectasis severity index. an international derivation and validation study changes in prevalence and load of airway bacteria using quantitative pcr in stable and exacerbated copd period, and the number of days fulfilling the criteria for symptomatic exacerbation over the entire study period.we then calculated correlation coefficients between the sgrq total score and the number of days on which specific symptoms were present, cumulative total symptom count, and cumulative number of days of symptomatic exacerbation. an in-house multiplex rt-pcr was used for detection of 15 rna viruses (influenza a, influenza b, parainfluenza virus [piv] 1, piv 2, piv 3, piv 4, rhinovirus, enterovirus, human metapneumovirus, respiratory syncytial virus, parechovirus, human coronavirus oc43, nl68, 229e, hku) and 1 dna virus (adenovirus). phocine distemper virus was added as internal control to each sample and a primer pair and probe were designed to amplify k-ras oncogene. cloned complementary dna (cdna) positive controls for each of the targeted viruses were included; a negative control consisting of the reaction mixture and pcr-grade water was included in each run. nucleic acid was extracted from 0.5 ml of nasopharyngeal swab using the automated extraction platform nuclisens(r) easymag(r) (biomerieux, marcy l'etoile, france). the superscript iii platinum one-step reverse transcription kit (invitrogen, paisley, uk) was used to generate and amplify cdna. rt-pcr was performed on the taqman 7500 sequence detection system (applied biosystems, foster city, calif). sputum samples were examined by microscopy and culture for bacteria and mycobacteria plus an in-house multiplex rt-pcr for chlamydia pneumoniae, legionella pneumophila, and mycoplasma pneumoniae. techniques used in our laboratories for sputum processing, microbiological culture, and multiplex pcr detection of bacteria have been described in greater detail elsewhere. e3 we included multiple samples from a single patient if the samples were separated by at least 2 weeks and the patient was asymptomatic between episodes. airway colonization by pathogenic bacteria was considered possible if the same organism had been isolated more than twice within the 2 years before our study. key: cord-285228-famhbr16 authors: larsen, joseph r.; martin, margaret r.; martin, john d.; kuhn, peter; hicks, james b. title: modeling the onset of symptoms of covid-19 date: 2020-08-13 journal: front public health doi: 10.3389/fpubh.2020.00473 sha: doc_id: 285228 cord_uid: famhbr16 covid-19 is a pandemic viral disease with catastrophic global impact. this disease is more contagious than influenza such that cluster outbreaks occur frequently. if patients with symptoms quickly underwent testing and contact tracing, these outbreaks could be contained. unfortunately, covid-19 patients have symptoms similar to other common illnesses. here, we hypothesize the order of symptom occurrence could help patients and medical professionals more quickly distinguish covid-19 from other respiratory diseases, yet such essential information is largely unavailable. to this end, we apply a markov process to a graded partially ordered set based on clinical observations of covid-19 cases to ascertain the most likely order of discernible symptoms (i.e., fever, cough, nausea/vomiting, and diarrhea) in covid-19 patients. we then compared the progression of these symptoms in covid-19 to other respiratory diseases, such as influenza, sars, and mers, to observe if the diseases present differently. our model predicts that influenza initiates with cough, whereas covid-19 like other coronavirus-related diseases initiates with fever. however, covid-19 differs from sars and mers in the order of gastrointestinal symptoms. our results support the notion that fever should be used to screen for entry into facilities as regions begin to reopen after the outbreak of spring 2020. additionally, our findings suggest that good clinical practice should involve recording the order of symptom occurrence in covid-19 and other diseases. if such a systemic clinical practice had been standard since ancient diseases, perhaps the transition from local outbreak to pandemic could have been avoided. the current pandemic of coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), has undergone an observed exponential increase of cases that has overrun hospitals across the world (1). many people have mild forms of the disease and are advised not to go to the hospital or to seek a diagnostic test because they can recover at home. a large number of others are asymptomatic (2) . infected individuals are highly contagious and can transmit the disease even if they are asymptomatic, and this fact furthers the need to isolate and test often (2) . in addition, covid-19 is two to three times more contagious than influenza (3) . due to these characteristics, outbreaks of covid-19 occur in clusters (4) . identifying covid-19 early could reduce the number and size of clusters, but early symptoms are not well-defined. the center for disease control and prevention (cdc) in the usa and the world health organization (who) currently advise the public to call their doctor if they believe they have been exposed to covid-19 or exhibit fever and cough (5) . however, fever and cough are associated with other respiratory diseases such as influenza (6) (7) (8) . influenza, with an estimated number of symptomatic cases in the millions annually in the u.s. alone (9) , also is commonly associated with fever and cough (6) . similarly to covid-19, the middle east respiratory syndrome (mers) and the severe acute respiratory syndrome (sars) are respiratory illnesses contracted from coronaviruses called the mers-related coronavirus (mers-cov) and sars-related coronavirus (sars-cov), respectively (7) . the symptoms of these diseases also overlap with covid-19. the capacity to discern differences in these common symptoms, such as order of occurrence and likely first symptoms, would aid in early recognition. if health care workers recorded and published clinically-observed and/or patient-reported sequences of symptoms, the reported data could be evaluated as an additional tool for early recognition of covid-19 to increase self-surveillance and reduce spread. if such a widespread clinical practice had been instituted in the past, perhaps local outbreaks of influenzas, coronaviruses, and other diseases might have been contained before becoming pandemics. to this end, we assumed that symptoms and their orders are independent variables and created a model that approximates the probability of symptoms occurring in specific orders using available, non-ordered patient data. the use of these assumptions and data was necessary given the lack of ordered data. to do this, we applied a markov process to determine the order of occurrence of common symptoms of respiratory diseases. we have previously used a markov chain to predict cancer metastasis location (10) (11) (12) (13) (14) . a markov process is defined as a stochastic sequence of events in which the likelihood of the next state only depends on the current state rather than past or future states (15) . in this case, we defined each state to be the specific symptoms that a patient has experienced, and each transition is only dependent on these symptoms. as a result, we can determine the likelihood of each symptom stepwise using a markov process. we defined the state probability of a node as the frequency that a patient has a particular combination of symptoms divided by the total number of patients that exhibit the same number of symptoms. the transition probability between two states is defined as the likelihood of acquiring a single specific symptom divided by the likelihood of acquiring all possible next symptoms. we then applied a greedy algorithmic approach using the transition probabilities to calculate the probability of all possible orders toward determining the most and least likely orders of symptoms. in this study, we first defined this specific application of a markov process applied to a graded partially ordered set (poset), which we refer to as the stochastic progression model. in this case, our graded poset represents all possible combinations of symptoms and all possible orders of symptom occurrence. it is graded because the possible combinations of symptoms are ranked by the number of symptoms that they each represent. for example, the symptom combination of fever and cough has the same rank as the combination of cough and diarrhea. we found that the stochastic progression model for adults that are symptomatic indicates that there may be an order of discernible symptoms in covid-19, but the order of symptoms seems to be independent of severity of the case on admission. from there, we compared the most likely order of symptoms in other respiratory diseases to covid-19. to expand on our results, we analyzed a larger set of symptoms that are common to all respiratory diseases studied here and sought to decipher further distinctions. patient data from this study was collected from various reports in literature on the frequencies of symptoms in covid-19, influenza, mers, and sars (supplemental tables 1, 2) . each dataset was used either to approximate order of symptoms, to confirm our results, or to analyze first symptoms in covid-19 or influenza. for all of these applications, we used the reported patient data to simulate patients with various combinations of symptoms experienced and then applied the simulated data to perform the analyses. the main dataset of covid-19 patients of the world health organization, containing 55,924 confirmed cases, was obtained through review of national and local governmental reports and observations made during visits to areas with infected individuals in china that occurred from february 16 to 24, 2020 (8) . a confirmation dataset of covid-19 patients, containing 1,099 confirmed cases, was obtained by the china medical treatment expert group for covid-19 from medical records and other compiled data of hospitalized patients and outpatients that were diagnosed with covid-19. this data was reported to the national health commission of china from december 11, 2019 to january 29, 2020 (16) . for both covid-19 datasets, myalgia was reported as myalgia or arthralgia. we assumed that most patients with myalgia also had arthralgia, and therefore we used the frequency of myalgia or arthralgia as a frequency for myalgia when simulating data. the influenza dataset, containing 2,470 confirmed cases, was collected by researchers at the university of michigan from a retrospective pooled analysis of mostly unvaccinated patients participating in phase 2 and 3 clinical trials that were conducted in north america, europe, and the southern hemisphere from 1994 to 1998 (6) . this group of patients has a mean age of 35 and each exhibited multiple symptoms. vomiting and diarrhea were not reported in this influenza dataset, but they are common among respiratory disease. although adult patients at times may experience vomiting and diarrhea when infected with influenza, these symptoms are rare (17) . therefore, we approximate the frequency of these symptoms as 0.010 in this case. the datasets representing symptom frequency in mers, containing 245 patients, and sars, containing 357 patients, were collected on admission and were reported as clinical data from physicians, dr. yin, at the beijing chao-yang hospital and dr. wunderink, at the northwestern university feinberg school of medicine (7) . the patients included in these datasets varied in age and pre-existing conditions. in the cases of sars, the patients tended to be younger and have fewer pre-existing conditions than in the cases of mers. we used initial frequency data of mers and sars to further ascertain early symptoms of disease. the mers initial symptom frequency dataset, containing 45 confirmed cases, was collected from electronic medical records at the samsung medical center in seoul, south korea that contained onset symptom data about patients in the 2015 korean mers outbreak (supplemental table 3 ) (18) . the sars initial symptom frequency dataset, containing 144 confirmed cases, was collected from hospital records including information of early symptoms in patients dating from march 7 to april 10, 2003 during an outbreak in the greater toronto area (supplemental table 4 ) (19) . lastly, two additional datasets were collected to determine the utility of using first symptoms as early indicators of covid-19 and influenza. the covid-19 dataset used, containing 138 patients, was independent of all prior covid-19 datasets. this data was obtained from electronic medical records of patients admitted to the zhongnan hospital of wuhan university from january 1 to 28, 2020 (20) . the symptom data was collected at onset of disease and all patients experienced pneumonia due to covid-19. in this dataset, nausea and vomiting were reported separately for covid-19. we assumed that most patients who experience vomiting, which is reported with a frequency of 0.036, also experience nausea, which is reported with a frequency of 0.101, and therefore to simulate the data, we defined the frequency for nausea/vomiting as 0.101. the influenza dataset used reported 20 confirmed cases of influenza and 400 confirmed negative cases of influenza and is independent from any other influenza dataset we used (21) . the symptom data was collected through questionnaires and observations by medical professionals during the influenza seasons of 2006 and 2007 of infected patients admitted at the department of internal medicine and infectious diseases and the department of pulmonology at the university medical center utrecht. like the other influenza dataset described above, vomiting and diarrhea were not reported in this dataset. so, we once again assumed the frequency of these symptoms to be 0.010 (17) . because this study was conducted in 2006 and 2007, prior to the covid-19 outbreak, we assumed these patients were negative for covid-19 as well. so, this 400-patient group was used as the dataset that represents individuals negative for both covid-19 and influenza (supplemental table 5 ). the stochastic progression model was built in r under version 3.5.2 and was illustrated by using the hasse function in the hassediagram_0.1.3 library (code available online: https:// github.com/j-larsen/stochastic_progression_of_covid-19_ symptoms) (22, 23) . each respiratory disease report was represented by a corresponding data frame, with columns as symptoms, one row as the frequency of the symptoms observed in the study, and the other row as the frequency multiplied by 1,000. the multiple of the frequency is defined as the frequency count, which represents the probability of a symptom in a theoretical sample size of 1,000 simulated patients. additionally, the state of an individual is displayed through a character array of ones and zeros, where ones represent the presence of a symptom and zeroes represent its absence. this process of simulating a symptom is analogous to a jar of marbles of either two colors. the probability of pulling one color of marble (i.e., a specific symptom) is illustrated by the frequency count because the total number of marbles in the jar is 1,000 and the frequency count for each is the number of the specific color of marbles in the jar. we then simulated data of 500,000 patients, by randomly selecting if a patient has or does not have a symptom using the procedure described above and storing that information in a data frame that represents patients as rows and symptoms as columns. we assumed the occurrence of symptoms are random and independent. considering these assumptions, we built the character arrays by applying the jar of marbles method for each simulated patient. the method repeats for each patient and involves pulling a marble from a series of jars representing each symptom. the information from each randomly pulled marble is stored in the corresponding cell of the character array in the correct column representing the symptom and the row representing the simulated patient. this process is repeated for all 500,000 simulated patients for all symptoms. the stochastic progression model is illustrated as a directed acyclic graph with nodes, representing the power set of boolean vectors. the power sets of boolean vectors each represent a possible state of a patient by noting the absence or presence of specific symptoms. the edges, which illustrate the transition from one state to another, were selected specifically using key definitions and assumptions to create a poset. we defined the states at the nodes as symptoms that a patient has experienced up until this point. we created and directed edges from states with fewer symptoms to more starting at the minimum set of a boolean vector of all zeros, which indicates a person with no symptoms. first, we assume that each symptom occurs one at a time, even if the difference in time is infinitesimal. with this assumption, a node can only be directed to other nodes that denote the same set of symptoms plus one additional symptom. second, we assume that if a patient does not digress and does not die, they will eventually acquire all symptoms reaching the maximum set of a boolean vector, which represents a patient that has exhibited all symptoms. applying these assumptions to form the directed acyclic graph creates a hasse diagram of a graded poset that follows a markov process altogether comprising the stochastic progression model. the nodes in the hasse diagram represent states of a patient by indicating the specific symptoms exhibited, and the edges represent transitions between these states. therefore, we next needed to apply state probabilities to each node and transition probabilities to the directed edges. first, we labeled each simulated patient by summing the respective boolean vector to find the number of symptoms for each patient. then, to get the state probability of each node, we divided the number of simulated patients that are represented by the current boolean vector by the total number of patients who have the same number of symptoms. to approximate the transition probability between two nodes (originating and terminating), we divided the number of simulated patients that are represented by the terminating node by the number of simulated patients that are represented by nodes characterized by the same number of symptoms as the terminating node, including the terminating node. the error of each node is determined by the sum of the products of the transition probabilities leading to that node subtracted from the state probability of the node. then, the error of each implementation of the model was defined as the error of the node with the highest absolute value of error (supplemental figures 2-13) . the transition probabilities signify the likelihoods of transitions from one node to another, and the aggregates of the transition probabilities in a sequence represent the likelihoods of the paths. these paths illustrate the order of symptoms when infected with a respiratory disease by observing the stepwise addition of symptoms when traversing down nodes in the path. the most and least likely paths were determined using a greedy algorithmic approach. this approach consists of selecting local maximum or minimum edges stepwise, which results in a most and least likely path, respectively. if the maximum (or minimum) transition probability from a specific node was within error of other transition probabilities of edges from the same originating node, we grouped the terminating nodes when finding the most (or least) likely path. in these cases, we could not distinguish a difference in likelihood between these specific transitions. the paths create a possible order of symptoms via the poset, each having a specific likelihood of occurrence. the who-china joint report from february 16 to 24, 2020 includes rates of symptom occurrence at presentation from 55,924 confirmed cases of covid-19 (8) . we identified symptoms that were easily discernible or objective (i.e., fever, cough, diarrhea, and nausea/vomiting) in comparison to other reported symptoms, such as inflammations of blood vessel epithelia (24) , neurological effects (25) , and rash-like symptoms (26) . these symptoms are also common in other respiratory diseases. thus, we chose to implement these four symptoms in the stochastic progression model (supplemental table 1 ). to confirm the validity of the model, we first determined the possible sequences of symptom occurrence when the probabilities are uniformly random for each symptom. in addition to all possible orders of occurrence of the four symptoms, the diagram displays the most and least likely paths of the four symptoms, depicted by red lines and blue lines, respectively (figures 1a,b) . the most and least likely paths describe the most and least likely series of symptoms that a random infected person from the population in the dataset may experience. in this case, each possible path is equally likely, with no path having any higher probability than any other. we then created another implementation of the stochastic progression model and utilized the data in the who-china joint report (covid-19 with n = 55,924) (8) . with this implementation, we determined the most and least likely paths ( figure 1c) . in this case, a person infected with covid-19 is most likely to experience symptoms in the order of fever, cough, nausea/vomiting, then diarrhea ( figure 1d) . the least likely path starts at diarrhea and nausea/vomiting and is followed by cough, and finally fever ( figure 1e) . we confirmed these results with a smaller dataset (covid-19 with n = 1,099) (figures 1d,e , and supplemental figure 1 ) (16) . the likelihoods of transitioning to fever, 0.769, and then to cough, 0.958, are high, and these observations indicate that a large portion of infected symptomatic patients may follow this path. finally, this implementation of the model predicts that nausea/vomiting occurs before diarrhea. these two results suggest that in patients with sars-cov-2, the body first develops fever, then upper respiratory symptoms and finally symptoms of the upper then lower gastrointestinal (gi) tract. to further investigate these symptom paths, we implemented the stochastic progression model with the main dataset (covid-19 with n = 55,924) (8), to determine the likely downstream paths when the first one or two symptoms are forced to a certain state (figures 1f-i) . the gray lines represent the "forced" paths. the rest of the paths were determined as before with a greedy algorithmic approach. we found that the most likely orders of the downstream path are consistent with the most likely orders of the unforced paths. even if the first symptom is forced to be an unlikely one (e.g., diarrhea), the downstream paths maintain the most likely order of the other three symptoms that we originally determined ( figure 1f) . similarly, the gi tract effects occur first in the forced least likely paths ( figure 1g) . when forcing the path one step further by predetermining the first two symptoms for both the most and least likely paths, the findings remain the same (figures 1h,i) . the confirmation dataset of covid-19 cases (n = 1,099) separates the reported 1,099 cases between severe and nonsevere patients as designated on admission (16) . to investigate the effects of severity on the order of discernible symptoms, we implemented each set of cases separately using the stochastic progression model. we found that the most and least likely paths are identical in severe and non-severe cases and to our original findings above (figure 2) . to illustrate the similarities, the largest difference in likelihood is observed when transitioning from no symptoms to fever in the most likely path. in severe and non-severe cases, the probability is 0.775 and 0.818, respectively, indicating a difference of 0.043. these results suggest that severity does not affect the order of discernible symptoms, and they are consistent with the hypothesis of fever as the first symptom of covid-19. the four discernible symptoms are objective and relatively easy for patients and clinicians to confirm. so, we developed implementations of the stochastic progression model using these symptoms to determine the most likely and least likely paths for four respiratory diseases: covid-19, influenza, mers, and sars (figures 3a-d) (6) (7) (8) . the most likely order of occurrence of symptoms in covid-19 is fever, cough, nausea/vomiting, and diarrhea ( figure 3a) . this path is identical to influenza except the order of the initial two symptoms is switched (figure 3b) . on the other hand, the predicted most likely paths (i.e., fever, cough, diarrhea, and then nausea/vomiting) are the same for mers and sars (figures 3c,d) . this order has one difference from the most likely path in covid-19 in that the order of the final two symptoms are reversed. the least likely path of mers starts with either nausea/vomiting or diarrhea as the first step. these steps are followed by cough, and finally fever. in contrast, the least likely path of sars is cough, nausea/vomiting, and diarrhea in any order, and then finally fever. however, the least likely path of symptoms in covid-19 is the same as the least likely path in mers, and the least likely path of influenza is unique compared to the other diseases. it is not detectable whether nausea/vomiting or diarrhea are the first symptoms in influenza, but after these two, the least likely path continues from there to fever then cough. this observation further illustrates the strong link of cough to influenza. as for coronavirus-related diseases, the strongest first indicator is fever followed by cough. although active surveillance of the order discernible symptoms (i.e., fever, cough, nausea/vomiting, and diarrhea) could be useful due to the distinctive most and least likely paths that we determined, we expanded our analysis to the seven symptoms commonly observed in all four respiratory diseases studied here. so, we created a second set of symptoms that amends sore throat, myalgia, and headache to the original set of symptoms (supplemental table 2 ). the three additional symptoms are more subjective (6) (7) (8) . the seven-symptom implementation of the stochastic progression model of covid-19 shows that these additional symptoms did not perturb our initial ordering of fever, coughing, nausea/vomiting, and diarrhea, but instead added another level of intricacy in the middle of the likely paths (figure 4) . we still find that the most likely path first transitions to fever, indicating that fever is the most likely first symptom. from there, the most likely next symptom is cough once again. then, we observe an undetectable difference in likelihood of transitioning to either sore throat, headache, or myalgia, indicating that all three are likely to occur next before proceeding. the final two nodes are consistent with the foursymptom order by indicating that nausea/vomiting then diarrhea occur last. although this implementation is more complex because it has seven symptoms, it is consistent with our earlier findings. the most likely path of covid-19 symptoms is fever, then cough, and next either sore throat, myalgia, or headache, followed by nausea/vomiting, and finally diarrhea, and this order is the same as the one indicated by the implementation developed from the confirmation dataset (covid-19 with n = 1,099) (figure 4) (16) . we also implemented the stochastic progression model with the same seven symptoms in influenza, sars, and mers datasets to compare and contrast disease progression with that in covid-19 ( figure 5 ) (6) (7) (8) . the results for influenza indicate that cough or myalgia may occur first (figure 5a ). after these two symptoms occur, the order of symptoms is headache, sore throat and fever. finally, vomiting/nausea and diarrhea have an undetectable difference in probability of occurring last. the mers implementation displays a most likely path in which fever will occur first, followed by cough, headache, and then myalgia ( figure 5b ). these are followed by an undetectable difference in likelihood of headache and diarrhea occurring. finally, sore throat and nausea/vomiting will occur last with an undetectable difference. the implementation for sars shows that fever is most likely to occur first, followed by an undetectable difference in transition probability of cough and myalgia, which is similar to the other coronavirus-related diseases ( figure 5c ). next, headache is most likely. finally, diarrhea, sore throat and nausea/vomiting occur with an undetectable difference in likelihood. to illustrate the uniqueness of the most likely path of covid-19, we found the transition probabilities of the same path in the other respiratory diseases (figure 6) . when comparing and contrasting the probabilities, we found that the implementation representing covid-19 strongly asserts that the first symptom will be fever and cough will soon follow because the transition probabilities are 0.731 and 0.783, respectively (figure 6a) , whereas the influenza implementation indicates that fever is very unlikely to occur first with a probability of only 0.035 ( figure 6b) . additionally, the implementations of mers and sars data also have a high likelihood of transitioning to fever first, with a probability of 0.627 and 0.988, respectively (figures 6c,d) . the second symptom of the most likely path of covid-19 is cough, with a probability of 0.783, but the others do not have a similar high probability. for example, the respiratory disease with the highest probability at that transition is mers at 0.536. however, after fever and cough, covid-19 and the other three respiratory diseases have a similarly high likelihood of the three subjective symptoms (i.e., sore throat, headache, and myalgia). finally, the most likely path of covid-19 ends with nausea/vomiting and then diarrhea. these observations are consistent with the symptoms described by the cdc and support the notion that fever followed by cough seems highly likely to be diagnosed as covid-19 (5) . also, comparing the transition probabilities of paths in the same disease illustrates the significance of the most likely pathways. for example, the lowest transition probability in the most likely path of influenza is 0.578 (figure 5a) , whereas when analyzing influenza as it traverses down the most likely path of covid-19, the transition probabilities observed are 0.5 or less ( figure 6b) . however, in that same path, the transition probability from fever and cough to fever, cough, sore throat, headache, and myalgia is >0.999. this value displays how unlikely nausea/vomiting and diarrhea are to be initial symptoms of influenza. additionally, when observing the most likely path of covid-19, the first two symptoms seem to have a strong probability of occurring in the order of fever and then cough, with a likelihood of 0.731 ( figure 5a) . however, the likelihood of cough occurring first in covid-19 is 0.229, which is a low probability (figure 5a ). this observation further supports the hypothesis of fever occurring first and cough occurring second. the covid-19 and influenza implementations of the stochastic progression model suggest that there is a high likelihood of fever and cough occurring first, respectively. we desired to find metrics quantifying the possible link between first symptom and these two diseases. so, we determined the recall and the selectivity when using the initial symptom as an indicator of covid-19 or influenza, with all other possible diseases excluded in a theoretical patient population. first, we simulated patient datasets using reported data that were independent from all previous work that we integrated in our analyses above (supplemental table 5 ) (20) . two simulated patient datasets were created to analyze covid-19 and influenza separately to portray the specific link of each disease with the corresponding initial symptom that we determined, fever and cough, respectively. the simulated data contained information about the patients' state of disease (covid-19, influenza or not) and their first symptom experienced. based on the information of the first symptom alone, we categorized the simulated patient data as infected with covid-19 or not and influenza or not. the recall was calculated as the number of simulated patients that we correctly identified as having the disease over the number of simulated patients that truly had the disease (27) . selectivity was defined here as the number of simulated patients that we correctly identified as not having the disease over the number of simulated patients that truly did not have the disease (28) . for both diseases, we performed this analysis for five simulated samples of different sizes, each containing 5% infected individuals. we repeated this process 10 times and calculated the average and standard deviation across each sample size for both covid-19 and influenza (tables 1, 2) . the recall ranges from 0.966 to 0.990 with a standard deviation of 0.031 and 0.021, respectively when analyzing the link between covid-19 and fever as a first symptom. the maximum standard deviation of any sample size is 0.063 for the mean of 0.980. on the other hand, the selectivity of fever as a first symptom of covid-19 ranges from 0.661 to 0.668 with a standard deviation of 0.030 and 0.020, respectively, and 0.030 is the maximum standard deviation with corresponding means of 0.661 and 0.665 ( table 1) . as for cough as a first symptom of influenza, the recall ranges from 0.765 to 0.820 with corresponding standard deviations 0.092 and 0.067. the highest standard deviation is 0.110 with a mean of 0.810, and the selectivity ranges from 0.362 to 0.369 with standard deviations of 0.014 and 0.031, respectively, and the maximum standard deviation is 0.031 ( table 2) . the recall in both cases is lower than the selectivity, and this observation indicates that this analysis categorizes patients as infected when they are not, but the high recall indicates that most infected patients did align with the first symptom that we predicted. in the future, we expect to confirm this analysis with data on first symptoms, as opposed to simulated data, but the purpose of this analysis was to display that further study of order of symptoms might lead to earlier recognition. in this study, we found evidence that supports the notion that there is a most common order of discernible symptoms in covid-19 that is also different from other prominent respiratory diseases. the most likely initial symptom is fever in the three diseases studied that are caused by coronaviruses (i.e., covid-19, sars, and mers) and cough in influenza. the most likely order of the four easily discernible symptoms is identical in mers and sars, but the most likely path of covid-19 has one key difference. the first two symptoms of covid-19, sars, and mers are fever and cough. however, the upper gi tract (i.e., nausea/vomiting) seems to be affected before the lower gi tract (i.e., diarrhea) in covid-19, which is the opposite from mers and sars. in all diseases, we found that fever and cough occur before nausea/vomiting and diarrhea. when observing the set of seven symptoms including three subjective ones (i.e., sore throat, headache, and myalgia), we found that the initial symptoms of the most likely path are the same as in the most likely path of the four discernible symptoms. also, in both the four and seven symptoms implementations, the gi tract symptoms are last. a separate mers dataset included the initial symptoms of patients on admission, which listed the symptoms from highest to lowest probability as fever, myalgia, cough, and diarrhea (18) . this order is similar to the most likely path that we determined. a very small percent of patients experienced diarrhea as an initial symptom. this report suggests that diarrhea as an early symptom indicates a more aggressive disease, because each patient in this dataset that initially experienced diarrhea had pneumonia or respiratory failure eventually (supplemental table 3 ). we propose that these patients may be experiencing a more aggressive form of the disease and have accelerated through the most likely path, having already experienced diarrhea. these findings align with another dataset provided for sars, which also contained the percentage of the various symptoms to be reported first (supplemental table 4 ). the highest reported symptom is fever, followed by cough or dyspnea, and then finally, a small percent of patients reported diarrhea (19) . this order confirms the most likely paths that we have determined. the observation that diarrhea was very uncommon as a first symptom and had a nonzero probability of occurrence is consistent with our analysis. this aligns with our hypothesis that early occurrence of diarrhea implies that those patients may have a much more aggressive form of the disease. the simulation data used to approximate the state and transition probabilities in the stochastic progression model relies on the assumption that symptoms included in the model are independent. using the definition of independence, we observed the individual probabilities of fever and cough in a dataset from a case study of influenza, and we found that the product of the individual probabilities of fever and cough is almost equal to the probability of both occurring (21) . considering this outcome, we proceeded under the assumption of independence, which we will reevaluate when more symptom data becomes available. we simulated combinations of symptoms for 500,000 patients, which we chose because it was the lowest attempted number that empirically produced the theoretical expected outcome for random frequency symptoms: that all paths would be equally likely, up to 100ths of a decimal place. we then utilized these simulated patients to approximate the state probabilities and transition probabilities described above. this study supports the idea that symptoms occur in a predictable order, but future work is needed to improve aspects of the stochastic progression model and confirm the results found here. our finding that covid-19 first presents with a fever supports the recommended measures by the cdc which state that the public should take their temperature at home and when entering facilities as an early checking method (29) . this application of the stochastic progression model may be improved if there were objective ways to measure the more subjective symptoms (i.e., sore throat, headache, and myalgia). also, improved error calculations of the transition probabilities would lead to more accurate results. our current error calculation is conservative, because when more symptoms were added, we observed that the error compounded as we progressed further down the paths (supplemental figures 2-13) . the conservative error estimate creates issues in discerning the difference in probabilities of symptoms. specifically, in implementations of seven symptoms, the likelihoods are more difficult to ascertain due to subjective reporting and compounding error calculations. datasets that contain the order of symptoms for each patient would lower the error. additionally, these sorts of datasets would better the approximations of the transition probabilities and increase accuracy. this improvement could be achieved by physicians implementing the practice of recording the order of occurrence of symptoms. with this information, we may approximate the likelihood of a patient acquiring a symptom based on their current symptoms with patient data instead of simulations based on frequency. applying objective criteria for symptoms, improving error calculations, and collecting the order of symptoms would not only allow us to improve our findings here, but also allow the stochastic progression model to predict orders of a larger set of symptoms. the optimal form of the stochastic progression model would be developed by determining state probabilities from observed true frequencies of patients' symptoms and determining transition probabilities from the patients' true order of symptoms. however, until this data is available, improved approximations, simulations and error calculations are needed. furthermore, when analyzing fever as the first symptom of covid-19, a low selectivity indicates a high type i error (i.e., rate of false positive), and a high recall indicates a low type ii error (i.e., rate of false negative). we found a moderate selectivity value and as a result, a moderate type i error in this case. this type i error is acceptable in our use of investigating fever as an initial symptom of covid-19, because it suggests that more people get tested who are not infected, rather than less people get tested who are infected, as with type ii error (30) . we are not proposing initial symptom as a diagnostic test, but instead as a possible sign to get tested. covid-19 outbreaks in clusters, and these unusual clusters of disease are characteristic of a pandemic disease that must be addressed immediately with aggressive testing to curb transmission (31) . the importance of knowing first symptoms is rooted in the need to stop the spread of covid-19, a disease that is two to three times more transmissible than influenza and results in outbreaks of clusters (3, 4) . there is a heightened risk in covid-19 being passed on, so faster testing and social distancing are important, especially when social distancing and quarantine measures are relaxed. our results assert that fever is the most likely symptom to occur first in symptomatic adult patients with covid-19. we hope that the hypotheses generated in this work are tested with prospective clinical data to confirm that a cough occurs first more often in influenza and likewise fever in covid-19. we believe that early detectors that any individual can recognize to seek medical attention earlier is useful. in addition, datasets that contain information of symptom order and strains of covid-19 allow for further studies that may determine whether onset of symptoms vary in specific strains (32) , and whether risk factors, such as obesity (33) , and environmental factors, such as temperature (34) affect symptom order. to slow the spread of covid-19, our results support the practice that fever should be tested before allowing entry to facilities and that those with fever should immediately seek medical attention for diagnosis and contact tracing. such measures as these may help to reduce transmission despite the high contagion of sars-cov-2. publicly available datasets were analyzed for this study. these can be found here: https://www.who.int/publicationsdetail/report-of-the-who-china-joint-mission-on-coronavirusdisease-2019-(covid-19), https://www.nejm.org/doi/full/10.1056/ nejmoa2002032, https://jamanetwork.com/journals/jamainter nalmedicine/fullarticle/485554, https://onlinelibrary.wiley.com/ doi/full/10.1111/resp.13196, https://www.journalofinfection. com/article/s0163-44531630209-2/abstract, https://jamanet work.com/journals/jama/fullarticle/196681, https://jamanet work.com/journals/jama/fullarticle/2761044, https://www.camb ridge.org/core/journals/infection-control-and-hospital-epidemio logy/article/symptoms-of-influenza-virus-infection-in-hospita lized-patients/8f1b478ba4b861d356393ea77ad8b83b#. an interactive web-based dashboard to track covid-19 in real time evaluation and treatment coronavirus (covid-19) how will country-based mitigation measures influence the course of the covid-19 epidemic? early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study world health organization declares global emergency: a review of the 2019 novel coronavirus (covid-19) clinical signs and symptoms predicting influenza infection sars and other coronaviruses as causes of pneumonia report of the who-china joint mission on coronavirus disease estimated influenza illnesses and hospitalizations averted by vaccination-united states, 2013-14 influenza season a stochastic markov chain model to describe lung cancer growth and metastasis spreaders and sponges define metastasis in lung cancer: a markov chain monte carlo mathematical model adrenal metastases in lung cancer: clinical implications of a mathematical model entropy, complexity, and markov diagrams for random walk cancer models spatiotemporal progression of metastatic breast cancer: a markov chain model highlighting the role of early metastatic sites markov chains on graded posets clinical characteristics of coronavirus disease 2019 in china seasonal influenza a virus in feces of hospitalized adults predictive factors for pneumonia development and progression to respiratory failure in mers-cov infected patients clinical features and short-term outcomes of 144 patients with sars in the greater toronto area clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan symptoms of influenza virus infection in hospitalized patients drawing hasse diagram team rc. r: a language and environment for statistical computing. r foundation for statistical computing endothelial cell infection and endotheliitis in covid-19 nervous system involvement after infection with covid-19 and other coronaviruses petechial skin rash associated with severe acute respiratory syndrome coronavirus 2 infection evaluation: from precision, recall and fmeasure to roc, informedness, markedness and correlation classification of white wine aromas with an electronic nose evaluation of the effectiveness of surveillance and containment measures for the first 100 patients with covid-19 in singapore adaptative significance levels using optimal decision rules: balancing by weighting the error probabilities challenges to global surveillance and response to infectious disease outbreaks of international importance on the origin and continuing evolution of sars-cov-2 obesity in patients younger than 60 years is a risk factor for covid-19 hospital admission temperature decreases spread parameters of the new covid-19 case dynamics jl and jh conceived the model. jl and jm conceived the project. jl created the model. jl, mm, and jm analyzed results. jl and mm wrote the manuscript. pk and jh supervised the project. all authors read, edited, and approved the final manuscript. we wish to thank dr. jorge nieva for discussions and advisement and libere ndacayisaba for critical reading of the manuscript. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpubh. 2020.00473/full#supplementary-material conflict of interest: mm is employed by the company nexus development pa llc. jm is employed by the company nanocarrier co., ltd.the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright â© 2020 larsen, martin, martin, kuhn and hicks. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-287452-nslygsdf authors: hamam, asmaa abu; milo, shai; mor, inbar; shaked, elit; eliav, ayala sultana; lahav, yael title: peritraumatic reactions during the covid-19 pandemic – the contribution of posttraumatic growth attributed to prior trauma date: 2020-09-30 journal: j psychiatr res doi: 10.1016/j.jpsychires.2020.09.029 sha: doc_id: 287452 cord_uid: nslygsdf trauma survivors who suffer from posttraumatic stress disorder (ptsd) symptoms may be particularly vulnerable when facing the covid-19 pandemic. yet trauma exposure may also lead to salutogenic outcomes, known as posttraumatic growth (ptg). nevertheless, the implications of ptg attributed to prior trauma, for trauma survivors’ adjustment when facing additional stressors, are unclear. addressing this gap, 528 israeli trauma survivors were assessed for ptg and ptsd symptoms attributed to prior trauma, as well as peritraumatic stress symptoms related to the pandemic, as part of an online survey. analyses revealed that being younger, female, quarantined, negatively self-rating one’s health status, and suffering from ptsd symptoms were associated with elevated peritraumatic stress symptoms. furthermore, ptg attributed to prior trauma made a significant contribution in explaining elevated intrusion, avoidance, and hyperarousal symptoms. the present results point to the need for clinicians to take into account reports of ptg attributed to prior trauma when treating trauma survivors during the current pandemic. the covid-19 pandemic might be traumatogenic, leading to the development of peritraumatic stress symptoms. individuals who have a history of trauma exposure and, as a result, suffer from posttraumatic stress disorder (ptsd) symptoms might be particularly vulnerable. at the same time, prior exposure to trauma has also been claimed to have salutogenic effects, known as posttraumatic growth (ptg). nevertheless, the implications of ptg attributed to prior trauma for trauma survivors' adjustment when they face an additional stressor, such as , has yet to be investigated. the rationale of the present study was to shed light on the unique contribution of ptg attributed to prior trauma in explaining peritraumatic stress symptoms related to covid-19 among trauma survivors. the novel coronavirus and the disease it causes, covid-19, first appeared in wuhan, china, presenting a global health threat (world health organization). symptoms of infection consist of fever, chills, cough, coryza, sore throat, breathing difficulty, myalgia, nausea, vomiting, and diarrhea , and severe cases can result in cardiac damage, respiratory failure, acute respiratory distress syndrome, and death (holshue et al., 2020) . since late december 2019, when the outbreak was first revealed, the number of cases of this highly contagious virus (ryu et al., 2020) has escalated exponentially, spreading to many parts of the world (world health organization). according to the world health organization (2020), the virus was identified for the first time in israel at the end of february 2020. since then, there have been 16,314 confirmed cases of covid-19, and 238 deaths, with the highest infection rate being documented at the end of march and early april 2020 (world health organization). the government of israel, in an attempt to prevent the spread of the disease, took a variety of stringent measures: issuing shelter-in-place orders (individuals were not to go further than 100 meters from their j o u r n a l p r e -p r o o f homes, and only for essential goods); closing schools, synagogues, and other places where people might gather; quarantining anyone who might have come into contact with an infected individual, etc. the manifold stressors entailed by the covid-19 pandemic could very well have substantial implications for individuals' mental health. being diagnosed with the virus, belonging to a risk group for covid-19 complications, and appraising one's health negatively, may intensify fears of falling sick, feelings of helplessness, and stigma (shi et al., 2003; wang et al., 2020a) . worries about close others who are ill or who belong to a covid-19 risk group might add to the emotional burden, exacerbating one's psychological distress (wang et al., 2020a) . social distancing, closures of schools and businesses, and being under quarantine, might fuel negative emotions, which could eventuate in psychopathology (s. k. van bortel et al., 2016) . lastly, the economic crisis related to the shutdown of businesses and workplaces may result in mental health difficulties (bareket-bojmel et al., 2020; reger et al., 2020) . as such, and as suggested above, the covid-19 pandemic could very well take a toll on individuals' mental health, leading to the development or exacerbation of psychopathology lai et al., 2020; qiu et al., 2020; shigemura, ursano, morganstein, kurosawa, & benedek, 2020) . furthermore, for some individuals in particular, this pandemic could be highly traumatic, and could lead to trauma-related symptoms (horesh and brown, 2020) . peritraumatic stress symptoms -the focus of the present investigationare responses that occur during and immediately following a traumatic event. these symptoms constitute four clusters: intrusion, avoidance, changes in mood and cognition, and hyperarousal. intrusion symptoms reflect a reexperiencing of the traumatic event (e.g., intrusive memories, flashbacks, nightmares). avoidance symptoms are manifested in evading stimuli associated with the event (e.g., avoidance of trauma-related thoughts or feelings and j o u r n a l p r e -p r o o f reminders). changes in mood and cognition consist of pessimistic beliefs (e.g., overly negative thoughts and assumptions about oneself or the world) and negative mood states (e.g., fear, sadness, anger, guilt, shame). lastly, hyperarousal symptoms reflect increased reactivity to stimuli (e.g., irritability and aggression, difficulty sleeping; american psychiatric association, 2013). studies exploring the implications of covid-19 for individuals' mental health have documented various types of psychiatric symptoms as well as traumarelated symptoms (jiang et al., 2020; lahav, under review; wang et al., 2020b) . specifically, increases in psychiatric symptomatology, such as anxiety and depression (gao et al., 2020; qiu et al., 2020) , have been detected. findings of a longitudinal study conducted among the general population in china during the pandemic indicated clinically significant peritraumatic stress symptoms, which did not change significantly from the time of the initial outbreak to four weeks later (wang et al., 2020b) . additionally, a study among 6,049 chinese individuals uncovered three profiles consisting of mild (80.9%), moderate (13.0%), and high levels of peritraumatic stress symptoms (6.1%; jiang, nan, lv, & yang, 2020) . according to scholars, prior trauma exposure and subsequent ptsd symptoms might intensify one's vulnerability when facing additional stressors. trauma-exposure and ptsd symptoms might drain one's resources (hobfoll, 2002 (hobfoll, , 2001 , as well as one's coping capacity, and might heighten one's sensitivity to stress (resnick et al., 1995; yehuda et al., 1995) . empirical evidence has supported this claim, indicating that a history of trauma exposure and resultant ptsd were associated with an elevated risk for ptsd following a later trauma (breslau et al., 2008; cougle et al., 2009; green et al., 2000; kessler et al., 2018; ozer et al., 2003) . furthermore, a recent study that explored psychological distress related to covid-19 indicated that prior trauma exposure and j o u r n a l p r e -p r o o f subsequent ptsd symptoms were associated with elevated levels of psychiatric symptomatology and peritraumatic stress symptoms during the pandemic (lahav, under review) . alongside the negative ramifications of prior trauma exposure, such exposure may also have salutogenic effects, with posttraumatic growth (ptg) being one of the most prevalent terms used to describe it. posttraumatic growth denotes the tendency to report a positive transformation in the aftermath of trauma exposure (tedeschi et al., 2018; calhoun, 2004, 1996) . this transformation is assumed to reflect changes which go beyond pre-trauma adjustment and which are manifested in an enhanced appreciation for life, changes in priorities, more meaningful relationships with others, a sense of increased personal strength, new possibilities for the future, and existential/ spiritual thriving (e.g., tedeschi et al., 2018) . reports of ptg have been documented among survivors of various types of traumatic events. these include combat or other military-related traumatic events (mark et al., 2018; stein et al., 2020; zerach, 2020) , natural and manmade disasters (s. palgi et al., 2020) , accidents, life-threatening physical illnesses (hefferon et al., 2009) , bereavement (waugh et al., 2018) , and childhood abuse (kaye-tzadok and davidson-arad, 2016; lev-wiesel et al., 2004; shakespeare-finch and de dassel, 2009 ). nevertheless, scrutinizing the clinical and empirical literature suggests that the phenomenon of ptg is yet to be fully understood. in fact, both the essence and implications of ptg for adjustment have been the focus of a great deal of controversy. whereas some view ptg as reflecting authentic positive changes that result from struggling with the trauma calhoun, 2004, 1996) , others claim that ptg might consist of illusory or avoidant elements, which may be maladaptive, at least to some degree (davis and j o u r n a l p r e -p r o o f mckearney, 2003; maercker and zoellner, 2004; mcfarland and alvaro, 2000) . a recent theoretical model further elaborated on this latter line of thought, and suggested that ptg should be understood in terms of dissociation, which denotes a disruption in the integration of mental processes (lahav et al., 2016a (lahav et al., , 2017b . according to this perspective, whereas some reports of ptg may in fact reflect a deep, genuine, positive transformation that either has no effect or a beneficial effect on adjustment over time, other reports of ptg may be rooted in dissociative mechanisms and might be maladaptive . research on the implications of ptg for adjustment has further deepened questions regarding the nature of ptg, as it has provided mix findings. for example, previous studies exploring the associations between ptg and psychological distress in regard to a wide range of traumatic events revealed positive, negative, and no relations between the two (helgeson et al., 2006; linley and joseph, 2004; a.-n. liu et al., 2017; shakespeare-finch and lurie-beck, 2014; zoellner and maercker, 2006) . the theoretical debate and the inconsistent findings regarding the nature and consequences of ptg point to the need to further illuminate the association between ptg, adjustment, and distress. furthermore, to the best of our knowledge, no research to date has explored the relations between ptg attributed to prior trauma and adjustment in the face of additional trauma exposure. given the high prevalence of trauma exposure worldwide, and the fact that trauma survivors are argued to suffer from heightened vulnerability in the face of new stressors, investigating this subject matter is imperative. the current study, conducted among trauma survivors in the midst of the covid-19 pandemic in israel, was designed to fill this lacuna. specifically, it explored the unique contribution of ptg attributed to prior trauma in explaining peritraumatic stress symptoms j o u r n a l p r e -p r o o f related to the pandemic, above and beyond background characteristics, covid-19-related stressors, and ptsd symptoms resulting from past trauma. in this way, the current study aimed to reveal whether ptg resulting from prior trauma was related to low distress in the face of an additional traumatic event (in this case, or, alternatively, was either unrelated to distress or related to higher levels of distress due to an additional stressor (again, in this case, the pandemic). being the first, presumably, to address this subject matter, the current study consisted of three main objectives: 1. to describe peritraumatic stress symptoms related to covid-19, and their relation with background characteristics and covid-19-related stressors, among trauma survivors. 2. to explore the relation between ptg and ptsd symptoms attributed to prior exposure, on the one hand, and peritraumatic stress symptoms related to covid-19, on the other hand. 3. to assess the unique contribution of ptg attributed to prior trauma exposure in explaining peritraumatic stress symptoms related to covid-19, above and beyond background characteristics, covid-19-related stressors, and ptsd symptoms related to prior trauma exposure. participants and procedure. an online survey was conducted among a convenience sample of israeli adults. the survey was accessible through qualtrics, a secure web-based survey data collection system. the survey took an average of 25 minutes to complete and was open from april 2, 2020 to april 19, 2020. it was anonymous, and no data were collected that linked participants to recruitment sources. the [masked for review] institutional review board (irb) approved all procedures and instruments. clicking on the link to the survey guided potential respondents to a page that provided information about the purpose of the study, the j o u r n a l p r e -p r o o f nature of the questions, and a consent form (i.e., the survey was voluntary; respondents could quit at any time; responses would be anonymous). the first page also offered researcher contact information. each participant was given the opportunity to take part in a lottery that included four $60 gift vouchers. a total of 1,263 people answered some of the questionnaires. based on the trauma history screen (ths; carlson et al., 2011) , 793 participants were classified as having been exposed to traumatic events. of them, only 528 participants (66.6%) who had data regarding all of the study's variables were included in the present analyses. no differences were found between participants who were included in the study and those who were not in terms of gender, χ 2 (1) = 1.12, p = .29; relationship status, χ 2 (1) =.89, p = .37; education, χ 2 (1) =.79, p = .37; or income, χ 2 (1) =.04, p = .85. however, there was a significant difference between the groups in terms of age, t(565.48)= 4.80, p < .001, so that the average age among the group of participants who were not included in the study was higher (m = 47.67, sd = 15.00) than among the study sample (m = 42.61, sd = 13.61). participants' ages ranged from 18 to 75 (m = 42.61, sd = 13.61), with the majority of the sample being below the age of 50 (66.1%). most of the participants were jewish (96.6%) women (82.8%); were secular (69.9%); had a high school education or below (51.3%); were in a relationship (62.5%); and had an average or below-average income (50.2%). traumatic events consisted of exposure to rocket attacks (n = 238, 45.1%), accidents (n = 111 21.0%), a physical or sexual assault during childhood (n = 105. 19.9%), a natural disaster (n = 12, 2.3%), a physical or sexual assault in adulthood (n = 80, 15.6%), being attacked with a gun, knife, or other weapon (n = 26, 4.9%), the sudden death of a family member or close friend (n = 194, 36.7%), seeing someone die or get badly hurt or killed (n = 77, 14.6%), and seeing something traumatizing during military service (n = 58, 11.0%). the vast majority of participants reported two traumatic events or more (57.6%). measures background variables. participants completed a brief demographic questionnaire that assessed age, gender, education, relational status, religiosity, and income. covid-19-related stressors. participants were asked to generally indicate which of the potential implications of the pandemic were the most concerning to them and to state whether they experienced specific stressors related to the covid-19 pandemic. these were measured via nine items designed by the research team. participants were asked 1) how they perceived their own physical health, 2) whether they were diagnosed with the disease, 3) whether they were quarantined, 4) whether they were living alone during the outbreak, 5) whether they belonged to a high-risk group for covid-19, 6) whether they had close others who belonged to a high-risk group, 7) whether they had close others who had been diagnosed with the disease, 8) whether they had close others who had been hospitalized due to the disease, and 9) whether they had experienced the loss of close others as a result of the disease. given that only four participants reported being diagnosed with the disease, this specific stressor was not included in the present analyses. in addition, in order to assess a pandemic-related economic stressor, participants were asked whether they had become unemployed or furloughed since the outbreak of the pandemic. all stressors apart from perceived health were coded as dummy variables, with "0" reflecting the absence of stressor and "1" reflecting the presence of stressor. perceived health ranged from "1" reflecting poor health to "5" reflecting excellent health. peritraumatic stress symptoms related to covid-19. peritraumatic stress symptoms in response to covid-19 were measured via a modified version of the ptsd checklist (pcl-5) (weathers et al., 2013 ). this 20-item self-report measure asks participants to indicate the extent to which they experienced each ptsd symptom, on a 5-point likert scale ranging from 0 (not at all) to 4 (extremely). items correspond to the newly approved ptsd symptom criteria in the diagnostic and statistical manual of mental disorders (5th ed., dsm-5; american psychiatric association, 2013). the original version was adapted so that the timeframe for experiencing each symptom was changed from "in the past month" to "since the outbreak of the covid-19 pandemic and subsequent to the pandemic," and the index event was the covid-19 pandemic. a total score of peritraumatic stress symptoms was calculated by summing all 20 items. although not a definitive diagnostic measure, preliminary research suggests that a cutoff score of 33 is a useful threshold to indicate symptomatology which may be at clinical levels (bovin et al., 2016) . the pcl-5 demonstrates high internal consistency and test-retest reliability (bovin et al., 2016) . internal consistency reliability in this study for intrusion, avoidance, negative alterations in mood and cognition, and hyperarousal clusters, as well as the pcl-5 total score, ranged from good to excellent (α = 0.89, 0.82, 0.83, 0.83, 0.94, respectively). ptsd symptoms as a result of prior trauma exposure. ptsd symptoms were measured via the pcl-5 (weathers et al., 2013) . participants were asked to anchor responses to "stressful/traumatic life experiences" other than the pandemic, which they had experienced in the past and reported via the ths (carlson et al., 2011), on a scale ranging from 0 (not at all) to 4 (extremely). a total score is also calculated to assess the overall ptsd severity. internal consistency reliability in this study for the pcl-5 total score subscales was excellent (α = 0.95). ptg attributed to prior trauma exposure. ptg attributed to prior trauma exposure was assessed via the post traumatic growth inventory (ptgi; tedeschi & calhoun, 1996) . for each of the 21 statements in the questionnaire, participants were asked to rate the extent to which the indicated change occurred in their lives as a result of their stressful/traumatic life experiences" other than the pandemic, which they had experienced in the past and reported via the ths (carlson et al., 2011) . each item was scored on a 4-point scale ranging from 1 (i didn't experience this change at all) to 4 (i experienced this change to a very great degree). the total score was computed according to five subscales: relating to others (i.e., "i learned a great deal about how wonderful people are"), new possibilities (i.e., "i established a new path for my life"), personal strength (i.e., "i discovered that i'm stronger than i thought i was"), spiritual change (i.e., "a better understanding of spiritual matters"), and appreciation of life (i.e., "appreciating each day"). the ptgi has shown good internal consistency, construct, convergent and discriminant validities (tedeschi & calhoun, 1996) . internal consistency reliabilities were good (α = 0.91, 0.90, 0.89, 0.70, 0.80, 0.96, for relating to others, new possibilities, personal strength, spiritual change, appreciation of life, and total score, respectively). the current analyses were conducted using spss 25. to assess associations between background characteristics and covid-19-related stressors, on the one hand, and peritraumatic stress symptoms related to covid-19, on the other, four linear regressions were conducted for each of the clusters of peritraumatic stress symptoms. to assess the associations between ptsd symptoms and ptg as a result of prior trauma exposure, on the one hand, and peritraumatic stress symptoms related to covid-19, on the other, pearson correlation analyses were conducted. lastly, to explore the unique contribution of ptg attributed to prior trauma exposure in explaining peritraumatic stress symptoms related to the pandemic, above and beyond background characteristics, covid-19-related stressors, and ptsd symptoms resulting from prior trauma, four hierarchical regressions were conducted for each cluster of peritraumatic stress symptoms. to determine whether including the independent and control variables in the regression analyses was adequate, we assessed for multicollinearity and examined the variance inflation factors (vifs) for the study's variables. findings indicated that all were j o u r n a l p r e -p r o o f within the acceptable range (all vifs were smaller than 2), indicating that multicollinearity was not a problem in our analyses. the analyses included four blocks. the first block consisted of background characteristics. the second block consisted of covid-19-related stressors. the third block consisted of ptsd symptoms related to prior trauma exposure. the fourth block consisted of the ptg total score attributed to prior trauma exposure. respondents reported experiencing several covid-19-related stressors. these consisted of being quarantined (n = 58, 11.0%), living alone during the outbreak (n = 78, 13.8%), belonging to a high-risk group for covid-19 (n = 175, 33.1%), perceiving one's physical health in a negative fashion (n = 46, 8.8%), having a close other who was diagnosed with covid-19 (n = 38, 7.2%), having a close other who belonged to a high-risk group (n = 467, 88.4%), having a close other hospitalized due to the disease (n = 11, 2.1%), experiencing the loss of close others as a result of the disease (n = 6, 1.1%), and becoming unemployed or furloughed since the outbreak of the pandemic (n = 114, 21.6%). these covid-19-related stressors seemed to capture respondents' main areas of concern regarding the pandemic, which consisted of potential threats to their own health or their close others' health (n=222, 42.0%), negative economic consequences (n=109, 20.6%), social distancing and loneliness (n=62, 11.7%), and other (n=135, 25.6%). of the total sample, 43.2% (n = 228) reported at least one intrusion symptom, 29.7% (n = 157) reported at least one avoidance symptom, 61.7% (n = 326) reported at least one symptom reflecting negative alterations in mood and cognition, and 66.3% (n = 350) reported at least one hyperarousal symptom. furthermore, 13.4% (n = 71) of the participants had a peritraumatic stress symptom total score of 33 or above, indicating that their symptoms were clinically significant. table 1 as can be seen in the table, age, gender, and education were related to peritraumatic stress symptoms. being younger was associated with higher levels in all clusters of peritraumatic stress symptoms. being female and having a high school education or below were also associated with higher intrusion, hyperarousal, and negative alterations in mood and cognition symptoms. covid-19-related stressors were associated with peritraumatic stress symptoms as well. negative perceived health was related to higher levels in all clusters of peritraumatic stress symptoms. living alone during the outbreak was related to higher levels of hyperarousal and negative alterations in mood and cognition symptoms, and being quarantined was related to higher levels of negative alterations in mood and cognition symptoms. all other covid-19-related stressors had a nonsignificant effect in explaining peritraumatic stress symptoms. pearson correlations between ptsd symptoms resulting from prior trauma exposure, ptg attributed to prior trauma exposure, and peritraumatic stress symptoms related to are presented in table 2 . as can be seen in the table, ptsd symptoms subsequent to prior trauma exposure were significantly associated with peritraumatic symptoms related to covid-19. the higher the ptsd symptoms subsequent to prior trauma exposure, the higher the levels of all peritraumatic symptom clusters. posttraumatic stress disorder symptoms were significantly associated with ptg attributed to prior exposure. the higher the ptsd symptoms, the higher the ptg scores. furthermore, results indicated significant associations between ptg attributed to prior trauma exposure and peritraumatic symptoms related to covid-19. the higher the ptg scores subsequent to prior trauma exposure, the higher the scores in all peritraumatic symptom clusters. to explore the unique contribution of ptg in explaining peritraumatic stress symptoms, above and beyond background characteristics, covid-19-related stressors, and ptsd symptoms, four hierarchical regressions were conducted. the first block consisted of the background characteristics of age, gender, and education -all three of which variables had the largest contribution in explaining peritraumatic stress symptoms compared to the other background variables. the second block consisted of the covid-19-related stressors of perceived health, living alone during the outbreak, and being quarantined -all three of which variables had the largest contribution in explaining peritraumatic stress symptoms compared to the other covid-19-related stressors. the third block consisted of ptsd symptoms resulting from prior trauma exposure. the fourth block consisted of the ptg total score attributed to prior trauma exposure. results of the analyses are presented in table 3 . as can be seen in table 3 , ptg attributed to prior trauma exposure had a unique effect in explaining intrusion, avoidance, and hyperarousal peritraumatic stress symptoms. higher scores of the ptg total score were associated with higher intrusion, avoidance, and hyperarousal symptoms related to covid-19. these effects were found above and beyond background characteristics, covid-19-related stressors, and ptsd symptoms. the only exception was found in regard to the "alteration in cognition and mood symptoms" cluster, where ptg had a non-significant effect. this study described the unique contribution of ptg attributed to prior trauma in explaining trauma-related symptoms during the covid-19 pandemic, among trauma survivors. findings indicated that more than a quarter of the sample reported having at least one peritraumatic stress symptom related to the pandemic, and 13.4% of the participants had a peritraumatic stress symptom total score of 33 or above, indicating that their symptoms were clinically significant. these findings provide further support for the notion that the covid-19 pandemic has the potential to be traumatogenic (horesh and brown, 2020) , and are in line with findings of recent studies that documented peritraumatic stress symptoms as a result of covid-19 (jiang et al., 2020; qiu et al., 2020; wang et al., 2020b) . our results revealed that several background characteristics and covid-19-related stressors were associated with peritraumatic stress symptoms during the pandemic, even after taking into account ptsd symptoms and ptg attributed to prior trauma. consistent with recent studies that explored the effects of the covid-19 pandemic (jiang et al., 2020; wang et al., 2020b) , we found that young age and being female were associated with elevated peritraumatic stress symptoms. the increased vulnerability of the female population when facing trauma has been consistently documented in trauma research (e.g., haskell et al., 2010; j o u r n a l p r e -p r o o f sareen, 2014) and might be the result of sex differences in psychophysiology, threat appraisal, and coping style (irish et al., 2011; olff et al., 2007) . in regard to the age factor, the relation between younger age and elevated peritraumatic reactions found in our study might reflect the negative effects of exposure to information about the pandemic via social media (roberts et al., 2018 ) -exposure which is presumed to be higher among younger than older individuals. in addition, and in line with previous findings (e.g., fiorillo & gorwood, 2020; wang, pan, wan, tan, xu, ho, et al., 2020) , we found that being in quarantine and negatively self-rating one's health status explained elevated levels of peritraumatic stress reactions. being quarantined might impair feelings of belongingness, as well as limit social support; the latter (limited social support) has been found to have buffering effects when one faces psychological trauma (kaniasty and norris, 2008) . appraising one's health negatively may produce fears of becoming ill (wang et al., 2020a) and may lead to evaluating the pandemic as particularly threatening and traumatic. conversely, becoming unemployed or furloughed since the outbreak of the pandemic was unrelated to peritraumatic stress symptoms. these findings are surprising and inconsistent with former findings that indicated the negative implications of the pandemic-related economic crisis for individuals' mental health (bareket-bojmel et al., 2020; reger et al., 2020) . it might be that the negative effects of economic difficulties are not manifested in trauma-related symptoms, but in other types of psychopathology such as depression or anxiety, which were not assessed in the current study. alternatively, it might be that the economic stressor that was assessed in this study was only one of potentially many such stressors and did not capture the full economic implications of the pandemic. our results revealed that ptsd symptoms resulting from prior trauma were associated with trauma-related symptoms during the covid-19 pandemic, with effect sizes ranging from medium to large. these findings are in line with theory, as well as with empirical j o u r n a l p r e -p r o o f evidence (breslau et al., 2008; kessler et al., 2018) , suggesting that ptsd might heighten trauma survivors' vulnerability when facing additional traumas. a number of processes might be at the basis of this susceptibility. these include physiological alterations related to ptsd, such as greater brainstem and hippocampal activity in response to threat stimuli (felmingham et al., 2010; nutt and malizia, 2004) , which might intensify arousal and distress; negative appraisals of new stressors (lee et al., 2020) , which might further fuel distress; as well as a tendency to adopt avoidant coping strategies that are known to impede adjustment to trauma (badour et al., 2012; foa and kozak, 1986) . although the present findings regarding the adverse implications of ptsd symptoms may be somewhat predictable, our investigation of the contribution of ptg yielded innovative findings. the current results indicated that ptg attributed to prior trauma was associated with elevated peritraumatic stress symptoms related to covid-19; specifically, the higher the level of ptg, the higher the scores on the peritraumatic stress symptoms. furthermore, we found that ptg made a unique contribution in explaining elevated peritraumatic stress symptoms, above and beyond background characteristics, covid-19related stressors, and ptsd symptoms resulting from prior trauma. this trend was found in regard to all of the clusters of peritraumatic stress symptoms, apart from the cluster of negative alterations in cognition and mood. in view of the heightened vulnerability of traumatized individuals when facing new stressors (e.g., kessler et al., 2018; ozer et al., 2003) , and given the high prevalence of reports of ptg among this population (tedeschi et al., 2018) , the questions concerning the quality and implications of ptg raised by the present findings are weighty. several explanatory routes can be proposed in regard to these results. first, the present findings may reflect a greater willingness on the part of trauma survivors who experienced ptg to acknowledge their distress. according to calhoun & tedeschi (2014) , a positive transformation resulting from trauma stems from schema j o u r n a l p r e -p r o o f reconstruction. trauma survivors who report ptg seem to experience, as a result of their trauma, the rebuilding of their schemas, which eventually leads to wider, more complex, and integrated views, consisting of both negative and positive cognitions (calhoun and tedeschi, 2014) . as part of this new belief system, trauma survivors might view themselves as "vulnerable yet stronger" (calhoun & tedeschi, 2014, p.5) ; that is, they may experience themselves as less immune or impervious to life's adversities, but at the same time, as having the strength to cope with and survive it. thus, it might be that the current study participants who experienced positive changes as a result of their prior trauma were more inclined to recognize and report their distress when facing covid-19. at the same time, it could be that the reports of ptg in the present study were shaped by participants' current distress and reflected their efforts to rely on positive retrospective appraisals of prior trauma as a way to cope with the threat of the pandemic. trauma survivors who participated in the present study and suffered from elevated peritraumatic stress symptoms during the pandemic might have painted their prior trauma in bright, positive colors, attributing to it beneficial effects, as a way to find comfort and better cope with their current plight. previous research has provided some support for this explanation, indicating that perceptions of personal improvement might reflect strongly-held illusions that are aimed at helping the individual cope with threatening life events (mcfarland and alvaro, 2000) . finally, the results of this study could also reflect illusory-defensive aspects of reports of ptg, which might be maladaptive, at least to some degree (e.g., maercker & zoellner, 2004) . this illusory-defensive facet of ptg may be rooted in an over-reliance on dissociative mechanisms which -although potentially providing emotional relief in the short term -may hamper an individual's ability to reprocess and overcome the trauma in the long term (lahav et al., 2016a) . thus, it may be that whereas trauma survivors are generally more vulnerable to distress when exposed to additional stressors, those who report ptg may end j o u r n a l p r e -p r o o f up being even more susceptible to the various negative effects of such future traumas, such as those posed by today's global pandemic. specifically, these individuals might suffer from elevated levels of intrusion, avoidance, and hyperarousal peritraumatic stress symptoms. previous findings which have indicated associations between ptg and various negative outcomes (dekel et al., 2015; lahav et al., 2017a lahav et al., , 2016b a.-n. liu et al., 2017; shakespeare-finch and de dassel, 2009 ) provide some support for this explanation. the idea that reports of ptg are reflective of dissociative beliefs might also explain the lack of ptg's contribution in regard to the negative alterations in cognition and mood cluster, found in the present study. these dissociative beliefs are argued to reflect the formation of a fragmented and disintegrated belief system that includes, in a disconnected manner, cognitions regarding a positive transformation attributed to prior trauma, on the one hand, and negative cognitions that echo the pain and suffering caused by the trauma, on the other (lahav et al., , 2016a . hence, although these beliefs might be associated with individuals' distress when facing an additional trauma, such as the covid-19 pandemic, they may be unrelated to the co-existing split-off negative cognitions, which remain separated and detached. empirical evidence that has revealed associations between reports of ptg and dissociation (greene, 2018; lahav et al., 2020 lahav et al., , 2016a suggest such a prospect. nevertheless, as the present investigation did not explore the mechanisms underlying the relations between ptg and peritraumatic stress symptoms, all three explanations offered herein are speculative. the present findings must be considered in light of several limitations. first, a major limitation of the present study is its cross-sectional design. although participants in the present study were specifically asked to report peritraumatic stress symptoms subsequent to the covid-19 pandemic, the present data does not allow identifying the time of the symptoms' onset. additionally, based on the current data the direction of association between ptg and peritraumatic stress symptoms cannot be inferred. second, the present study relied on convenience sampling. the majority of participants in the sample were below the age of 50, and there was an overrepresentation of the female gender. these trends, which have been found in other surveys on the covid-19 pandemic (lai et al., 2020; mazza et al., 2020; wang et al., 2020b) , should be acknowledged prior to generalizing from the results to the population at large. third, although many covid-19-related stressors were explored in this study, there was only one pandemic-related economic crisis stressor explored (i.e., becoming unemployed or furloughed since the outbreak of the pandemic). thus, other effects of the economic crisis on trauma-related symptoms during the pandemic might not have been identified. fourth, the current study relied on self-report measures, which may be subject to response biases and shared method variance. additionally, the validity of the posttraumatic growth inventory (tedeschi and calhoun, 1996) , one of the most commonly used measurements of ptg, was, in an earlier study, called into question (frazier et al., 2009) . future studies should therefore include additional methods of data collection such as clinical interviews and other types of self-report measures tapping ptg. fifth, the present study did not include data regarding the time that had passed since the prior trauma, a factor that might affect the process of schema reconstruction that lies at the basis of ptg. furthermore, we did not include data regarding potential mechanisms that might underlie the link between ptg and peritraumatic distress, such as avoidance coping strategies. finally, our analyses focused on israeli trauma survivors, and thus the study's generalizability might be limited. future prospective studies should explore the relation between ptg attributed to prior trauma and adjustment in the face of additional traumas over time, among survivors of various traumatic events with diverse cultural backgrounds. bearing in mind these limitations, this study represents a step toward understanding the potential implications of trauma survivors' ptg under conditions of additional trauma exposure. though the processes at its basis are yet to be investigated, the current findings j o u r n a l p r e -p r o o f reveal associations between ptg attributed to prior trauma, on the one hand, and peritraumatic stress symptoms in the face of additional trauma, on the other. in light of a possible second wave of covid-19, and the expected long-term repercussions of this pandemic, the results indicate the need to provide therapy to trauma survivors and particularly to those who suffer from ptsd symptoms. adapting evidence-based treatments for trauma, such as prolonged exposure therapy (foa, hembree, & rothbaum, 2007) or eye movement desensitization and reprocessing therapy (emdr; shapiro, 2017) to the current conditions, and providing them online (wind et al., 2020) , might allow traumatized individuals to reprocess their prior traumatic event as well as their current peritraumatic reactions during the pandemic, and thus alleviate their distress. furthermore, the current results suggest that clinicians should not only assess ptsd symptoms attributed to prior trauma but ptg as well, and should take a cautious approach when treating trauma survivors who report ptg, given that the essence of ptg is still unclear. reports of ptg might reflect a positive transformation subsequent to prior trauma, or alternatively may mirror efforts to cope with current distress or maladaptive dissociative beliefs. exploring patients' reports of ptg while taking into account their current distress as well as their tendency to rely on dissociative mechanisms may help clinicians to treat these patients more effectively. nevertheless, future longitudinal studies exploring the implications of ptg for individuals' mental health in the face of additional stressors, while assessing potential mechanisms underlying these effects, are needed in order to promote the development of clinical practice guidelines. j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f note: gender values: 0 = male, 1 = female; education values: 0 = high school education or below, 1 = higher level education. all stressors apart from perceived health were coded as dummy variables, with "0" reflecting the absence of stressor and "1" reflecting presence of the stressor. lower scores on perceived health reflect negative perceptions of one's health. *p < 0.05, **p < 0.01, ***p < 0.001 j o u r n a l p r e -p r o o f table 2 . inter-correlations between ptsd symptoms and ptg attributed to former trauma exposure, and peritraumatic stress symptoms related to ** p < .01. *** p < .001 step 1 age -.03 .03** -.06 .02* -.22*** .08*** -.24*** .08*** gender .13** .08 .10* .12* education -.12** -.10* -.12** -.05 step 2 age -.09* .05*** -.12** .05*** -.29*** .08*** -.30*** .06*** gender .11** .06 .08 .10* education -.10* -.08 -.09* -.02 perceived health -.20*** -.17*** -.21*** -.20*** in quarantine .06 .07 .09* .07 live alone during outbreak -.06 -.09* -.14** -.09* step 3 j o u r n a l p r e -p r o o f age -.03 .14*** -.07 .09*** -.21*** .20*** -.21*** .24*** j o u r n a l p r e -p r o o f note: gender values: 0 = male, 1 = female; education values: 0 = high school education or below, 1 = higher level education. all stressors apart from perceived health were coded as dummy variables, with "0" reflecting the absence of stressor and "1" reflecting presence of the stressor. lower scores on perceived health reflect negative perceptions of one's health. *p < 0.05, **p < 0.01, ***p < 0.001 ptg total score .08* .15*** .06 .09* j o u r n a l p r e -p r o o f diagnostic and statistical manual of mental health disorders: dsm-5 a longitudinal test of the bi-directional relations between avoidance coping and ptsd severity during and after ptsd treatment covid-19-related economic anxiety is as high as health anxiety: findings from the usa, the uk, and israel psychometric properties of the ptsd checklist for diagnostic and statistical manual of mental disorders-fifth edition (pcl-5) in veterans a second look at prior trauma and the posttraumatic stress disorder effects of subsequent trauma: a prospective epidemiological study psychological resilience and posttraumatic growth in disaster-exposed organisations: overview of the literature the psychological impact of quarantine and how to reduce it: rapid review of the evidence handbook of posttraumatic growth: research and practice epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study does prior exposure to interpersonal violence increase risk of ptsd following subsequent exposure? how do people grow from their experience with trauma or loss? posttraumatic growth among spouses of combat veterans: adaptive or maladaptive for adjustment? neural responses to masked fear faces: sex differences and trauma exposure in posttraumatic stress disorder the consequences of the covid-19 pandemic on mental health and implications for clinical practice prolonged exposure therapy for ptsd: emotional processing of traumatic experiences therapist guide emotional processing of fear: exposure to corrective information does selfreported posttraumatic growth reflect genuine positive change? mental health problems and social media exposure during covid-19 outbreak trauma history as a predictor of psychologic symptoms in women with breast cancer do acute dissociation reactions predict subsequent posttraumatic stress and growth? a prospective experience sampling method study gender differences in rates of depression, ptsd, pain, obesity, and military sexual trauma among connecticut war veterans of iraq and afghanistan post-traumatic growth and life threatening physical illness: a systematic review of the qualitative literature a meta-analytic review of benefit finding and growth social and psychological resources and adaptation the influence of culture, community, and the nested-self in the stress process: advancing conservation of resources theory first case of 2019 novel coronavirus in the united states traumatic stress in the age of covid-19: a call to close critical gaps and adapt to new realities gender differences in ptsd symptoms: an exploration of peritraumatic mechanisms psychological impacts of the covid-19 epidemic on chinese people: exposure, post-traumatic stress symptom, and emotion regulation longitudinal linkages between perceived social support and posttraumatic stress symptoms: sequential roles of social causation and social selection posttraumatic growth among women survivors of childhood sexual abuse: its relation to cognitive strategies, posttraumatic symptoms psychological distress related to covid-19 -the contribution of continuous traumatic stress posttraumatic growth and shattered world assumptions among ex-pows: the role of dissociation posttraumatic growth and shattered world assumptions among ex-pows: the role of dissociation post-traumatic growth, dissociation, and sexual revictimization in female childhood sexual abuse survivors posttraumatic growth and dyadic adjustment among war veterans and their wives countertransference in the face of growth: reenactment of the trauma posttraumatic growth and perceived health: the exposed to coronavirus disease how trauma influences cardiovascular responses to stress: contributions of posttraumatic stress and cognitive appraisals posttraumatic growth among female survivors of childhood sexual abuse in relation to the perpetrator identity positive change following trauma and adversity: a review correlation between posttraumatic growth and posttraumatic stress disorder symptoms based on pearson correlation coefficient: a meta-analysis association of dsm-iv posttraumatic stress disorder with traumatic experience type and history in the world health organization world mental health surveys the janus face of self-perceived growth: toward a twocomponent model of posttraumatic growth pandemic: immediate psychological responses and associated factors mechanisms of stress in the brain the impact of motivation on temporal comparisons: coping with traumatic events by perceiving personal growth structural and functional brain changes in posttraumatic stress disorder gender differences in posttraumatic stress disorder predictors of posttraumatic stress disorder and symptoms in adults: a meta-analysis evaluating a community fire as human-made vs. natural disaster moderates the relationship between peritraumatic distress and both ptsd symptoms and posttraumatic growth a nationwide survey of psychological distress among chinese people in the covid-19 epidemic: implications and policy recommendations effect of previous trauma on acute plasma cortisol level following rape factors associated with health service utilisation for common mental disorders: a systematic review an interim review of the epidemiological characteristics of 2019 novel coronavirus posttraumatic stress disorder in adults: impact, comorbidity, risk factors, and treatment exploring posttraumatic outcomes as a function of childhood sexual abuse a meta-analytic clarification of the relationship between posttraumatic growth and symptoms of posttraumatic distress disorder eye movement desensitization and reprocessing (emdr) therapy: basic principles, protocols, and procedures rationality of 17 cities' public perception of sars and predictive model of psychological behavior public responses to the novel 2019 coronavirus (2019-ncov) in japan: mental health consequences and target populations the aging of heroes: posttraumatic stress, resilience and growth among aging decorated veterans posttraumatic growth: conceptual foundations and empirical evidence the posttraumatic growth inventory: measuring the positive legacy of trauma posttraumatic growth: theory, research, and applications psychosocial effects of an ebola outbreak at individual, community and international levels immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china a longitudinal study on the mental health of general population during the covid-19 epidemic in china what aspects of post-traumatic growth are experienced by bereaved parents? a systematic review the ptsd checklist for dsm-5 (pcl-5). scale available from the nationalcenter for ptsd at www the covid-19 pandemic: the 'black swan' for mental health care and a turning point for e-health world health organization situation report -90 impact of cumulative lifetime trauma and recent stress on current posttraumatic stress disorder symptoms in holocaust survivors posttraumatic growth among combat veterans and their siblings: a dyadic approach posttraumatic growth in clinical psychology-a critical review and introduction of a two component model key: cord-309790-rx9cux8i authors: sarker, abeed; lakamana, sahithi; hogg-bremer, whitney; xie, angel; al-garadi, mohammed ali; yang, yuan-chi title: self-reported covid-19 symptoms on twitter: an analysis and a research resource date: 2020-07-04 journal: j am med inform assoc doi: 10.1093/jamia/ocaa116 sha: doc_id: 309790 cord_uid: rx9cux8i objective: to mine twitter and quantitatively analyze covid-19 symptoms self-reported by users, compare symptom distributions across studies, and create a symptom lexicon for future research. materials and methods: we retrieved tweets using covid-19-related keywords, and performed semiautomatic filtering to curate self-reports of positive-tested users. we extracted covid-19-related symptoms mentioned by the users, mapped them to standard concept ids in the unified medical language system, and compared the distributions to those reported in early studies from clinical settings. results: we identified 203 positive-tested users who reported 1002 symptoms using 668 unique expressions. the most frequently-reported symptoms were fever/pyrexia (66.1%), cough (57.9%), body ache/pain (42.7%), fatigue (42.1%), headache (37.4%), and dyspnea (36.3%) amongst users who reported at least 1 symptom. mild symptoms, such as anosmia (28.7%) and ageusia (28.1%), were frequently reported on twitter, but not in clinical studies. conclusion: the spectrum of covid-19 symptoms identified from twitter may complement those identified in clinical settings. the outbreak of the coronavirus disease 2019 (covid-19) is 1 of the worst pandemics in the known world history. 1, 2 as of may 8, 2020, over 4 million confirmed positive cases have been reported globally, causing over 275 000 deaths. 3 as the pandemic continues to ravage the world, numerous research studies are being conducted whose focuses range from trialing possible vaccines and predicting the trajectory of the outbreak to investigating the characteristics of the virus by studying infected patients. early studies focusing on identifying the symptoms experienced by those infected by the virus mostly included patients who were hospitalized or received clinical care. [4] [5] [6] many infected people only experience mild symptoms or are asymptomatic and do not seek clinical care, although the specific portion of asymptomatic carriers is unknown. [7] [8] [9] to better understand the full spectrum of symptoms experienced by infected people, there is a need to look beyond hospital-or clinic-focused studies. with this in mind, we explored the possibility of using social media, namely twitter, to study symptoms self-reported by users who tested positive for covid-19. our primary goals were to (i) verify that users report their experiences with covid-19-including their positive test results and symptoms experienced-on twitter, and (ii) compare the distribution of self-reported symptoms with those reported in studies conducted in clinical settings. our secondary objectives were to (i) create a covid-19 symptom corpus that captures the multitude of ways in which users express symptoms so that natural language processing (nlp) systems may be developed for automated symptom detection, and (ii) collect a cohort of covid-19-positive twitter users whose longitudinal self-reported information may be studied in the future. to the best of our knowledge, this is the first study that focuses on extracting covid-19 symptoms from public social media. we have made the symptom corpus public with this article to assist the research community, and it will be part of a larger, maintained data resource-a social media covid-19 data bundle (https://sarkerlab. org/covid_sm_data_bundle/). we collected tweets, including texts and metadata, from twitter via its public streaming application programming interface. first, we used a set of keywords/phrases related to the coronavirus to detect tweets through the interface: covid, covid19, covid-19, coronavirus, and corona and virus, including their hashtag equivalents (eg, #covid19). due to the high global interest on this topic, these keywords retrieved very large numbers of tweets. therefore, we applied a first level of filtering to only keep tweets that also mentioned at least 1 of the following terms: positive, negative, test, and tested, along with at least 1 of the personal pronouns: i, my, us, we, and me; and only these tweets were stored in our database. to discover users who self-reported positive covid-19 tests with high precision, we applied another layer of filtering using regular expressions. we used the expressions "i.*test[ed] positive," "we.*test [ed] positive," "test.*came back positive," "my.*[covidjcoronavirusjcovid19].*symptoms," and "[covidjcoro-navirusjcovid19].*[testjtested].*us." we also collected tweets from a publicly available twitter dataset that contained ids of over 100 million covid-19-related tweets 10 and applied the same layers of filers. three authors manually reviewed the tweets and profiles to identify true self-reports, while discarding the clear false positives (eg, ". . . i dreamt that i tested positive for covid . . ."). we further removed users from our covid-19-positive set if their self-reports were deemed to be fake or were duplicates of posts from other users, or if they stated that their tests had come back negative despite their initial beliefs about contracting the virus. these multiple layers of filtering gave us a manageable set of potential covid-19-positive users (a few hundred) whose tweets we could analyze semiautomatically. the filtering decisions were made iteratively by collecting sample data for hours and days and then updating the collection strategy based on analyses of the collected data. for all the covid-19-positive users identified, we collected all their past posts dating back to february 1, 2020. we excluded non-english tweets and those posted earlier than the mentioned date. we assumed that symptoms posted prior to february 1 were unlikely to be related to covid-19, particularly because our data collection started in late february, and most of the positive test announcements we detected were from late march to early april. since we were interested only in identifying patient-reported symptoms in this study, we attempted to shortlist tweets that were likely to mention symptoms. to perform this, we first created a meta-lexicon by combining meddra, 11 consumer health vocabulary (chv), 12 and sider. 13 lexicon-based approaches are known to have low recall-particularly for social media data, since social media expressions are often nonstandard and contain misspellings. 14, 15 therefore, instead of searching the tweets for exact expressions from the tweets, we performed inexact matching using a string similarity metric. specifically, for every symptom in the lexicon, we searched windows of term sequences in each tweet, computed their similarities with the symptom, and extracted sequences that had similarity values above a prespecified threshold. we used the levenshtein ratio as the similarity metric, computed as 1 à lev: dist: maxðlengthþ , where lev. dist. represents the levenshtein distance between the 2 strings and max(length) represents the length of the longer string. our intent was to attain high recall, so that we were unlikely to miss possible expressions of symptoms while filtering out many tweets that were completely off topic. we set the threshold via trial and error over sample tweets, and because of the focus on high recall, this approach still retrieved many false positives (eg, tweets mentioning body parts but not in the context of an illness or a symptom). after running this inexact matching approach on approximately 50 user profiles, we manually extracted the true positive expressions (ie, those that expressed symptoms in the context of a covid-19) and added them to the meta-lexicon. following these multiple filtering methods, we manually reviewed all the posts from all the users, identified each true symptom expressed, and removed the false positives. we semiautomatically mapped the expressions to standardized concept ids in the unified medical language system using the meta-lexicon we developed and the national center for biomedical ontology bioportal. 16 in the absence of exact matches, we searched the bioportal to find the most appropriate mappings. using twitter's web interface, we manually reviewed all the profiles, paying particularly close attention to those with less than 5 potential symptom-containing tweets, to identify possible false negatives left by the similarity-based matching algorithms. all annotations and mappings were reviewed, and the reviewers' questions were discussed at meetings. in general, we found that it was easy for annotators to detect expressions of symptoms, even when the expressions were nonstandard (eg, "pounding in my head" ¼ headache). each detected symptom was reviewed by at least 2 authors, and the first author of the article reviewed all the annotations. once the annotations were completed, we computed the frequencies of the patient-reported symptoms on twitter and compared them with several other recent studies that used data from other sources. we also identified users who reported that they had tested positive and also specifically stated that they showed "no symptoms." we excluded nonspecific statements about symptoms, such as "feeling sick" and "signs of pneumonia." when computing the frequencies and percentages of symptoms, we used 2 models: (i) computing raw frequencies over all the detected users, and (ii) computing frequencies for only those users who reported at least 1 symptom or explicitly stated that they had no symptoms. we believe the frequency distribution for (ii) was more reliable since for users who reported no specific symptoms, we could not verify if they had actually not experienced any symptoms (ie, asymptomatic) or just did not share any symptoms over twitter. our initial keyword-based data collection and filtering from the different sources retrieved millions of tweets, excluding retweets. we found many duplicate tweets, which were mostly reposts (not retweets) of tweets posted by celebrities. removing duplicates left us with 305 users (499 601 tweets). 102 of them were labeled as "negatives"-users who stated that their tests had come back negative, removed their original covid-19-positive self-reports, or posted fake information about testing positive (eg, we found some users claiming they tested positive as an april fools' joke). this left us with 203 covid-19-positive users with 68 318 tweets since february 1. the similarity-based symptom detection approach reduced the number of unique tweets to review to 7945. the 203 users expressed 1002 total symptoms (mean: 4.94; median: 4) using 668 unique expressions, which we grouped into 46 categories, including a "no symptoms" category (table 1) . 171 users expressed at least 1 symptom or stated that they were asymptomatic (84.2%). 32 (15.8%) users did not mention any symptoms or only expressed generic symptoms, which we did not include in the counts (we provide these expressions in the lexicon accompanying this paper). 10 users explicitly mentioned that they experienced no symptoms. as table 1 shows, fever/pyrexia was the most commonly reported symptom, followed by cough, body ache & pain, headache, fatigue, dyspnea, chills, anosmia, ageusia, throat pain and chest pain-each mentioned by over 20% of the users who reported at least 1 symptom. figure 1 illustrates the first detected report of each symptom from the cohort members on a timeline, and figure 2 shows the distribution of the number of symptoms reported by the cohort. table 2 compares the symptom percentages reported by our twitter cohort with several early studies conducted in clinical settings (ie, patients who were either hospitalized or visited hospitals/ clinics for treatment). the top symptoms remained fairly consistent across the studies-fever/pyrexia, cough, dyspnea, headache, body ache, and fatigue. the percentage of fever (66%), though the highest in our dataset, is lower than all the studies conducted in clinical settings. in our study, we distinguished, where possible, between myalgia and arthralgia and combined pain (any pain other than those explicitly specified) and body ache. combining all these into 1 category, as some studies had done, would result in a higher proportion. we found considerable numbers of reports of anosmia (29%) and ageusia (28%), with approximately one-fourth of our cohort reporting these symptoms. reports of these symptoms, however, were missing from the referenced studies conducted in clinical settings. our study revealed that there were many self-reports of covid-19 positive tests on twitter, although such reports are buried in large amounts of noise. we observed a common trend among twitter users of describing their day-to-day disease progression since the onset of symptoms. this trend perhaps became popular as celebrities started describing their symptoms on twitter. we saw many reports from users who reported to have tested positive but initially showed no symptoms, and some who expressed anosmia and/or ageusia (first reported on march 5) as the only symptoms, which were undocumented in the comparison studies. there are some studies that suggest that anosmia and ageusia may be the only symptoms of covid-19 among otherwise asymptomatic patients. [20] [21] [22] the most likely explanation behind the differences between symptoms reported on twitter and the clinical studies is that the former were reported mostly by users who had milder infections, while people who visited hospitals often went there to receive treatment for serious symptoms. also, the median ages of the patients studied in clinical studies tended to be much higher than the median age of twitter users (in the us, median twitter user age is 40 23 ). in contrast to the clinical studies, in our cohort, some users expressed mental healthrelated consequences (eg, stress/anxiety) of testing positive. it was difficult in many cases to ascertain if the mental health issues were directly related to covid-19 or whether the users had prior histories of such conditions. to the best of our knowledge, this is the first study to have utilized twitter to curate symptoms posted by covid-19-positive users. in the interest of community-driven research, we have made the symptom lexicon available with this publication. the cohort of users detected over social media will enable us to conduct targeted studies in the future, enable us to study relatively unexplored topics such as the mental health impacts of the pandemic, and the longterm health-related consequences of those infected by the virus. the work reported in this article was supported by funding from emory university, school of medicine. funding for computational huang et al. 6 chen et al. 5 wang et al. 17 chen et al. 18 guan for users who expressed at least 1 symptom or expressed that they did not have any symptoms. *the study provided a combined number for myalgia and fatigue. headache and dizziness was combined for this study. the reported number is for myalgia/muscle ache and/or arthralgia. in our study, we separated myalgia, arthralgia, body ache, and pain. who director-general's opening remarks at the media briefing on covid-19 -11 effects of the covid-19 pandemic on the world population: lessons to adopt from past years global pandemics covid-19 map -johns hopkins coronavirus resource center clinical characteristics of coronavirus disease 2019 in china clinical progression of patients with covid-19 in shanghai clinical features of patients infected with 2019 novel coronavirus in wuhan, china presumed asymptomatic carrier transmission of covid-19 a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia tracking social media discourse about the covid-19 pandemic: development of a public meddra: an overview of the medical dictionary for regulatory activities exploring and developing consumer health vocabularies the sider database of drugs and side effects semi-supervised approach to monitoring clinical depressive symptoms in social media combining lexicon-based and learning-based methods for twitter sentiment analysis welcome to the ncbo bioportal j ncbo bioportal clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study report of the who-china joint mission on coronavirus disease isolated sudden onset anosmia in covid-19 infection. a novel syndrome? loss of smell or taste as the only symptom of covid-19. covid-19 med nedsatt lukte-og smakssans som eneste symptom anosmia and dysgeusia in the absence of other respiratory diseases: should covid-19 infection be considered? sizing up twitter users j pew research center none declared. as designed the study and data collection/filtering strategies. all authors contributed to the analyses, annotation process, and the writing of the manuscript. the authors would like to acknowledge the feedback provided by collaborators from emory university and the georgia department of public health (gdph) through the emory-gdph partnership for covid-19. key: cord-018239-n7axd9bq authors: rusoke-dierich, olaf title: travel medicine date: 2018-03-13 journal: diving medicine doi: 10.1007/978-3-319-73836-9_32 sha: doc_id: 18239 cord_uid: n7axd9bq before travelling to other countries, thorough travel advice should be provided. not only information about diseases of specific countries but also general advice for travelling should be given on this consultation. before travelling to other countries, thorough travel advice should be provided. not only information about diseases of specific countries but also general advice for travelling should be given on this consultation. the following topics should be included in the travel advice consultation: 5 vaccinations (general and country specific) 5 country-specific diseases 5 malaria prophylaxis 5 mosquito prophylaxis (wearing bright long-sleeved clothes, avoiding perfume, staying in air-conditioned rooms, using a mosquito net, using insect repellents, staying inside at dawn and dusk) 5 food consumption and drinking overseas (no consumption of ice cubes, uncooked meals, salads and food, which is exposed to flies, limited alcohol consumption) 5 uv protection (using sun cream, avoiding sun exposure between 11.00 and 15.00 o' clock, remaining in shaded areas, wearing a hat and covering skin) 5 fitness assessment for travelling, flying and diving 5 challenges of different climates and their effects on the personal health (dehydration, hyperthermia) 5 medications 5 thrombosis counselling 5 counselling on symptoms on return, which require review (fever, skin changes, abnormal bleeding, lymphadenopathy, diarrhoea) 5 sexual transmitted diseases 5 contraception 5 rabies the following items should be asked to enable to give the appropriate advice: 5 risk assessment of the travel in a particular country (transport, area of stay/ rural or resort, reason for travelling, appropriate conduct overseas, pre-existing diseases and medications) 5 vaccination status 5 accomodation and stopovers 5 duration of the stay the vast majority of up-to-date travel information and information about tropical disease are available on who (world health organization) or cdc (centres for disease control and prevention) websites. information on these websites are frequently updated. before giving appropriate advice based on these online resources, it should be checked, which medications are available in the particular countries. hence, recommendations need to be adjusted individually. usually, a medication record is required at the customs. however, it might be sufficient, if the original medication box has the patients and prescribing doctors details (. table 32 .1). malaria is a tropical disease transmitted by the female anopheles mosquito. the distribution of malaria is primarily in the tropics and subtropics of africa, central and south america, asia, papua new guinea and the western pacific islands. as popular diving spots are located in these areas, malaria prophylaxis and advice should be given. the who (world health organization) estimates the worldwide number of people affected by malaria with about 198 million and 1,200,000 deaths (2013). the plasmodium parasites need temperatures above 20 °c in order to complete the entire growth cycle. therefore, malaria occurs in some places only seasonal. additionally, there are differences in anopheles species regarding the affinity to the host and their local distribution. some genetic factors are protected against malaria. for example, sickle cell anaemia gives a certain protection against p. falciparum and duffy negative blood group against p. vivax. it appears that after recurrent malaria infections, the body adapts to the disease. this means that an infection is possible, but the symptoms of malaria seem to be reduced. children and pregnant women have an increased risk of being affected by malaria. additionally, children have a high mortality rate. during pregnancy the resistance against malaria is reduced. it also poses an increased risk for the unborn child (low birth weight). anopheles is active especially at sunrise and sunset. different kinds of mosquitoes are rather active during the day and can transmit other diseases such as dengue. especially p. falciparum and p. vivax have resistances against antimalaria drugs. there are different plasmodium pathogens: 5 p. falciparum: worldwide tropical and subtropical distribution, mainly in africa; pathogen of severe malaria causes 1 million deaths per year; rapid growth in the blood with haemolysis and emboli due to cytoadherence of affected erythrocytes; 7-30 days of incubation, irregular fever spikes. 5 p. vivax: mainly in asia, latin america and some countries in africa; the disease can be activated after months or years. incubation period of 12-18 days; fever spikes every 2 days. 5 p. ovale: mainly west africa and the western pacific islands. similar to the p. vivax, it can also infect people with duffy-negative blood group; incubation period of 12-18 days; fever spikes every 2 days. 5 p. malariae: worldwide distribution; typical 3-day cycle, untreated can lead to lifelong chronic malaria; incubation period 16-50 days; fever spikes every 3 days. 5 p. knowlesi: southeast asia, mainly infected animals. after the anopheles mosquito aspirates with gametocytes infected blood, the gametocytes develop to gamete in the mosquito's intestines. in the blood of the mosquito, the microgametes (male) penetrate the macrogametes (female), forming zygotes. then cells are changed to an elongated, motile ookinete. this evolves into an oocyst. after the oocyst bursts, sporozoites are released and get in the saliva of the mosquito. the entire cycle inside the mosquito takes 8-16 days. if sporozoites enter the human bloodstream through the saliva of the . symptoms of malaria appear after the incubation period. the incubation period varies depending on the pathogen. it can be between a few weeks and also takes up to several months or even a year (p. vivax or occasionally p. ovale). malaria can be divided in three different forms: 5 malaria tertiana: pathogen: p. vivax and p. ovale; fever every second day with one day without fever, spontaneous remission after max. 5 years 5 malaria quartana: pathogen: p. malaria; fever every third day with 2 days without fever, no spontaneous remission 5 malaria tropica: pathogen: p. falciparum, irregular fevers due to the lack of synchronisation of the parasite reproduction, severe form of malaria (malaria maligna) with high fatality, recurrence up to 2 years the fever has a specific pattern. in the first hour, strong rigors and increasing fever typically develop. the fever can reach 40 °c and more for duration of about 4 h. it is often associated with flushing, vomiting and nausea. the fever stage is followed by an approximately 3-h stage of severe sweating with decreasing fever. severe forms of malaria can be fatal in within few days. causes of death are cerebral malaria, respiratory failure with adrs and kidney failure. the main reason of these complications is the cyto-adherence ("bonding") of the erythrocytes. it results in a failure of the microcirculation followed by ischaemia of vital organs. . the treatment depends on the severity and the pathogen. in complicated malaria, admission to the intensive care should be considered, if more than one of the following criteria exists: 5 inability of the oral intake of medication 5 parasite load of erythrocytes >2% 5 severe symptoms of malaria (see table above) the treatment options of complicated malaria are: 5 artesunate (allowed only in some countries): 2.4 mg/kg/bw iv; first dose on admission, repeated after 12 and 24 h, minimum duration of therapy 24 h and then once a day, till oral therapy is tolerated. or 5 combination of quinine + doxycycline or clindamycin. 5 quinine: ȥ first dose: 20 mg/kg/bw iv over 4 h or 7 mg/kg/bw iv over 30 min with subsequent administration of 10 mg/kg/bw iv over 4 h. ȥ maintenance therapy: 10 mg/kg/bw iv over 4 h three times a day, beginning 4 h after the completion of the first dose. ȥ exemption: if the patient received three or more doses of quinine in the last 48 h or had an mefloquine prophylaxis in the last 24 h or received a mefloquine treatment in the last 3 days. + 5 doxycycline: 100 mg iv twice daily for 7 days (iv or oral) or 5 clindamycin: ȥ initial dose: 10 mg/kg/bw ȥ maintenance dose: 5 mg/bw every 8 h for 7 days (iv or oral) 5 after clinical improvement medication can be changed to a complete cycle of the oral therapy of an uncomplicated malaria (riamet ® or quinine with doxycycline or clindamycin). uncomplicated malaria can be handled on the normal ward. outpatient therapy with close supervision can be considered under the following conditions: 5 parasite load of erythrocytes <1%. 5 age > 12 months. 5 no co-morbidity. 5 pregnancy is excluded. 5 ability of oral medication intake. 5 p. falciparum is excluded. 5 clinically stable under medical therapy for the last 24 h. a daily blood smear is necessary during treatment to follow the process of the disease. the patient can be discharged from the hospital and continue treatment at home; if oral therapy is tolerated, a clinical improvement is achieved and the parasite count decreases. a week and a month after discharge, blood smears should be repeated. primaquine as eradication therapy is approved in some countries. it is the only drug that can be used to eliminate hypnozoites, which are the dormant forms of the malaria parasites that occur with p. ovale and p. vivax. because primaquine causes haemolysis in g-6-pd deficiency, g-6-pd status prior therapy needs to be established. if an eradication with primaquine is required in patients with g-6-pd deficiency, a dose up to 45 mg weekly for 8 weeks, with monitoring for haemolysis, could be considered. in children methaemoglobinaemia can be provoked by giving primaquine. a single dose of primaquine 45 mg for p. falciparum, p malaria and p. knowlesi can be given to sterilise the gametocytes. if malaria caused by p. vivax or p. ovale or co-infection with these parasites is suspected, a 14-day treatment with 15 mg of primaquine twice a day is recommended. before commencing holidays overseas, medical advice should be given in order to assess the malaria risk of the particular country. in nearly all tropical areas, there is a risk of getting infected with malaria. in some tourist areas, this risk might be small, but infection is still possible. in particular day trips to more remote areas pose a risk. some areas have malaria outbreaks and therefore should be avoided. in general, mosquito bites should be avoided to minimise the risk of any mosquitoborne infections. mosquitoes transmitting malaria are mainly active at night, sunrise and sunset. however, mosquito bites are also possible throughout the day. long-sleeved shirts, long pants and closed shoes cover the skin and provide protection against insect bites. insect repellent for the skin and clothes offer additional protection. higher concentrations offer better and longer protection. the protection period of a normal insect repellent lasts usually only 1-2 h. slow release products can prolong the effect. mosquitoes avoid air-conditioned rooms. so staying in air conditioned rooms itself provides certain protection. spraying insecticides in rooms and surroundings can be helpful to repel and minimise the quantities of mosquitoes. the bed should be covered with a mosquito net (. fig. 32 .2). chemoprophylaxis is important, because the main cause of malaria deaths is still inadequate chemoprophylaxis. there are different drugs for chemoprophylaxis available. they are subject to the travel location and the parasite's resistances to certain drugs. in addition, they differ in side effects, dosage and cost. except malarone ® , all other drugs for the chemoprophylaxis against malaria have to be taken 4 weeks after leaving the country as they aren't sufficiently effective against the primary liver stages of malaria. mefloquine (lariam ® ) is the only malaria prophylaxis without absolute contraindication in pregnancy. diving (decrease in vigilance); 2-3 weeks (at least 1 week) before entering the malaria-endemic country and 4 weeks after return; lariam ® is a category b medication and is the only medication against malaria without absolute contraindication in pregnancy. the use in the first trimester should only be considered, if the expected benefits justify the potential risk to the foetus. however, recent studies suggest that even in the first trimester this medication is safe to take. the dengue virus is an arbovirus. it has four different serotypes (denv 1-4). dengue has a worldwide distribution in the tropics and subtropics, especially in asia and south america. approximately 50-100 million cases and about 100,000 with serious complications per year occur. there is a 10% mortality, which can be reduced to 1% with timely diagnosis and appropriate treatment. it has an increased risk for children under 15 years and persons with previous dengue infections. the dengue virus is transmitted by the aedes aegypti mosquitoes. these mosquitoes mainly bite at day and in twilight (. fig. 32 .3). z symptoms the incubation period is 2-10 days. there is a wide range in severity of dengue symptoms. the majority of infections cause minor symptoms. but dengue infections can be also quite severe (. table 32 .3). in particular recurrent infections with dengue are associated with complications and severity of the disease. it is important for the treating doctor to remember that after the initial fever, the critical phase follows. therefore, the patient must be monitored closely during this time. the disease goes through three stages: 5 fever phase (day 1-3): sudden high fever 40 °c occasional associated with bradycardia; myalgia mainly in the spine, arms and legs ("breakbone fever"), headache; retrobulbar pain; rigors; metallic/bitter taste; vomiting; and dehydration. . 5 critical phase (day 4-5): normal temperature with possible mild fever later on, leucopenia, exanthema, petechiae and lymphadenopathy. severe dengue: abdominal pain, spontaneous bleeding, volume shift in to the peritoneal space ("plasma leak"), pleural effusion, hepatomegaly (≥2 cm), rapid increase in haematocrit and decreasing thrombocytes, shock (dengue haemorrhagic shock = dhs or dengue shock syndrome = dss), increased bleeding (dengue haemorrhagic fever = dhf) and organ failure (particularly liver). 5 remission (after 6 days lasting sometimes for weeks): risk of hyperhydration is given when extravascular fluid is reabsorbed without reducing the intravenous fluid administration. in particular in long remissions, fatigue and depression may be present. normally there are no long-term damages after a dengue infection, and the vascular changes recover completely. z treatment there is no medication available to treat dengue directly. the diagnosis of dengue can be demonstrated by pcr in the initial phase and using igm and igg a few days later. due to severe complications, the haematocrit, coagulation parameters, leukocytes and platelets have to be tested daily. thrombocytes <100,000 cells/mm 3 can rise the suspicion of dhf. if pleural effusion is suspected, a cxr should be obtained. by tightening a blood pressure cuff petechiae can be provoked (medium pressure of the systolic and diastolic pressure for 5 min). this can be used as a diagnostic tool. an increase of the haematocrit of >20%, pleural effusion, ascites or hypoproteinaemia could be a sign for extravascular fluid loss. the extravascular fluid loss is typically found in the initial phase. hence, fluid replacement therapy is crucial in this phase. as the extravascular fluid loss can come to an end quite quickly, a complication of the fluid replacement therapy is hyperhydration. decrease of haematocrit of >20% after fluid administration can represent a fluid excess and hyperhydration. hence, careful monitoring of the fluid balance and weight are necessary. the therapy is adjusted according to its severity. if necessary, dic, blood loss or shock require specific treatment. like dengue, chikungunya is a mosquitoborne disease. the species transmitting the chikungunya virus (chikv) are aedes aegypti in the tropics and subtropics and aedes albopictus in colder regions (. fig. 32 .4). these mosquitoes bite day and night, but mainly in the early morning hours and late afternoon. the incubation period is between 2 and 12 days. the symptoms are similar to that of dengue. patients suffer from sudden fever with headache, skin rash, fatigue, strong limbs and muscle pain. affected joints often are swollen. the symptoms generally last for few days but can persist for weeks and years. the disease has no long-term effects. for diagnosis rt-pcr and virological methods can be used in the initial phase. later, it can be diagnosed by igm and igg. igm peaks after 3-5 weeks and can be detected up to 2 months. the treatment requires analgesia only. . yellow fever is a disease transmitted mainly by the aedes aegypti mosquito but also by other mosquitoes or ticks. the pathogen is a rnacontaining flavivirus. it has approximately 200,000 infections with approximately 30,000 deaths annually. 90% of cases occur in africa and the remaining 10% in south america. the risk of getting infected with yellow fever is with 1:200-2000 in africa and higher than 1:20000 in south america (. fig. 32 .5). the transmission occurs in rainforest areas (jungle or sylvatic cycle), where mosquitoes transfer the virus from monkeys to humans, in endemic areas of the savannah (savannah or intermediate cycle) either transferred from monkeys or human to humans via mosquitoes or in urban areas from human to human via mosquitoes. the incubation period is 3-6 days. the disease has two phases. the acute phase comes with fever, headache, myalgia, headand backache, loss of appetite, nausea, vomiting and diarrhoea. the second phase occurs only in approx. 15% of infected humans within the next 24 h. jaundice, abdominal pain and vomiting are rapidly developing, followed by diffuse bleeding (epistaxis and gi bleeding) and multi-organ failure (mainly kidneys). if symptoms of the more severe second phase develop, 50% of the patients die within the next 10-15 days. patients who survive usually recover without significant organ damage. the diagnosis can be made via a blood or tissue biopsy of the liver. there is no cure for yellow fever and only supportive measures can be taken. however, a very effective life-vaccination (stamaril ® ) is available. only authorised doctors are authorised to prescribe and give the vaccine. severe side effects of these vaccinations are severe allergic reaction (1:55000), vaccine-associated neurotropic disease/post-vaccinal encephalopathy (1:125000) and vaccine-associated viscerotropic disease/ multi-organ failure (1:400000). for travelling into countries where yellow fever is endemic, vaccination is mandatory. the side effects seem to be age-related and occur increasingly with progressive age or in young children. the vaccination is contraindicated in children 32.2 · other mosquito-borne diseases below 9 month and during pregnancy. analysis of yellow fever vaccines adverse events demonstrated an increased frequency of serious adverse events in persons age 60 years and older. the risk of viscerotropic side effects in <65 years is 1:400000, in a population of 65-75 years of age 1:40000 and in >75 years of age 1:4000. a failure to be vaccinated or being documented can lead to a refusal of entry into other countries or to a certain time in quarantine when leaving the area where yellow fever occurs. if there is a clinical indication against receiving yellow fever vaccine (e.g. children <9 month or poor immune status), a written medical exemption can be granted, to enable to travel to these countries without vaccination. absolute contraindications for a yellow fever vaccination are: 5 allergy against the vaccine or egg protein 5 age < 6 months 5 immunodeficiency 5 neoplasia 5 transplantations 5 immunosuppressive therapies relative contraindications for a yellow fever vaccination are: 5 age 6-9 months 5 age > 60 5 asymptomatic hiv infections and cd4+ t lymphocytes 200-499/mm 3 (15-24% of the total in children <6 years of age) 5 pregnancy 5 lactation aedes aegypti spreads also the zika virus. however, it is also sexually, intrauterine and perinatal transmitted. currently the main distribution is countries in south and north america as well as the caribbean islands, singapore and some countries in south pacific islands. symptoms of zika infection may be fever, rash, arthralgia, myalgia, headache and conjunctivitis. but in most cases, an infection is asymptomatic (~80%). these symptoms are lasting for several days to a week. the incubation period is 3-14 days but is likely to be a few days to a week. the diagnosis can be made via pcr or serology. blood pcr can be detected only in the first week of the disease. urine pcr can detect the virus up to 2 weeks. there is no specific treatment available. deaths are unlikely. there is a potential risk during pregnancy, as microcephaly or other birth defects (~20%) may develop. the zina virus cane be also transferred via semen and can affect unborn life. ross river virus (rrv) is transmitted by the bites of culex annulirostris, aedes vigilax, aedes normanensis and aedes notoscriptus in australia, papua new guinea, parts of indonesia and the western pacific islands. the main transmission time is in the humid summer month from december till march. the main symptoms are fever, rash, headache, myalgia, arthralgia and fatigue. the initial symptoms with fever last usually for 1-2 weeks. myalgia and arthralgia usually last longer. symptoms of fatigue and depression can be late complications. the incubation time is between 3 days and 3 weeks. the diagnosis is made with igm. there is only symptomatic treatment available. barmah forest virus (bfv) is transmitted by the same species as the rrv. it mainly can be found in australia. many people don't develop any symptoms. the incubation time is 3-11 days. if symptoms appear, they are similar to the one of rrv. the initial symptoms last for 1-2 weeks, and the arthralgia and myalgia may last for 6 months. the diagnosis is made with igm. there is only symptomatic treatment available. sindbis virus (sinv) is related to the chikungunya virus. it is mainly transmitted via the culex and culiseta mosquitoes. it can be found in europe, africa, asia and oceania. the symptoms and the duration of the symptoms are quite similar to rrv and bfv. the diagnosis is made with igm. there is only symptomatic treatment available. the o'nyong-nyong virus (onnv) is related to the chikungunya virus but is restricted to africa. it has similar symptoms as the chikungunya virus but has additionally mainly cervical lymphadenopathy, and the affected joins rarely show signs of an effusion. most of the gastrointestinal tract infections are caused by poor hygienic conditions of the travel destination. occasionally ingested seawater can cause intestinal infections too. the main transmission routes are either food-borne or by contact. however, the most common cause for gastrointestinal infections is eating contaminated food. old, warmed up food, salads, unpeeled fruits, poorly cooked food, contaminated water (ice and already opened bottles with refilled water) and ice cream often have substantial quantities of pathogens and pose a risk. hence, the best protection against gi infections is avoiding contaminated food or drinks. usually gastrointestinal infections last for a few days and are self-limiting. if diarrhoea contains blood or mucus in combination of high fever for more than 2 days, more thorough assessment is required. blood and mucus without fever are most likely related to a parasitic disease. if fever is present, it's most likely a bacterial or viral disease. but also climate change by itself or dehydration may be caused by autonomic dysregulation gastrointestinal symptoms such as nausea, weakness, vomiting and diarrhoea. with dehydration the dci risk increases. rehydration and supply of certain electrolytes such as sodium, chloride and potassium are the most important treatments for gastroenteritis. fatigue is a common associated symptom. tannins of black tea boiled for more than 10 min might be beneficial for diarrhoea. the consumption of bananas is recommended because of the high content of potassium. but the best options are rehydration preparations in form of drinks, powders or icy poles. loperamide may slow down the peristaltic and give some relief from diarrhoea. probiotics may support recovery. a low fibre diet is rec-ommended in the active phase of diarrhoea. administration of antibiotics is rarely necessary and indicated. it only is used for serious illnesses or symptoms. 5 reservoir: poultry or meals prepared with egg 5 incubation: 8-48 h 5 symptoms: fever, vomiting nausea, diarrhoea, occasionally blood and mucous in the stool 5 duration: 4-7 days 5 treatment: symptomatic; azithromycin 1 g od for 5 days or ciprofloxacin 500 mg bd for 7 days or ceftriaxone 2 g od 5 reservoir: water and food 5 incubation: 1-2 weeks 5 symptoms: headache, myalgia, bradycardia, roseola in the abdominal area, continuous fever 39-40 °c, porridge -like diarrhoea, intestinal bleeding and decrease of the fever after 4 weeks 5 treatment: symptomatic; azithromycin 1 g od for 5 days or ciprofloxacin 500 mg bd for 7 days or ceftriaxone 2 g od; vaccination available 5 reservoir: human, flies, food and faeces 5 incubation: 2-5 days 5 symptoms: fever, diarrhoea, sometimes with blood and mucus in the stool and severe abdominal pain 5 treatment: symptomatic; ciprofloxacin 500 bd for 5 days, norfloxacin 400 mg bd for 5 days or bactrim 160/800 mg bd for 5 days 5 reservoir: food and water 5 incubation: 0-2 days 5 symptoms: mild to severe diarrhoea with fever and blood and mucous in the stool, most common cause for diarrhoea overseas 5 treatment: symptomatic; norfloxacin 400 mg od and ciprofloxacin 500 mg od 5 reservoir: food (particular strawberries) and water 5 incubation: 1-4 weeks 5 symptoms: diarrhoea like raspberry jelly, no fever! blood and mucous in the stool, risk for developing a liver abscess 5 treatment: symptomatic, asymptomatic carrier, paromomycin 500 mg tds for 7 days; invasive, tinidazole 2 g od for 3 days or metronidazole 400 mg tds for 7 to 10 days 32.3.6 cholera (vibrio cholerae) 5 reservoir: contaminated food and water 5 incubation: 0-5 days 5 symptoms: often mild gi symptoms, 5-10% develop severe symptom with nausea vomiting, rice water-like diarrhoea and severe dehydration, mortality risk of 25-50% 5 treatment: rehydration, electrolyte substitution; vaccination available; azithromycin 1 g single dose, ciprofloxacin 1 g single dose 5 reservoir: food (in particular sea food) and water 5 incubation: 15-50 days 5 symptoms: initial phase (2-7 days)flulike symptoms, gastrointestinal, hepatomegaly; hepatic manifestation (4-8 weeks), no jaundice (approx. 70%), jaundice (30%) with dark urine, jaundice, pruritus; hepatitis a has no chronic form, rarely fatal (fatality is age dependent) 5 treatment: symptomatic, bed rest, avoidance of liver toxic substances (alcohol, medication); vaccination available japanese encephalitis is caused by a flavivirus, which is transmitted by mosquitoes (culex particularly c. tritaeniorhynchus). the hosts are usually pigs and water birds. in humans there are usually not sufficiently high concentrations of virus to serve as a host. the distribution is the asia, especially in rural areas. epidemics occur every 2-15 years (. fig. 32.6 ). the transmission can occur throughout the year but frequently peaks in the rainy season. there are about 68,000 cases per year. only about 1% of the patients are symptomatic. however, if symptoms develop, the mortality rate is 20-30%. approx. 30-50% of patients who survive have long-term neurological or psychiatric complications. mild courses of japanese encephalitis may be accompanied by mild fever and headache. severe cases show high fever, neck stiffness, photophobia, headache, disorientation, coma, convulsions, spastic paralysis or death. consequential damages may be behavioural disorders, convulsions, paralysis and speech disorders. the diagnosis can be established with blood tests and lumbar puncture. there is currently no treatment option. the vaccination is usually well tolerated and available for prophylaxis. there are various tropical diseases, which are present in poorer countries causing more or less severe symptoms. these diseases are termed "neglected tropical diseases" (ntd). the more common ntds are summarised in this chapter. there are three main conditions caused by these pathogens. the african trypanosomiasis (sleeping sickness) is transmitted by the tsetse fly. the distribution is only in some countries of the sub-saharan africa. seventy percent occur in the democratic republic of congo. tsetse flies are mainly found in rural areas. there are two forms causing sleeping sickness, t. brucei rhodesiense and t. brucei gambiense. t. brucei gambiense has an incubation period of months to years and t. brucei rhodesiense weeks to months. the initial phase is the haemolytic-lymphatic phase, in which pathogens replicate in tissues, blood and lymphatic tissues. symptoms are intermittent fever, headache, myalgia and pruritus. additionally, a painless, indurated chancre on the skin 5-15 days after the bite and lymphadenopathy (axillary and inguinal) can be associated. in the second phase, the cns affected causes continuous headache, behavioural disorders (mood swings and depression), delirium, sensitivity disorders, coordination problems and disruptions of the sleeping cycle (daytime somnolence). the diagnosis is mainly made clinically. only for the t. b. rhodesiense, a blood test (centrifuged or wet preparation) to data . detect the parasite is available. examination of buffy coat increases sensitivity. a biopsy of the lymph node to detect the pathogens can be diagnostic for t. brunei gambiense or be used for a culture and pcr. the card agglutination test for trypanosomiasis (catt) is a field test suitable for mass population screening in endemic areas for t. b. gambienses but has a low specificity and is hence only used for identifying suspected cases. all diagnosed patients need to have their cerebrospinal fluid examined for staging, which influences treatment options (. table 32 .4). the treatment is dependent on the pathogen and the staging. if untreated, infections of both forms lead to coma and death. leishmaniasis has three forms: visceral, cutaneous and mucosal (kala-azar). there are about 30 different pathogens, from which approx. 20 are held responsible for these diseases. the disease is transmitted by mosquitoes or sandflies (phlebotomus and lutzomyia). the cutaneous form is the most common one, which causes skin ulcerations. typically this form appears weeks to months after the initial mosquito bite. initially papules are formed, which later ulcerate. they can be painful or painless. the visceral form affects organs, especially the liver, spleen and bone marrow. therefore, this form can be quite dangerous. the changes occur within months and years. hepatosplenomegaly and pancytopenia develop. the mucus form is rare. ulcerative changes of the mucous membranes (e.g. nose, mouth and throat) are typical for this. endemic areas for leishmaniasis are east africa, some arabic countries, india, bangladesh, brazil and some other south american countries. historically, the diagnosis was made by taking a biopsy (skin, bone marrow or other tissues) for culture. now pcr or serological testing with high sensitivity replaced biopsies for making diagnosis. as the visceral disease is fatal without treatment, it needs to be treated in any case. all other forms require normally no treatment. following medication is available: 5 pentavalent antimonial (sb v ) compounds (20 mg per day iv or im for 28 days) 5 liposomal amphotericin b (3 mg od iv on day 1-5, 14 and 21) 5 miltefosine (in adults > 45 kg 50 mg 3 times daily for 28 days) 5 azoles (fluconazole 200 mg od for 6 weeks, itraconazole 200 mg bd for 28 days, ketoconazole 600 mg od for at least 28 days) 5 paromomycin (uncommonly used) 5 pentamidine isethionate (uncommonly used) the chagas' disease is transmitted via an insect bite ("kissing bug") or by contaminated food. it occurs in central and south america. it has . an acute and chronic phase. in the acute phase within 1-2 weeks after the infection, localised swelling of the area of the insect bite (skin or mucous membranes), lymphadenopathy, bilateral orbital oedema, meningoencephalitis and myocarditis can occur. 20-30% of all infections become chronic, causing arrhythmias with risk of "sudden death", cardiomyopathy and enlargement of the oesophagus (megaoesophagus) or of the colon (megacolon) even after years or decades. the cardiomyopathy consists of fibrosing myocarditis, causing arrhythmia (rbbb, left anterior fascicular block, st changes, premature ventricular beats and bradycardia) and ventricular failure. the diagnosis in the acute phase is made by a blood smear (thick and thin) to visualise the parasite. a serological test is also available. treatment is recommended in the acute phase and in patient up to the age of 50 and no advanced cardiomyopathy with chronic chagas' disease (. table 32 .5). in age groups above 50, benefits and risk need to be outweighed. worm infections are a major problem in underdeveloped countries. they occur mainly in rural areas. these conditions may cause insignificant symptoms but also lead to serious consequences or even cause death. because some dive sites are located far away from tourist centres, these infections should be discussed before travelling. this kind of roundworm is found in the tropical and subtropical regions of africa and southeast asia. the transfer follows on oral intake of eggs by contaminated food. the larvae are entering the bloodstream after hatching in the intestine. they reach the lungs via the blood and penetrate the lung tissue, and the larvae can be coughed up. if the sputum is swallowed again, the larvae reach the intestine, mature there within the next 2-3 months and lay eggs, which are then excreted via the faeces. the adult worms live about 1-2 years. infection is usually asymptomatic. however, abdominal pain, flulike symptoms, allergic skin manifestations, malnutrition, productive cough and a stridor can occur. the diagnosis can be made by examining the faeces (eggs, worms) or sputum (larvae). hookworms are found in tropical and subtropical regions of africa and latin america. the transmission is percutaneously or orally by ingestion of contaminated soil. in contaminated soil the larva is able to survive for about 3-4 weeks. larvae can penetrate the skin and enter the blood and reach the alveoli in the . lungs. from there they ascend in the airways, are swallowed again and finally get into the intestines. there larvae mature to adult worms. the worms attach themselves to the wall of the intestine and feed on blood. the eggs are excreted in the faeces and reach again the soil. the eggs can survive up to 2 years. common symptoms are pruritus and rash at the entry site, abdominal pain, diarrhoea, weight loss, anaemia and extreme fatigue. the diagnosis can be made of the faeces. z filariasis filariasis has a worldwide distribution in tropical and subtropical regions. it is caused by wuchereria bancrofti and brugia malayi. it is transmitted by mosquitoes. the infective filariform grow inside mosquitoes and enter via its saliva during the bite. they migrate to the lymphatic vessels and lymph nodes where they develop into adults. they can live there for about 6 years. the female worms produce microfila, which are circulating in the blood. absorbed by mosquitoes they develop within 1-2 weeks to the infective filariform. initially there are no symptoms. later lymph oedema in extremities or genitals is a common symptom. in men hydrocele can develop. the skin typically swells and hardens ("elephantiasis"). the diagnosis is made via the blood. detection in the blood smear has to be performed at night, as larvae only circulate in the blood at night. there is also a serological detection of anti-filaria igg4 available for diagnosis. the treatment with dec is the drug of choice. concurrent disease of loa loa or onchocerciasis is a contraindication for dec, because of the serious side effects (encephalopathy and deaths). ivermectin is used as a prophylaxis, but not as a therapy. z schistosomiasis (bilharziose) schistosomiasis can be found in tropical and subtropical regions worldwide. in addition to malaria, it is the most common parasitic disease. the parasite schistosoma is housed in freshwater snails. by being exposed to freshwater in these regions, infections can occur. the eggs are excreted in urine or faeces of the host. they hatch under optimal conditions and release miracidia. these miracidia infect freshwater snails and develop into sporocysts. these develop into cercariae and get released into the water, where they can penetrate the skin of the host. there, they shed their tail and become schistosomulae and migrate to the liver. in the liver they mature into adults. the paired adult worms migrate to the bowel and bladder, where they lay the eggs. a rash ("swimmers itch") may develop at the entry site on the skin. suprapubic pain and haematuria, abdominal pain, myalgia, fever, swelling of the lymph nodes, liver and spleen enlargement and eosinophilia can be additional symptoms. the risk of bladder cancer is increased with schistosomiasis. the diagnosis can be made in the stool and urine. the maximum excretion of eggs in the urine is between 12 and 3 pm. z trichuriasis (whipworm) whipworms have a worldwide distribution in the humid tropics. the eggs are orally absorbed via soil or unwashed vegetables or fruits. the whipworm grows in the large intestine. the eggs are excreted via the faeces. in the soil the eggs pass through various stages before getting absorbed again. the symptoms are abdominal pain, chronic diarrhoea, nausea, vomiting, inflammation of the intestine, anaemia and eosinophilia. the diagnosis is made with a stool sample. the treatment on the infection is dependent on the parasite (. table 32 .6). leptospirae are long, motile spirochetes. they have a worldwide distribution, but infections occur more commonly in tropical and subtropical regions. they spread through infected urine, which enters water or soil. leptospires can survive for several weeks and months. infections can be caused by contact with either direct contact with the urine or other body fluids except saliva as well as with contaminated soil and water. the bacteria enter the body through the skin or mucous membranes. a broken skin increases the risk of infection. increased risk is after heavy rainfall or flooding. the incubation period is usually 5-14 days, but can range from 2-30 days. symptoms vary greatly. usually sudden onset of headaches, fever, chills, myalgia, nausea and vomiting, diarrhoea, rash and jaundice are common signs of the first phase for 3-8 days. if the patient doesn't recover the second phase (weil's disease) develops, with renal failure, ards, hepatomegaly, jaundice, haemorrhage and meningitis. this has a fatality rate of 1-5%. untreated symptoms can persist for several months. treatment is either doxycyclin 100 mg bd or benzylpenicillin 1.2 g qid or ceftriaxone 1 g od for 7 days. infections caused by rickettsia, orienta, ehrlichia, neorickettsia, neoehrlichia and anaplasma are summarised as rickettsial infections. rickettsias are divided into the typhus group and the spotted fever group. orienta make up the typhus group. the reservoir is found in mainly animals, like rodents, but some species are found in fish. the vector is commonly ticks. in scrub typhus the vectors are larval mites. others have fleas and lice as a vector. infection occurs either by bites of the vectors or by direct contact, inoculation or inhalation of contaminated fluids or faeces. the clinical presentation varies. mild symptoms are headache, myalgia, abdominal pain, cough and rash. some rickettsial infections, . q-fever is a zoonosis caused by the protozoa coxiella burnetii. the bacterium is quite resilient due to its sporelike life cycle and remains virulent for months even up to more than a year. the primary reservoir is cattle, goats, sheep and other wildlife like kangaroos, rats and cats. rarely is it transmitted by tick bites or by ingestion of unpasteurised milk or dairy products. the incubation time is usually 2-3 weeks but can range from 2 days to 6 weeks. the initial acute q-fever comes with sudden onset of high fever up to 40 °c, headache (retrobulbar), myalgia, chills, non-productive cough and sweats. the symptoms settle within 5-14 days. 50% of all infections are however asymptomatic. often thrombocytopenia and abnormal lfts are found. complications are ards, endocarditis and meningoencephalitis. the diagnosis is based on detecting phase ii and phase i antibodies (igg) 4 weeks apart. the initial test (phase ii) should be taken at the end of the first week of illness. igm and igg rise almost at the same time. a fourfold rise is diagnostic. an initial negative titre doesn't rule out q-fever. seroconversion occurs usually between days 7 and 15 but is almost always present by 21 days. pcr testing can be used in the first 2 weeks but before antibiotic administration. however, a negative pcr result doesn't rule out q-fever. chronic q-fever develops in 0.2-4%. it can result in endocarditis, aneurysms, osteomyelitis, hepatitis, neurogic (mononeuritis, optic neuritis), pulmonary (interstitial fibrosis, pseudotu-mor) and renal (glomerulonephritis) disease. chronic q-fever usually develops shortly after the infection. however, chronic endocarditis may not come apparent until 2-4 years or even longer. chronic fatigue syndrome is described in approx. 10%. typically in chronic q-fever, the initial igg titre is increasing (>1:800). the treatment for acute q-fever is doxycyclin 100 mg bd for 14 days or for at least 3 days after fever subsides and until clinical improvement. as serological confirmation takes time, treatment should not be delayed. early treatment is effective at preventing severe complications. for chronic q-fever, 18 months of doxycyclin 100 mg bd and hydroxychloroquine 200 mg tds is recommended as standard treatment. rabies has an almost worldwide distribution. more than 95% of deaths occur in africa and asia. about 40% are children under 15 years of age. dogs are the main vectors. in asia, there is also a risk of transmission through monkeys. in addition to other diseases, like the lyssavirus, bats or flying foxes can transfer rabies. it is transmitted by bites or scratch wounds but also by inoculation of saliva onto mucous membranes or eye of an infected animal. thorough cleaning of the wound and vaccination within hours can prevent the disease. the incubation period is usually 1-3 months but can be less than 1 week and more than a year. initial symptoms include paraesthesia in the wound area. the disease can pass in two forms. the hyperactive form (70%) shows up with hyperactivity, manic behaviour, paranoia, hallucinations, delirium, hydrophobicity and occasionally aerophobia (triggered by the extremely painful spasms in the larynx area). the paralytic form (30%) is characterised by a slow but steady increasing paralysis. the paralysis begins in the area of the infection. the diagnostics can be established on the animal that has inflicted the wound. the tissue samples of the animal are taken from the brain (brainstem and cerebel-lum). the diagnosis in humans is difficult and unreliable. investigation of blood (antibodies), saliva (pcr), spinal fluid (antibodies) and skin biopsies (rabies antigen) are available. the vaccine and the immune globulin can be given during pregnancy. typical side effects of the vaccine are headache, myalgia, malaise, fatigue and nausea. treatment after potential infection (postexposure prophylaxis pep) includes: 5 irrigation of the wound for a minimum of 15 min and washing of the wound with water, soap, iodine or other disinfecting substances 5 rabies vaccine 5 rabies immunoglobulin into the wound area within 7 days after the first vaccination following data should be recorded when a rabies vaccine is given overseas: 5 address, email and telephone of the practice or hospital 5 date of vaccinations 5 batch number, name of the vaccine and manufacturer 5 how many vaccinations are given 5 application: subcutaneous or intramuscular injection who recommends the following approach with potential rabies after animal contact: vaccination against rabies is recommended for: 5 travellers, who for more than 1 month in areas, in which rabies is present 5 professions that deal with bats or fruit bats 5 professions, in which might get with rabies in contact (e.g., veterinary surgeon or nurse) 5 laboratory workers who handle objects with rabies or lyssavirus 5 after animal contact category 2 + 3 pre-exposure prophylaxis (prep) includes three vaccinations on day 0, 7 and 21-28. the dose is 0.1 ml intramuscularly or subcutaneously. the vaccination lasts for 10 years. follow-up vaccinations (post-exposure prophylaxis = pep) include four vaccinations on day 0, 3, 7 and 14. the dose is 1.0 ml intramuscularly. immunocompromised patients should receive five vaccinations with an additional vaccination on the 28th day. with previous vaccinations, two vaccinations are recommended on day 0 and 3 after exposure. it is not recommended to change the brand or the manufacturer during the course of vaccinations. however, it is possible, if that particular vaccine is not available. immunoglobulin should be administered with the first vaccination. the dose is 20 iu/kgbw. the immunoglobulin preferably should be given in proximity of the wound. the immunoglobulin can be diluted, if the wounds is large, to enable to cover the entire wound area. the immunoglobulin is not recommended, if the first vaccination was given more than 7 days ago, if prep or pep was completed or if an adequate serologic detection of vnab titres (≥0.5 iu/ml) is present. to avoid infection, no animals should be fed. bringing your own food or carrying items like handbags, water bottles, etc. should be avoided, if you stay in the range of monkeys. distance should be maintained to stray cats and dogs. the middle east respiratory syndrome (mers) is caused by a corona virus. corona viruses can cause mild flulike symptoms but also severe symptoms like the severe acute respiratory syndrome (sars). the mers-cov occurs 32.7 · mers mainly on the arabian peninsula (iran, jordan, kuwait, lebanon, oman, qatar, saudi arabia, united arab emirates and yemen). but through international travel, it can spread worldwide. recently it resulted in some cases in korea. mers has 37% mortality. the disease is transmitted through droplets or direct contact. the mers-cov also has a wide range of symptoms, from mild common cold symptoms and infections of the upper respiratory tract to a rapidly progressive pneumonitis, respiratory failure, septic shock and multi-organ failure. it seems the mers-cov has a low virulence, since the transmission occurs usually only through close contact by human to human, such as the care of a person suffering from mers. camels seem to be the original reservoir. mild forms with fever and mild respiratory symptoms, mers should be considered, if close contact with infected people existed prior to these symptoms. mers can be asymptomatic but also lead to respiratory failure and death. typical symptoms include fever, cough and shortness of breath. pneumonia or pneumonitis is often associated with mers. sometimes gastrointestinal symptoms such as diarrhoea and vomiting can occur. it has a high mortality of 36%. the treatment depends on the severity of the disease. caution in contact with camels in affected countries should be taken. eating insufficient heated camel meat and milk should be avoided. a suspicion of mers should be considered in individuals with the following risk profile: 5 fever and pneumonia/pneumonitis and stay in endemic areas or contact with a symptomatic person from an endemic area within 14 days before onset of symptoms 5 fever and pneumonia/pneumonitis and hospitalisation in endemic areas or contact with camels and camel products in an endemic area within 14 days before onset of symptoms 5 fever and pneumonia/pneumonitis and contact with a mers diseased person within 14 days before onset of symptoms 5 cluster of patient (especially medical personnel) with severe respiratory symptoms with unclear aetiology tuberculosis is caused by an acid-resistant mycobacterium. m. tuberculosis is responsible for tuberculosis in more than 95%. it has global distribution but occurs more frequently in countries with low hygienic standards. tuberculosis spreads around the globe through international travel and immigration. it also shows a rising rate of resistances to conventional therapies. the time between the initial infection and tuberculin conversion takes approx. the diagnosis can be made with the tuberculin skin test (tst/mendel mantoux). 3 days after the strictly intradermal injection of the substance, the induration at the injection site is measured. an induration of >5 mm may be suggestive of tuberculosis. it is considered a positive test if either the patient has a radiological proof, had close contact with someone with tuberculosis, and has symptoms of tuberculosis, is hiv positive or suffers from immunodeficiency. an induration >10 mm is considered as positive, when the patient who travelled to a country with high tb prevalence is an iv. drug user, homeless and a resident of nursing home or prison and has diabetes mellitus, silicosis, m. hodgkin's or end-stage renal failure. an induration >15 mm is considered as evidence of tuberculosis without any risk factors or symptoms. the tst can be negative in the first 8 weeks after an infection as well as in patients suffering from miliary tuberculosis, m. hodgkin, sarcoidosis, viral infections, and lowered immunity, receiving an immunosuppressive therapy or at high age. a false-positive test can occur after multiple tsts, after vaccination against tuberculosis and infection of other mycobacteria. the interferon-γ test (quantiferon ® tb gold) offers an alternative testing method. this test has the same sensitivity as the tst but a higher specificity. moreover, this test is a confirmation test and isn't affected by previous bcg-immunisations. it consists of three parts, the control (to determine the baseline-interferon-γ), mitogen control (determining the ability of an immune response) and antigen detection (detection of prior infections). a cxr may demonstrate caverns or hilar lymph nodes, but is not a diagnostic tool to exclude tuberculosis. the treatment duration of uncomplicated tuberculosis is 6 months, of complicated tuberculosis 9-12 months (. table 32 .7). it's a combination treatment of different drugs. medications for the tuberculosis treatment are: 5 isoniazid: 5 mg/kgbw, max. 300 mg /d; side effects: elevated serum transaminases, polyneuropathy, prophylaxis to avoid side effects of pyridoxine 40-80 mg/d a vaccination bcg vaccine is not recommended due to its side effects and the lack of efficacy. all vaccinations should be given 28 days before travelling. minimum time for a sufficient protection is 2 weeks (. divers alert network (dan) is a non-profit organisation for divers. they provide medical information and articles, diving insurance, life insurance and travel insurance. they also offer courses, support and research. dan has an international hotline for support and coordination of diving accidents but also for general medical advice overseas. european underwater and baromedical society (eubs) is a european organisation for diving and hyperbaric medicine. they provide guidelines for hyperbaric treatment and training of medical professionals for the hyperbaric medicine. the german organisation for diving and hyperbaric medicine is the "gesellschaft für tauch-und überdruckmedizin" (getüm). . . single dose certificate is valid for 10 years, a new vaccination may be required after 10 years to renew the certificate they provide guidelines for hyperbaric treatment and training of medical professionals for the hyperbaric medicine. brazil; office: tel: +1-919-684-2948, emergency-hotline: +1-919-684-9111. japan: japan marine recreation association, kowa-ota-machi bldg office: tel: +81-45-228-3066, f ax southern africa: private bag x197, halfway house, midrand 1685 eubs: webmaster@eubs.org 5 gtuem: c/o bg-unfallklinik, professor-kuentscher-str. 8, d-82418 murnau spums: 630 st kilda road uhms: 631 us highway 1, suite dan: 7 www. diversalertnetwork. org 5 dan europe: 7 www. daneurope. org 5 emedicine yellow fever chikungunya virus middle east respiratory syndrome (mers) parasites -african trypamosiasis (also known as sleeping sickness) parasites -american trypanosomiasis (also known as chagas disease) parasites -trichuriasis (also known as whipworm) air embolism of the brain in rabbits pretreated with mechlorethamine an examination of the critical released gas concept in decompression sickness accessed 12 middle east respiratory syndrome (mers) middle east respiratory syndrome coronavirus (mers-cov) key: cord-317859-afvi0g0a authors: wilson, mathew g; hull, james h; rogers, john; pollock, noel; dodd, miranda; haines, jemma; harris, sally; loosemore, mike; malhotra, aneil; pieles, guido; shah, anand; taylor, lesley; vyas, aashish; haddad, fares s; sharma, sanjay title: cardiorespiratory considerations for return-to-play in elite athletes after covid-19 infection: a practical guide for sport and exercise medicine physicians date: 2020-09-02 journal: br j sports med doi: 10.1136/bjsports-2020-102710 sha: doc_id: 317859 cord_uid: afvi0g0a sars-cov-2 is the causative virus responsible for the covid-19 pandemic. this pandemic has necessitated that all professional and elite sport is either suspended, postponed or cancelled altogether to minimise the risk of viral spread. as infection rates drop and quarantine restrictions are lifted, the question how athletes can safely resume competitive sport is being asked. given the rapidly evolving knowledge base about the virus and changing governmental and public health recommendations, a precise answer to this question is fraught with complexity and nuance. without robust data to inform policy, return-to-play (rtp) decisions are especially difficult for elite athletes on the suspicion that the covid-19 virus could result in significant cardiorespiratory compromise in a minority of afflicted athletes. there are now consistent reports of athletes reporting persistent and residual symptoms many weeks to months after initial covid-19 infection. these symptoms include cough, tachycardia and extreme fatigue. to support safe rtp, we provide sport and exercise medicine physicians with practical recommendations on how to exclude cardiorespiratory complications of covid-19 in elite athletes who place high demand on their cardiorespiratory system. as new evidence emerges, guidance for a safe rtp should be updated. sars-cov-2 is the causative virus responsible for the covid-19 pandemic. the covid-19 pandemic has necessitated that all professional sport is either suspended, postponed or cancelled altogether to minimise the risk of viral spread. as infection rates drop and quarantine restrictions are lifted, questions are being asked of how athletes can safely resume competitive sport. given the rapidly evolving knowledge base about the virus and changing governmental and public health recommendations, 1 precise answers to this highly relevant question is fraught with complexity and nuance. 2 without robust data to inform policy, return-toplay (rtp) decisions are especially difficult for elite athletes on the suspicion that the covid-19 virus could result in significant cardiorespiratory compromise in a minority of afflicted athletes. there are now consistent reports that covid-19 positive athletes may present persistent and residual symptoms many weeks to months after initial infection, including cough, tachycardia and extreme fatigue. to support safe rtp, we provide sport and exercise medicine physicians with practical recommendations on how to exclude cardiorespiratory complications of covid-19 in elite athletes who place high demand on their cardiorespiratory system. given our rapidly emerging understanding of covid-19, these recommendations are subject to adjustments as new evidence becomes available. data from china suggest that covid-19 is associated with biochemical evidence of cardiac myocyte necrosis in almost one in five hospitalised patients and that patients with elevated serum cardiac troponin concentrations above the 99th percentile are more likely to require mechanical ventilation and/or die than those who do not have raised troponins. [3] [4] [5] [6] the precise mechanism for myocyte necrosis is unclear; however, current observations from the kinetics of the magnitude and duration of the elevation in troponin concentration suggest the most common cause reflects the systemic inflammatory response or cytokine storm associated with the infection. other mechanisms include profound hypoxaemia from the respiratory illness, right ventricular strain due to hypoxaemic pulmonary vasocontriction or thromboembolic complications, inflammatory atherosclerotic plaque rupture with distal embolisation or viral myocarditis. it is important to emphasise that such complications were apparent in patients considered ill enough to warrant hospitalisation; therefore, the prevalence of myocardial injury or raised troponin in athletes with asymptomatic infections or a relatively mild illness is unknown but likely to be low. it is also recognised that the sars-cov-2 virus binds to ace 2 (ace2) in the upper airways and lungs after the protein spike on the virus is activated by transmembrane protease serine 2. 7 the ace2 receptor is a membrane protein found in abundance in the lungs and serves many protective pathways. the myocardium also contains a high concentration of ace2 receptors, activation of which may facilitate direct toxic effects within the myocardium or offset the effects of the renin angiotensin aldosterone system. 7 a rare proportion of patients who review have been diagnosed with covid-19 infection have presented with chest pain and palpitations rather than symptoms due to respiratory tract involvement. 3 for athletes suffering with flu-like symptoms, myocarditis has always been a potential complication of viral syndromes. although the diagnosis is reliant on histological confirmation or the demonstration of myocardial oedema or late gadolinium enhancement (lge) on cardiac mri, emerging case reports appear to implicate myocarditis as an additional cause of cardiac damage from covid-19. 8 9 key symptoms include chest pain that may be made worse by deep inspiration, increasing breathlessness and palpitations. physical signs may be few; however, particular attention should be given to tachycardia, added heart sounds, bibasal crackles or signs of a pleural effusion. while serum biomarkers of myocardial damage are commonly elevated in the acute stages, it important to note that raised troponins do not equate to a diagnosis of myocarditis and may be secondary to intensive physical training. ecg manifestations may include non-specific signs such as st-segment elevation or depression, t-wave inversion and/or ventricular arrhythmias. it is noteworthy that repolarisations anomalies are also common to the electrical adaptations to athletic training. cardiac imaging techniques might show global or regional wall motion abnormalities along with variable degrees of pericardial effusion. myocardial oedema might be identified in early stages with cardiac mri, while lge can be present early in its evolution and remain as a sequela. 10 from available data thus far, it appears there is right ventricular (rv) impairment over left ventricular (lv) involvement in previously hospitalised patients with covid-19 infection. 11 the incidence of myocarditis associated arrhythmias is unknown, and while covid-19 infection led to a ≥50% increase in out-of-hospital cardiac arrest in the general population, 12 the data are descriptive and do not necessarily suggest an increased risk of sudden cardiac arrest or arrhythmias in otherwise 'healthy' covid-19 positive individuals. animal studies have, however, shown that exercising with myocarditis can increase viral replication and inflammation within the heart, resulting in permanent damage or occasionally sudden death. 13 indeed, myocarditis accounted for 20% of all non-traumatic sudden death among a cohort of military recruits. 14 to prevent sudden death in athletic populations, most professional and elite sport federations have an existing preparticipation cardiovascular evaluation protocol, 15 often using 12-lead ecg±echocardiography (echo). while this document does not stray far from established recommendations, we propose minor pathway modifications based on reasonable clinical indications (figure 1). 1. for athletes who have not presented with signs or symptoms of covid-19 during the pandemic, we recommend that no additional cardiac investigations are required before rtp. 2. athletes with mild to moderate covid-19 symptoms (eg, who managed their condition at home and have recovered) pose more of a challenge. few will have had testing with confirmed covid-19 infection and most will simply suspect they had the infection. for those that have fully recovered without ongoing cardiovascular symptoms (symptom free at rest for 7 days and no sooner than day 10 from the onset of symptoms), we recommend a thorough clinical assessment with a medical history and physical examination. it is essential that physicians managing potentially affected athletes are equipped with personal protective equipment and pay par the panel recommends that measurement of serum cardiac troponin should be confined to athletes with ongoing symptoms compatible with myocarditis and those where imaging studies reveal impaired myocardial function. in such circumstance, the athlete should be rested for at least 48 hours before investigation as intensive exercise itself may be associated with a transient increase in serum cardiac troponin concentration. routine troponin assessment in all athletes who may have had covid-19 infection is not recommended because there are no validated cut-off values for cardiac involvement in covid-19 and baseline troponin levels during normal health will not be available for most athletes. some elite clubs may choose to perform 12-lead ecg and/or echo through expediting the usual pre-season annual medical evaluation. if ecg is performed, it would be desirable to compare with previous ecgs as some repolarisation changes detected in myocarditis overlap with those observed in athletic training. it is anticipated that the majority of athletes with mild to moderate covid-19 infection will fully recover with little need for enhanced respiratory assessment. many athletes are, however, reporting a persistent cough and dyspnoea following infection, especially in the context of vigorous exercise. it is anticipated that in the majority of these cases, symptoms will fully resolve in the 4-week period following infection and that recovery should be progressive. 16 accordingly, any deterioration or deviation from a pattern of daily improvement and recovery or the development of new symptoms (eg, new productive cough, chest pain or worsening dyspnoea) should prompt immediate reappraisal with a temporary cessation of the rtp programme, until clinical work-up has been completed. this evaluation should begin with a chest x-ray, d-dimer and pulmonary function testing to check for new or worsening pneumonia, pulmonary embolism or postinflammatory bronchoconstriction. due to the potential overlap of cardiovascular and pulmonary symptoms, athletes with persistent cardiorespiratory symptoms should also undergo a comprehensive cardiac evaluation as previously outlined. in individuals hospitalised with covid-19 related respiratory illness, the presence of radiographic pneumonic change will be ubiquitous. emerging data also indicate that moderate to severe disease is associated with a high prevalence of thrombotic events and as such it is likely that the potential sequela of covid-19 pneumonic illness predominantly impacts the pulmonaryvascular interface. 17 this has implications for selection of the best tests to assess any post-covid-19 respiratory limitation and also highlights the importance of sports and exercise medicine clinicians being aware that any post-covid-19 breathlessness and/or chest pain may be arising due to serious pulmonary vascular pathology such as pulmonary embolism. overall, we recommend that any athletic individual that has been hospitalised with a radiologically confirmed covid-19 pneumonia and breathlessness undergoes specialist respiratory review prior to rtp, and this process is likely to involve the need for: (1) planned repeat imaging; (2) baseline physiological measures (including consideration of gas transfer measurement±lung volumes); and (3) the possible need for cardiopulmonary exercise testing with measurement of oxygen saturation in selected cases with ongoing dyspnoea on exertion. chronic post-covid-19 respiratory symptoms may include: breathlessness on exertion, new onset or persistence of a post-covid cough and wheeze and/or chest tightness that may or may not be related to exertion. in athletic populations, there is a high prevalence of background airways disease, with studies consistently showing that approximately one in four endurance athletes has evidence of airway dysfunction (eg, asthma±exercise-induced bronchoconstriction), and in many cases, this remains undetected and is only identified at screening assessment. 18 19 thus, a contribution from underdiagnosed or undertreated airways disease that has been exacerbated by covid-19 infection should not be overlooked. we speculate at this point that covid-19 infection could provoke new onset asthma-like symptoms (which may also include exercise-induced laryngeal obstruction). where applicable, it is vital that athletes are encouraged to strongly adhere to their routinely prescribed respiratory medication and clinicians should review inhaler technique and appropriate use of spacing devices. in cases of suspected airways disease, assessment with spirometry±bronchodilator challenge±bronchoprovocation testing and assessment of airway inflammation (eg, with exhaled nitric oxide (feno)) is recommended. 20 in order to optimise respiratory care, it is also important that allied respiratory issues are considered, for example, management of hay fever and allergies and any undertreated reflux. 21 if under-recognised and undertreated, then these factors may also contribute to ongoing exercise cough. 22 in some cases, covid-19 may cause chest restriction (eg, from pain or local areas of pulmonary collapse), present during the height of the pneumonia phase, which subsequently precipitate disordered breathing patterns. this may respond to the timely initiation of respiratory physiotherapy intervention. symptoms of early fatigability and reduced exercise performance may also be features of an increased work of breathing due to underlying respiratory disease and should also prompt a respiratory investigation. at the current time, it is difficult to fully know the long-term implications of post-covid-19 lung disease from severe spectrum disease, and the evidence base that does exist is based on a small sample size or extrapolated from previous experience of sar-cov-1 and middle east respiratory syndrome coronavirus. severe covid-19 related respiratory disease is associated with damage to the pulmonary airspaces, interstitium and pulmonary vascular interface. preliminary data indicate that the most sensitive pulmonary function test in this context is the measurement of gas transfer. 23 venous thrombosis in the lungs with or without the development of secondary pulmonary hypertension may occur. 24 25 case study reports in individuals with acute respiratory distress syndrome during their acute illness leading to pulmonary fibrosis and exertional breathlessness are present, though the prevalence of such presentations and implications for athletes with more mild disease is unknown. 1. for athletes without symptoms or signs of covid-19 during the pandemic, no formal respiratory testing is required (figure 1 ). those athletes with documented underlying respiratory issues, such as asthma, should continue treatment and have management optimised accordingly. 2. athletes with mild to moderate covid-19 symptoms who managed their condition at home but are now fully recovered (symptom free at rest for 7 days and no sooner than day 10 from the onset of symptoms), no formal respiratory testing is required. any recovery process should be progressive and thus, any deviation should result in a 'stop and reassess' situation. those athletes with documented underlying respiratory issues, such as asthma, should continue treatment and have management optimised accordingly. 3. in those athletes who report covid-19 related respiratory symptoms that are persistent and taking longer than 14 days to recover, we recommend a thorough assessment to exclude the presence of thromboembolic events, ongoing intrapulmonary pathology or cardiac injury. this assessment should consider a chest x-ray, ecg, biomarkers for inflammation, myocyte necrosis or thromboembolic disease (including c reactive protein, hs-ctnt and d-dimer if not arranged in the past) and lung function. it is also logical to discuss case management with a respiratory physician. in cases with a significant suspicion of thromboembolic or intrapulmonary abnormalities, we recommend a ct thorax with due consideration for the correct imaging protocol to identify post-covid-19 changes plus pulmonary vasculature pathology (eg, thromboembolism). if the cause of the breathlessness remains elusive, then proceed to a cardiopulmonary exercise test with o 2 saturation but ideally with blood gas monitoring. if cases of desaturation during exercise with a normal ct, consider a ventilation-perfusion scan for possible microemboli. if spirometry demonstrates evidence of obstructive airways disease, this should prompt consideration for a new diagnosis of asthma/postinfective bronchial hyper-reactivity and the assessment of bronchodilator reversibility and the presence of airways inflammation (eg, with feno), prior to planning treatment. 4. for athletes who have experienced respiratory symptoms severe enough to require hospital admission, we recommend a full respiratory review prior to rtp. in this scenario, it is likely that chest imaging and other measures (eg, troponin and d-dimer) will have already been undertaken, so management will be individualised based on prior findings and the recovery course. while a pragmatic approach is recommended, we recognise our proposed rtp pathway should be interpreted and modified on an individual basis (figure 1). it is important to consider that: (1) our rtp pathway is intended for elite athletes (eg, premier league football, professional rugby, potential olympiads and so on) who are currently being required to return to train and compete, (2) a standard cardiac evaluation typically performed during preseason may be sufficient in the vast majority of athletes to allow rtp, (3) most athletes will have previous preparticipation medical evaluations that can be used for comparison, (4) athletes with significant and prolonged symptoms or those that were hospitalised from covid-19 require a complete cardiac and respiratory workup even if now fully recovered and finally (5) in athletes that are/were infected with confirmed or suspected covid-19, any graded rtp decision starts when athletes are symptom free at rest for 7 days and no sooner than 10 days from the onset of symptoms. while the primary covid-19 concerns have focused on the cardiorespiratory system, covid-19 can have pathological consequences on other organ systems that may influence rtp decision making in athletes. when undertaking a detailed history and physical examination, consideration should also be given to the neurological, gastrointestinal and dermatological systems. 26 where recommendations are provided, especially for aerosolgenerating procedures (ie, spirometry and pulmonary function tests), medical facilities and clinicians should adhere to strict personal protective equipment policies and procedures. finally, physical and psychological deconditioning, mental health and underperformance issues may also be present as athletes emerge from quarantine restrictions. some athletes have already raised concern in the media with respect to health anxieties related to themselves or their families, particularly for black, asian and ethnic minorities, where they are at higher risk of death from covid-19. 27 for athletes recovering from covid-19, it is also important to consider the psychological impacts of a prolonged recovery. it is well known that psychological factors effect morbidity outcomes 28 and athletes are no different. the english institute of sport has published useful advice on the psychosocial considerations of phased return for athletes (health adjustment and transition). 29 in conclusion, we provide practical recommendations on how to medically evaluate the cardiorespiratory system of the athletes to safely return to intensive training and competitive sport. the potential for cardiorespiratory complications from covid-19 requires a careful assessment based on the clinical and symptom course and severity of illness. we appreciate a pragmatic approach must be taken and suggest our recommendations are interpreted on an individual basis. clinical assessment, rtp planning and review (progress) are circular in nature. this considers the dynamic nature of rtp with continual focus on the athlete's progress and assessment for new symptoms. author affiliations 1 elite sport return to training guidance: step one respiratory health in athletes: facing the covid-19 challenge clinical features of patients infected with 2019 novel coronavirus in wuhan association of cardiac injury with mortality in hospitalized patients with covid-19 in wuhan, china cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (covid-19) clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study ace2: from vasopeptidase to sars virus receptor acute myocarditis presenting as a reverse tako-tsubo syndrome in a patient with sars-cov-2 respiratory infection cardiac involvement in a patient with coronavirus disease 2019 (covid-19) cardiovascular magnetic resonance imaging for inflammatory heart diseases cardiac involvement in patients recovered from covid-2019 identified using magnetic resonance imaging out-of-hospital cardiac arrest during the covid-19 outbreak in italy etiology of mild acute infectious myocarditis. relation to clinical features sudden death in young adults: a 25-year review of autopsies in military recruits pre-participation cardiovascular evaluation for athletic participants to prevent sudden death: position paper from the ehra and the eacpr, branches of the esc. endorsed by aphrs, hrs, and solaece how long does covid-19 last pulmonary embolism in patients with covid-19 pneumonia managing respiratory problems in athletes misdiagnosis of exercise-induced bronchoconstriction in professional soccer players an official american thoracic society clinical practice guideline: exercise-induced bronchoconstriction exercise and the total airway: a call to action cough in exercise and athletes abnormal pulmonary function in covid-19 patients at time of hospital discharge prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid-19 extrapulmonary manifestations of covid-19 opensafely: factors associated with covid-19-related hospital death in the linked electronic health records of 17 million adult nhs patients meeting the psychological needs of people recovering from severe coronavirus mathew g wilson http:// orcid. org/ 0000-0002-6317-0168 james h hull http:// orcid. org/ 0000-0003-4697-1526 jemma haines http:// orcid. org/ 0000-0003-3813-041x mike loosemore http:// orcid. org/ 0000-0002-4855-0744 aneil malhotra http:// orcid. org/ 0000-0002-8670-3764 guido pieles http:// orcid. org/ 0000-0003-1203-688x anand shah http:// orcid. org/ 0000-0001-5257-520x sanjay sharma http:// orcid. org/ 0000-0002-3630-6138 contributors mgw manuscript conception. mgw, jhh, jr, np, fh and ss wrote first draft. all authors edited and approved final document.funding no public, commercial or not-for-profit funding was provided for this document.competing interests none declared. provenance and peer review not commissioned; externally peer reviewed.data availability statement there are no data in this work.this article is made freely available for use in accordance with bmj's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by bmj. you may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. key: cord-323551-22v2hn3v authors: galanti, m.; birger, r.; ud-dean, m.; filip, i.; morita, h.; comito, d.; anthony, s.; freyer, g. a.; ibrahim, s.; lane, b.; matienzo, n.; ligon, c.; rabadan, r.; shittu, a.; tagne, e.; shaman, j. title: rates of asymptomatic respiratory virus infection across age groups date: 2019-04-15 journal: epidemiol infect doi: 10.1017/s0950268819000505 sha: doc_id: 323551 cord_uid: 22v2hn3v respiratory viral infections are a leading cause of disease worldwide. a variety of respiratory viruses produce infections in humans with effects ranging from asymptomatic to life-treathening. standard surveillance systems typically only target severe infections (ed outpatients, hospitalisations, deaths) and fail to track asymptomatic or mild infections. here we performed a large-scale community study across multiple age groups to assess the pathogenicity of 18 respiratory viruses. we enrolled 214 individuals at multiple new york city locations and tested weekly for respiratory viral pathogens, irrespective of symptom status, from fall 2016 to spring 2018. we combined these test results with participant-provided daily records of cold and flu symptoms and used this information to characterise symptom severity by virus and age category. asymptomatic infection rates exceeded 70% for most viruses, excepting influenza and human metapneumovirus, which produced significantly more severe outcomes. symptoms were negatively associated with infection frequency, with children displaying the lowest score among age groups. upper respiratory manifestations were most common for all viruses, whereas systemic effects were less typical. these findings indicate a high burden of asymptomatic respiratory virus infection exists in the general population. respiratory viral infections are a leading cause of disease worldwide, affecting all age groups and representing a serious threat to human health, particularly for infants, older adults and the immunocompromised. the effects of infection on individuals can vary considerably and include completely asymptomatic manifestations, mild upper respiratory effects and severe symptoms requiring hospitalisation. the epidemiology of respiratory viral infections is generally analysed through passive symptom-based surveillance. when studying the burden of infection, many observational studies focus on severe outcomes, such as cardiac and pulmonary complications in hospitalised patients [1] [2] [3] [4] , or the role of respiratory viruses in the exacerbation of pre-existing respiratory conditions [5] [6] [7] . additionally, community-based longitudinal studies have generally been restricted to young children or households and involve the sampling of specimens to identify viruses after an index symptomatic episode occurs [8] [9] [10] . investigation of the prevalence and effects of respiratory viral infections in the broader population, not just among individuals seeking medical attention, is needed to more fully understand the burden of these infections within the community and to develop adequate preventive measures against these pathogens. in particular, the proportion of the population that is infected and yet does not develop symptoms must be determined to better quantify transmission risk, forecast future disease incidence and pathogen spread, and support public health response efforts. here, we document rates of asymptomatic respiratory virus infection through a large-scale community study across multiple age groups. we use data from a cohort of individuals who were tested weekly for respiratory viruses irrespective of symptom status. we combine these test results with participant-provided daily records of cold and flu symptoms and use this information to characterise symptom outcomes by virus and age category. we enrolled 214 individuals from multiple locations in manhattan borough, new york city. we refer to the participants as healthy as they were enrolled from the general population, as opposed to individuals seeking clinical care. the cohort included children attending two daycares, along with their siblings and their parents, teenagers and teachers from a high school, adults working at two emergency departments (a paediatric er and an adult er), and adults working at a university medical centre. the study period spanned 2 years from october 2016 to april 2018 with some individuals enrolled for a single cold and flu season (october-april) and others for the entire period. all individuals from the selected facilities who were willing to participate were enrolled in the study. enrolled individuals were asked to complete a baseline survey and provide two nasopharyngeal swab samples (one from each nostril). following this preliminary step, two nasopharyngeal samples were again collected weekly from each participant irrespective of symptoms. the baseline questionnaire completed at the time of enrolment included information on ethnicity, general health, daily habits, travel history and household structure. for the entire duration of the study, participants provided a daily report rating nine respiratory illness-related symptoms (fever, chills, muscle pain, watery eyes, runny nose, sneezing, sore throat, cough, chest pain), which were recorded on a likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). participants were also asked to note if they had sought medical attention, stayed home or taken influenza-like illness (ili)-related medications as a consequence of their listed symptoms. parents provided consent, baseline questionnaire answers and the daily survey information for their enrolled children. a total daily score was generated for each participant by summing the scores of the individual symptoms (total daily score ranges from 0 to 27). details on the participants are summarised in table 1 . two nasopharyngeal samples per participant were collected on a weekly basis using minitip flocked swabs. both samples were stored jointly in 2 ml dna/rna shield (zymo research, irvine, ca, usa) at 4-25°c for up to 30 days and then stored at −80°c in two aliquots. nucleic acids were extracted from 200 µl of sample and 10 µl of internal control using the easymag nuclisens system (biomerieux, durham, nc, usa). samples were then screened for viruses using the esensor xt-8 respiratory viral panel (rvp; genmark dx, carlsbad, ca, usa) [4] , a multiplex pcr assay. the rvp system separately detects influenza a (any subtype, a/h1n1, a/h3n2, a/h1n1pdm2009) and b; rsv a and b; parainfluenza (piv) 1, 2, 3 and 4; human metapneumovirus (hmpv); human rhinovirus (hrv); adenovirus b/e and c; and coronaviruses (cov) 229e, nl63, oc43 and hku1. samples positive for a particular virus were identified by an electrical signal intensity of ⩾2 na/mm 2 (with the exception of cov oc43 for which positive results were identified by an intensity of ⩾25 na/mm 2 , per manufacturer specifications). we classified all specimens, irrespective of result, as symptomatic or asymptomatic according to the individual symptom score in the days surrounding the date of swab collection. we used multiple definitions as a standard for symptomatic infection does not exist. definitions are summarised in table 2 : definitions 1-4 consider a time window of 7 days around the day of the collection, whereas definitions 5-8 use a window of 11 days. while some definitions use raw metrics, definitions 4 and 8 normalise scores by the average symptom score for each participant (average weekly total symptom scores for each participant ranged from 0 to 39). we refer to infections that do not satisfy one or more specified definitions as asymptomatic infections. the association between reporting respiratory symptoms and testing positive was calculated with the χ 2 test. a 'symptomatic week' was defined as a calendar week where the total symptom score was ⩾10. analyses were conducted using the total number of positive samples, as well as the number of illness-events. we defined an illness-event as a group of consecutive weekly swab specimens for a given individual that were positive for the same virus (allowing for a 1-week gap to account for false negatives and temporary low shedding). the effects of different viruses and the severity of symptoms among different age groups were assessed using analysis of variance (anova). the χ 2 statistic was also used to assess pairwise differences. participants were divided into four groups: children (under 10 years of age), teenagers (10-17 years of age), adults with daily contact with children (parents and pediatric er doctors) and adults without daily contact with children. to assign adult participants to the correct category, we used information on household composition derived from the initial questionnaire. in the analysis of symptoms by virus, specimens positive for more than one virus were excluded. to analyse the specific effects of different viruses, we grouped symptoms into upper respiratory symptoms (runny nose, sneezing, sore throat, watery eye), lower respiratory symptoms (cough, chest pain) and systemic symptoms (fever, chills, muscle pain). of the 4215 nasopharyngeal samples collected, 737 (17.5%) were positive for one or multiple respiratory viruses. among the positive results, between 69% and 74% of the samples were classified as asymptomatic depending on the chosen definition (table 2) . overall, 55% of positive specimens were asymptomatic by all definitions. testing positive for one or more respiratory viruses was associated with an increased likelihood of being symptomatic (p < 0.0001); however, for the majority of symptomatic weeks (67%), rvp did not identify the presence of any respiratory virus. there was a weak association between pre-existing respiratory conditions (asthma, allergies) and the likelihood of experiencing symptomatic infections. however, the association was significant only for some definitions, and the effect on symptom score was marginally significant (p = 0.08 anova). coinfections accounted for 10% of positive samples and were found most frequently among children; they occurred throughout the year and were predominantly a combination of hrv and adenovirus. pairwise comparisons between single infections and coinfections across all eight definitions showed that testing positive for multiple viruses was not associated with more severe symptoms. among the viruses considered, influenza and hmpv were associated with significantly higher symptom scores than rsv, hrv, cov, adenovirus and piv. as shown in figure 1 , more than 50% of influenza and hmpv infections were classified as symptomatic by a majority of definitions, whereas the other viruses were mostly asymptomatic according to all definitions (p < 0.01 and p < 0.001 when comparing, respectively, the ratio of symptomatic influenza and hmpv infections to the other viral infections). the analysis of specific symptoms confirmed the higher severity of influenza and hmpv for lower, upper and systemic 2 m. galanti et al. symptoms (fig. 2a) . upper respiratory symptoms were most commonly associated with positive results for all viruses and for all age groups, followed by lower respiratory symptoms and then systemic symptoms ( fig. 2a and b) . infected children showed a similar percentage of upper and lower respiratory symptoms, and teenagers showed a similar percentage of lower respiratory and systemic symptoms. the majority of hmpv infections presented with both upper and lower respiratory symptoms. higher severity of symptoms was not associated with higher frequency of infection. figure 3 shows that while children were most frequently infected with a respiratory virus (they presented with the highest number of viral shedding events per season), they recorded (as reported by their parents) the lowest symptom scores on average. adults without daily contact with children reported the highest symptom score (the difference was significant only between children and adults without contacts with children, p = 0.003). this finding holds when controlling for length of infection, as longer-lasting infections were more frequent in children. host response to respiratory viruses is heterogeneous: some presumed infections, measured by detectable shedding of virus, exhibit no symptoms or signs of disease, whereas others result in more serious symptoms. when assessing the burden of an [11] [12] [13] . in [11] we showed that most individuals, particularly children and their close contacts, contract multiple respiratory infections per year. here, we analysed the symptoms reported by the same infected individuals and characterised them by virus and by age group. the presence of respiratory symptoms was associated with testing positive for one or more respiratory viruses. however, the majority of symptomatic manifestations were not paired with a positive rvp result. the origin of these symptomatic, negative rvp results could be due to allergies, bacterial infections or potential viral infections with pathogens that have not yet been identified or for which the viral panel does not test. one of the main goals of this analysis was to estimate the asymptomatic ratio, that is, the fraction of infections occurring without symptoms. the asymptomatic ratio is an important indicator for constraining both true respiratory virus prevalence within a community and the potential for further disease transmission [14] . asymptomatic carriers can, in fact, contribute to disease spread by generating ( possibly symptomatic) secondary infections. estimates of the asymptomatic ratio vary widely not only across diseases (from 95% of polio virus infections to <10% of measles), but also within the same disease due to different diagnostic testing procedures (pcr vs. serological tests [15] ) and sampling approaches (household vs. longitudinal studies). among respiratory viruses, the role of asymptomatic infection is poorly understood. for influenza alone, the prevalence of asymptomatic infection has been estimated to be as low as 9.4% and as high as 90% depending on the virus type, study, season and definition of asymptomatic infection [15, 16] . there is also some evidence that viral shedding correlates with symptom severity and that the contagiousness of asymptomatic individuals is less than for symptomatic persons [17, 18] . the rationale is that respiratory symptoms (coughing, sneezing, runny nose) help spread pathogens through droplet transmission, either inhaled or settled [19] . however, the absence of symptoms might bring asymptomatic infected individuals into greater contact with susceptible persons outside the home. this is particularly true for infants and toddlers whose behaviour, hygiene habits and close physical contact typically favour the spread of germs, especially in childcare settings. whether greater contact occurs and makes asymptomatic individuals effectively as contagious as symptomatic persons is not known. an additional difficulty is that a standard, accepted definition of symptomatic infection does not exist. further, perception of symptoms is highly subjective, and it may be difficult to assess whether a symptom is caused by the pathogen. for example, chronic symptoms can occurrunny nose is a common sign in children that does not necessary imply viral infectionand allergies can cause sneezing. fever, muscle pain and chills may also be caused by infections other than respiratory viruses. for these reasons, we adopted multiple definitions of 'symptomatic episodes', including personalised metrics. more than half of the rsv, adenovirus, piv, cov and hrv infections documented here were asymptomatic according to all definitions. influenza and hmpv infections caused significantly more symptoms than these other viruses; however, given its high prevalence, hrv was responsible for more than half of symptomatic episodes. in general, all viral infections presented with similar symptoms, with upper respiratory manifestations being more frequent, whereas systemic symptoms such as fever, muscle pain and chills were less typical. for surveillance in which ili (defined as fever plus cough and/or sore throat) is used to record respiratory infections among people seeking care, this constraint may mean that many viral infections go undetected. consistent with previous findings [20, 21] we did not find an association between viral co-infection and the likelihood of being symptomatic or presenting with more severe symptoms. regardless of the definition, our findings underscore the extremely high proportion of respiratory viral infections that are asymptomatic. further analysis is required to capture the role played by asymptomatic individuals in outbreak transmission dynamics, specifically the relative infectiousness of asymptomatic vs. symptomatic infections. there was considerable heterogeneity in individual immune response: some individuals seemed to be consistently less predisposed to developing respiratory symptoms upon viral infection, whereas others were always symptomatic when testing positive. infections in children were less symptomatic than in adults, even though children proved to be more frequently infected with respiratory viruses [11] . frequent infections may enhance the ability of the immune system to identify and respond to pathogens; hence, the group subjected to the fewest respiratory viral infections (adults without children) reported the highest average symptom scores. however, the apparent lower pathogenicity among children may simply be an artefact introduced due to parents reporting symptoms for their children. some symptoms, such as sore throat, muscle pain and chest pain, are difficult to identify in young children, and in fact they were less reported in this age category than among adults and teenagers. this possible bias in the reporting of symptoms is one limitation of our study. the daycare and workplace connections among some individuals in our cohort are another possible bias: some infections were likely caused by the same strain; thus the symptom profiles could be due to specific features of the pathogen rather than individual immune response. further, all the children in our cohort were attending daycare or were siblings of children attending daycare. interactions within the daycare setting could be a confounder in this analysis. future studies should investigate the genetic basis of heterogeneity in host response to respiratory virus infection in order to identify the regulatory pathways controlling reactions to these infections. moreover, longitudinal studies of this type, involving large networks of connected individuals, are needed to assess the role of asymptomatic infections in the transmission of respiratory viruses. the burden of respiratory syncytial virus infection in young children estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the global burden of disease study mortality associated with influenza and respiratory syncytial virus in the united states comparison of the biofire filmarray rp, genmark esensor rvp, luminex xtag rvpv1, and luminex xtag rvp fast multiplex assays for detection of respiratory viruses role of viral respiratory infections in asthma and asthma exacerbations respiratory viruses and exacerbations of asthma in adults role of viruses in exacerbations of chronic obstructive pulmonary disease molecular epidemiology of respiratory syncytial virus transmission in childcare viral shedding and clinical illness in naturally acquired influenza virus infections epidemiology of viral respiratory tract infections in a prospective cohort of infants and toddlers attending daycare longitudinal active sampling for respiratory viral infections across age groups asymptomatic summertime shedding of respiratory viruses asymptomatic shedding of respiratory virus among an ambulatory population across seasons estimating pathogen-specific asymptomatic ratios the fraction of influenza virus infections that are asymptomatic: a systematic review and meta-analysis household transmission of the 2009 pandemic a/h1n1 influenza virus: elevated laboratory-confirmed secondary attack rates and evidence of asymptomatic infections does influenza transmission occur from asymptomatic infection or prior to symptom onset? world health organization writing group (2006) nonpharmaceutical interventions for pandemic influenza, international measures dynamics of infectious disease transmission by inhalable respiratory droplets epidemiology of multiple respiratory viruses in childcare attendees infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis author orcids.m. galanti, 0000-0002-9060-1250.financial support. this work was supported by the defense advanced research projects agency contract w911nf-16-2-0035. the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.conflict of interest. js and columbia university disclose partial ownership of sk analytics. all other authors declare no competing interests. key: cord-304838-r9w8milu authors: olaseni, abayomi o.; akinsola, olusola s.; agberotimi, samson f.; oguntayo, rotimi title: psychological distress experiences of nigerians during covid-19 pandemic; the gender difference date: 2020-12-31 journal: social sciences & humanities open doi: 10.1016/j.ssaho.2020.100052 sha: doc_id: 304838 cord_uid: r9w8milu this study examine the psychological distress experience of nigerians during the covid-19 pandemic, across gender. from march 20, 2020, to april 12, 2020, this descriptive survey used a snowballing sampling technique to select 502-nigerians with an online semi-structured questionnaire detailing the impact of event scale-revised, generalized anxiety disorder – 7 item scale, patient health questionnaire and insomnia severity index. gender had an insignificant difference in the level of insomnia (χ2 ​= ​04.93; df ​= ​3; p ​> ​0.05), however, 20.8% of males had sub-threshold of insomnia, 8.2% experienced moderate insomnia and 5.9% had severe insomnia; 32% females reported sub-threshold of insomnia, 12.4% had moderate insomnia while 3.6% had severe insomnia. also, gender had an insignificant difference in the measures of depression (χ2 ​= ​01.94; df ​= ​4; p ​> ​0.05); 55.4% males reported minimal depression, 22.3% had mild depression, 11.9% had moderate depression; 6.7%–3.7% males had moderate to severe depression while, 49.3% of the females had minimal depression, 26.7% reported mild depression, 14.29% had moderate depression, 4.4%–5.3% had moderate to severe depressive symptoms. posttraumatic stress symptoms (ptss) has no gender difference among respondents (χ2 ​= ​02.51; df ​= ​3; p ​> ​0.05); 23% of males reported partial ptss, 17.5% presented clinical ptss, and 21.6% males had severe ptss; while 29.3% of females had severe ptss, 24% reported partial ptss and 18.7% had clinical ptss. respondents reported insignificant gender differences on anxiety (χ2 ​= ​0.08; df ​= ​1; p ​> ​0.05), while 51% reported moderate anxiety and 49% exhibited severe anxiety during the covid-19 pandemic in nigeria. findings revealed that nigerians experienced psychological distress during covid-19 pandemic. the government and stakeholders should initiate tele-mental health services to serve as alternative to traditional treatment to manage present and future pandemic psychological implications among nigerians. a great threat of a novel viruscoronavirus otherwise known as covid-19 pandemic rocked the entire world in the wake of the year 2020. covid-19 which was first reported in december 2019 in wuhan china, declared as public health emergency of international concern in january 2020 and later a pandemic in march 2020 by the world health organisation (who) (web news, 2020; world health organisation, 2020). the threat is so strenuous that the entire world was placed on lockdown in the matter of social restriction such as on international and national transport links, market or business transaction, school and organisation activities, and all related social and religious gatherings. being a novel disease that is highly contagious, spreading fast across the world, and the fact that there is yet to be an established cure for it, the covid-19 pandemic has created a lot of panic in every part of the world. also, information and misinformation about such factors as those associated with the transmission of the virus, period of incubation, and impact on the socio-economic, political and psychological livelihood of people in the society put the general population at risk of mental health distress. in nigeria, there is no empirical finding (to the best knowledge of the investigators) establishing the impact of covid-19 pandemic on the mental health of the general populace. however, several studies especially in asia and europe (bao et al., 2020; brooks et al., 2020; kang et al., 2020; shigemura et al., 2020) have reported serious psychological distress experiences of members of the society in response to the covid-19 pandemic. considering its grave impact, the covid-19 pandemic has been likened to natural disasters , mass dispute, and war outbreaks (fiorillo & gorwood, 2020) . the present pandemic is, however, more devastating because unlike during a natural disaster or war outbreak whereby people can relocate or build a sophisticated defence system to minimize or escape any foreseeable negative impact, there is nowhere to run to escape the impact of covid-19 pandemic (olapegba et al., 2020) . the effect is far-reaching beyond a specific geographical location as the political and socio-economic structure of the whole world is disrupted and crashing, thus putting people more at risk of experiencing psychological distress (raviola et al., 2020) . it has also been argued that in periods of disease outbreaks, anxiety in the community can rise after the first death of a patient is being reported, also misinformation from media and increasing number of new cases can predispose people to serious psychopathology . kang et al. (kang et al., 2020) also opined that the present covid-19 pandemic will drastically increase global stress and mental health burden. according to xiang (xiang et al., 2020) , the experience of the ongoing covid-19 pandemic is triggering tension and a timely understanding of mental health is very essential for the government, health agencies and the public. recent studies affirm the high and huge level of psychosocial consequences of outbreaks like covid-19 on individuals, the general public, and the international community (hall et al., 2008; wang et al., 2020) . for instance, in the period of sars outbreak, many that were examined on the psychological consequence showed substantial psychological complications that were found to be related with young people and exacerbated blaming of self (sim et al., 2010) , while those older people who were females and highly schooled, displayed higher anxiety feelings for sars positivity, while the less educated had a moderate anxiety rate; those with known contact history with the infected individuals, perceived they have symptoms of sars and have more tendency to indulge in preventive measures against the disease (leung, 2003) . furthermore, the means of containing the pandemic such as; selfisolation, quarantine, social distancing, and treatment of infected persons can further pose a detrimental effect of psychological distress (fiorillo & gorwood, 2020; world health organisation, 2020) . specifically, the loneliness effect of reduced social interactions is a risk factor for several psychological disorders such as; anxiety, drug use, insomnia, major depression, and suicidal ideation especially among vulnerable populations like the elderly and those with health challenges. according to rubin et al. (rubin & wessely, 2020) , excessive quarantine tends to give rise to anxiety significantly, for multiple reasons; even the elevated anxiety may also trigger and initiate the implications for some related mental health issues. barbisch et al. (barbisch et al., 2015) had earlier pointed out the implication of confinement on the psychological well-being of the public, by identifying hysteria, rejection and dejection feelings, obsessive-compulsive symptoms and mood challenges as conditions that can lead to complicated health issues in the victims and the public. despite the devastating effect that dealing with highly contagious and threatening disease expose healthcare workers to in sub-saharan africa, a concern has been raised that the government in the region has not paid enough attention to the psychological distress implications of a pandemic such as a coronavirus on her healthcare workers (higgins, 2014) . in nigeria, it has been opined that despite financial aid and infrastructural support being received from both local and international organizations, the government pays little or no attention to the necessary psychological well-being of healthcare professionals on the frontline of combating coronavirus pandemic (guardian, 2015; web news, 2020) . concerning the aforementioned, it is noteworthy that seeking to devise a better approach to addressing the imminent and present psychological problems of people who witnessed the covid-19 outbreak is a necessity. this, therefore, calls for objective assessment of levels and patterns of possible psychological distress among the general population to inform necessary interventions. as at the time of data collection for this study, no study (to the best of knowledge of the investigators) existed that investigated the psychological impact of covid-19 on the general population in nigeria, therefore this study becomes very relevant. consequently, this study represents the first one examining the psychological impact of covid-19 among the general population in nigeria. this study aims to establish the prevalence of common psychological distress among the general public, and identify the specific pattern of occurring psychopathology among nigerians during the pandemic. to address the aim of this study, the following objectives were raised: 1. to examine the prevalence of insomnia outcomes among residents of nigeria among residents in nigeria during the covid-19 pandemic. 2. to investigate the prevalence of depression symptoms across categories of male and female residents in nigeria during the covid-19 pandemic. 3. to assess the prevalence of posttraumatic stress symptoms across male and female residents in nigeria during the covid-19 pandemic. nigeria during the covid-19 pandemic. this study utilised a cross-sectional descriptive survey research design that entailed collecting quantitative data on more than one case at a single point in time or simultaneously in survey research. the main variables of interest are depression, generalized anxiety, insomnia, and posttraumatic stress. this design was found applicable to describe the psychological distress experiences of nigerians during the covid-19 pandemic. a snowballing sampling technique was used in this study because data collection was conducted during a nationwide lockdown in response to the covid-19 pandemic which made it very difficult to physically access people at the time of data collection. an online semi-structured questionnaire was developed by using google forms, with a consent form appended to it. the link of the questionnaire was sent through emails, whatsapp, and other social media to people on the contact of the investigators. the prospective respondents were then encouraged to roll out the survey to as many of their colleagues as possible. thus, the link was forwarded to people apart from the first point of contact and so on. five hundred and two (502) nigerians aged between 18 years and 78 years (m ¼ 28.75, sd ¼ 8.17) participated in the study. the participants comprised 269 (53.6%) males, 225 (44.8%) females, while 8 (1.6%) did not disclose their sex. in terms of ethnic affiliations, the majority of the participants (86.3%) identified with ethnic groups in the southern region of nigeria, while 9.4% indicated they were from ethnic groups in northern nigeria, the remaining 4.4% did not disclose any specific nigerian ethnic affiliation. in terms of religious affiliation, the majority (67.1%) are christians, 31.7% are muslims, while only 0.8% practiced other religions, and 0.4% of the respondents identified themselves with traditional religion. data on the marital status of participants showed that 32.9% were married, 66.3% unmarried, and 0.8% were separated. finally, categorization based on the highest level of education, only 4.4% of the participants had secondary school education, 27.1% reported incomplete tertiary education, 39.4% completed tertiary education, and the remaining 29.1% had postgraduate education. data were collected via an online self-reported questionnaire designed by the investigators. the questionnaire contained five sections. the first section consisted of information assessing demographic attributes such as sex, age, religion, and marital status of participants. the second section contained the 22-item impact of event scale-revised (ies-r). the scale was developed to measure the subjective response to a specific traumatic event, especially in the response sets of intrusion, avoidance, and hyperarousal, as well as total subjective stress ies-r score. the ies-r is not meant to be diagnostic. the total ies-r score was divided into 0-23 (normal), 24-32 (mild psychological impact), 33-36 (moderate psychological impact), and >37 (severe psychological impact). weiss (weiss et al., 2007) affirmed the validity and reliability of the scale. cronbach's alpha 0.82 was established as the reliability coefficient for the scale in this study. in section three of the questionnaire is the generalized anxiety disorder 7-item (gad-7) scale (spitzer et al., 2006) consisting of 7 questions assessing generalized anxiety disorder, focusing on the frequency of symptoms during the preceding 2-week period. the gad-7 requires approximately 1-2 min to administer and for each symptom queried provides the following response options: "not at all," "several days," "over half the days" and "nearly every day" and these are scored, respectively, as 0, 1, 2 or 3. a score ranging from 0 to 21 is obtainable by respondents. scores of 5, 10, and 15 are taken as the cut-off points for mild, moderate and severe anxiety, respectively. cronbach's alpha 0.81 was established as the reliability coefficient for the scale in this study. the fourth section contained the patient health questionnaire (phq-9). the phq-9 is a nine-item depression scale that has the potential of being a dual-purpose instrument to establish the diagnosis of a depressive disorder, as well as the grade of symptom severity (kroenke et al., 2001) . statements measuring depressive symptoms such as "little interest/pleasure in doing things" were rated from 0 (not at all) to 3 (nearly every day) by respondents as applicable to them over the past two weeks. phq-9 score can range from 0 to 27. the scale has strong psychometric properties and has been widely used. cronbach's alpha 0.87 was established as the reliability coefficient for the scale in this study. the fifth section contained the insomnia severity index, a 7-item selfreport questionnaire assessing the nature, severity, and impact of insomnia. participants were required to rate their sleep condition in the last 2 weeks as described by each item of the scale. questions on the isi cut across the severity of sleep onset, sleep maintenance, and early morning awakening problems, sleep dissatisfaction, interference of sleep difficulties with daytime functioning, noticeability of sleep problems by others, and distress caused by the sleep difficulties. the scale is responded to on a 5-point likert scale with a score ranging from 0 to 4; thus, yielding a total score ranging from 0 to 28. the total score is interpreted as follows: the absence of insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and severe insomnia (22-28). previous studies have reported adequate psychometric properties for both the english and french versions (bastien et al., 2001) . cronbach's alpha 0.78 was established as the reliability coefficient for the scale in this study. this was an online study. participants with access to the internet were invited to participate in the study. participants with age more than 18 years, able to understand english and willing to give informed consent were included. a link to the survey on google form was sent to all participants. on receiving and clicking the link, the participants got auto directed to the information about the study. a detailed informed consent form was attached at the beginning of the online questionnaire and consent was a prerequisite to continue in the survey. therefore, only individuals who gave their consent participated in the study. the data collection was initiated on march 20, 2020 and closed on april 19, 2020. the sampling technique employed allowed the investigators to collect data from across various states of nigeria. five hundred and two (502) correctly filled questionnaires were recovered through the google form and processed for statistical analysis. the collected data was analyzed using the spss package (version 25) and graphpad prism (v8.4.2). the analyzed data respond to the four research questions stated in the early paragraph. the analyses include prevalence estimate analysis, and chi-square analysis was therefore presented. this phase presents the results and interpretation of data collected on the prevalence of psychological distress among five hundred and two (502) residents in nigeria during the outbreak of the pandemic. the prevalent rate of psychological distress outcomes was reported among residents of nigeria across the six geopolitical zones. based on the exploratory process, outcomes of the evaluated psychological constructs were presented in the chart below (see charts 1-4). chi-square contingency chart (see chart 1) revealed that there was no significant difference in the reported severity of insomnia among female and male residents in nigeria during pandemic (χ2 ¼ 04.93; df ¼ 3; p > 0.05). however, prevalence estimates analysis revealed that majority of the male respondents (65.1%) had no clinical insomnia, 20.8% of the male participants reported sub-threshold level of insomnia, 8.2% of the respondents had moderate insomnia symptoms, while 5.9% of the male respondents presented severe clinical insomnia during the covid-19 pandemic. it was further reported that majority of the female respondents (52%) had no clinical insomnia symptoms, 32% reported subthreshold level of insomnia, 12.4% had moderate insomnia symptoms, while 3.6% of the female respondents presented severe clinical insomnia during the covid-19 pandemic. further analysis that aimed to reveal the prevalence of depression symptoms across categories of male and female residents in nigeria was tested using a contingency analysis of the graphpad prism (see chart 2). chi-square contingency chart (see chart 2) revealed that there was no significant difference in the reported severity of depressive symptoms among female and male residents in nigeria during pandemic (χ2 ¼ 01.94; df ¼ 4; p > 0.05). however, prevalence estimates analysis revealed that majority of the male respondents (55.4%) had minimal depressive symptoms, 22.3% reported mild depressive symptoms, 11.9% of the respondents had moderate depressive symptoms, 6.7% had moderately severe depressive symptoms, while 3.7% of the male respondents presented severe depressive symptoms during the covid-19 pandemic. it was further reported that majority of the female respondents (49.3%) had minimal depressive symptoms, 26.7% reported mild depressive symptoms, 14.29% had moderate depressive symptoms, 4.4% had moderately severe depressive symptoms, while 5.3% of the female respondents presented severe depressive symptoms during the covid-19 pandemic. based on the study objectives, the analysis that aimed to reveal the prevalence of posttraumatic stress symptoms across male and female residents in nigeria was tested using a contingency analysis of the graphpad prism (see chart 3). chi-square contingency chart (see chart 2) revealed that there was no significant difference in the reported severity of posttraumatic stress symptoms (ptss) among female and male residents in nigeria during pandemic (χ2 ¼ 02.51; df ¼ 3; p > 0.05). however, prevalence estimates analysis revealed that the majority of the male respondents (37.9%) had no pts symptoms, 23% reported partial pts symptoms, 17.5% presented clinical pts symptoms, while 21.6% of the male respondents presented severe pts symptoms during the covid-19 pandemic in nigeria. it was further reported that the majority of the female respondents (29.3%) had severe pts symptoms, 24% reported partial pts symptoms, 18.7% had clinical pts symptoms, while 28% of the female respondents presented no pts symptoms during the covid-19 pandemic. further objective to explore the prevalence of anxiety symptoms among residents in nigeria during covid-19 pandemics was tested using prevalence estimate analysis of the graphpad prism (see chart 4). chart 4 revealed that there was no significant difference in the disparity of anxiety symptoms among residents of nigeria during the covid-19 pandemic (χ2 ¼ 0.08; df ¼ 1; p > 0.05). based on chart 4, it was revealed that the majority of the residents in nigeria insignificantly had moderate anxiety symptoms during the covid-19 pandemic. in other words, 51% of the participants in the study had moderate anxiety symptoms (i.e. incapacitating level of anxiety), while approximately 49% of the residents exhibited severe anxiety symptoms in nigeria. the outbreak of deadly disease is not a new occurrence in nigeria; the country has faced so many outbreaks of emerging and reoccurring diseases such as malaria, avian influenza, ebola virus, hiv/aids, meningitis, lassa fever, tuberculosis, monkeypox and many more (nigeria centre for disease control, 2020) and yet, it thrived above all these outbreaks. for a country that has no recent serious prior experience with natural disasters such as tsunami and earthquake (hansen, 2018) , and infectious disease such as sars, the country and its occupants seem overwhelmed with the covid-19 pandemic. the novel covid-19 pandemic has brought along with it, innovation and changes that nigerians are not used to which can lead to psychological distress. nigerians are distinct people with a rich social culture such as; partying, hanging out and routine dropping off and picking up of children at school, termed "school runs", is a social activity and opportunity of networking for most parents. therefore, the lockdown, physical and social distancing, closure of schools and the imposition of the use of face/nose mask could serve as stressors among this population. also, amidst the fear and risk of contagion of the covid-19, the changes in the day to day activities of so many nigerians would have caused the prevailing psychological distresses. the overall prevalence of insomnia indicated was 15% among the general public in nigeria (4.75% severe insomnia and 10.3% moderate insomnia), a little less than a quarter (23%) indicated experience of moderate depression to severe depression and a quarter (25%) of the population indicated experiencing symptoms of severe posttraumatic stress and 18.1% indicated experiencing symptoms of clinical posttraumatic stress. on april 28, 2020, the nigeria centre for disease control reported that nigeria has recorded 1532 confirmed cases of covid-19 and 24 deaths in 33 states and the federal capital territory (nigeria centre for disease control, 2020), this figure seems quite low in comparison to the figures reported in china and the global recorded death. the low reported confirmed cases (as at the time of data collection) may have culminated in the lower prevalence of depression reported (moderate depression 13.1%, moderately severe depression 5.55% and severe depression 4.5%) among nigerians as against higher reported prevalence of depression due to covid-19 pandemic among chinese citizens (gao et al., 2020) . the researchers reported the prevalence of depression among general chinese citizens has 48.3% and reported prevalence of depression among hospitalized patients in wuhan, china has 28.7% (gao et al., 2020) . confirming the output of our study, clinical psychological scientists at the university of washington have requested the need to prepare for a possible clinical depression epidemic because of covid-19 (the conversation, 1345) . consistent with our study findings of the prevalence of psychological distress among the public in nigeria, wang, et al. (wang et al., 2020) reported prevalence of moderate or severe psychological impact of the covid-19 outbreak among the public in china and bo et al. (bo et al., 2020) reported that before discharge, most clinical stable covid-19 patients suffered from significant posttraumatic stress symptoms. importantly, the prevalence of posttraumatic stress symptoms during covid-19 was lower among chinese citizens; sun et al. reported 4.6% posttraumatic stress symptoms and 7% in china hardest-hit areas (liu et al., 2020) , while the public in nigeria reported higher experience of posttraumatic stress symptoms (25%). the difference in prevalence between the two populations can be attributed to the direct experience of the covid-19 devastation by the chinese population at the early stage of the outbreak and the nigerian population observation of the event through mass media. the several misleading information on the social media relating to the covid-19 from its inception and the increase in confirmed cases in nigeria could have heightened the experience of posttraumatic stress symptoms of the nigerian population. adult females and even children (female) provide unpaid care in families (sandoiu, 2020) in nigeria, which ranges from cooking, washing, taking care of kids, and general cleaning of the house. due to the lockdown, stay at home mandate of the federal government and cleaning of surfaces mantra, most female household chores have been doubled or tripled in most cases and this can be distressing. there has been an upsurge in the issues of domestic violence against women and the girl child, which prompted amina mohammed (un deputy secretary-general) to call on all governments, civil society, and individuals to consider gender-based violence as a dominant issue of all domestic plans on covid-19 response (united nations, 2020). so many women in nigeria, especially those in abusive marriages and relationships have no escape because of the restriction of movements and lockdown in most states of the country (daniels, 2020) . against this backdrop, it was expected that females should indicate the higher experience of psychological distress but our study found no substantial variation between male and females' experiences on psychological distresses during covid-19 pandemic, though articles and studies have contrary opinions. women in eight countries across africa (nigeria not included) and asia were reported to have consistently self-reported higher sleep problems than men based on series of roles they play in families (stranges et al., 2012) , female more than their male counterpart were confirmed to be susceptible to insomnia (zhang & wing, 2006) and high posttraumatic stress symptoms (liu et al., 2020) . similar to our findings of 15% experience of insomnia (moderate to severe), a korean population reported an overall prevalence of insomnia symptoms of 10.7% which included difficulty in initiating sleep, difficulty in maintaining sleep and early morning awakening but the symptoms were more prevalent in female than in male (la et al., 2020) . the similarity of the genders on their psychological distress during the covid-19 based on the peculiarity of the population can be attributed to a deep culture that has made women in nigeria believe that it is socially acceptable to be hit and discipline (standard, 2013; trust, 2013) , hence, they might have adapted to the situation at a significant level that it does not cause them psychological distress. in conclusion, our findings expose the prevalence of insomnia, depression and posttraumatic stress symptoms among nigerians during the covid-19 pandemic. though this study recorded no significant difference between the gender (male and female) experiences of insomnia, depression, posttraumatic stress symptoms and anxiety, the study result reported a relevant prevalence of outcomes of psychological distress among the general public in nigeria. the government of nigeria should make available, if not for all, psychological health services for survivors of covid-19. the study does not involve larger numbers of nigerians to ascertain the generalizability of the current findings. it is also possible that outcomes would vary if measured over a thousand or more participants. some socioeconomic factors should have been included in this study to ascertain the comorbid factors that could aggravate psychological distress in the current pandemic among nigerians. finally, the issue of response bias, which is prevalent in self-report surveys could have influenced the result and considered a limitation to this study. considering the findings of this study, the following are suggested to enhance psychological wellbeing among nigerians during the pandemic period: 1. tele-psychotherapy means of managing psychological distress among the public should be adopted by stakeholders during a lockdown and infectious disease outbreak like this. this intervention has been found to be effective in treating disorders such as; anxiety, depression, suicide attempts, trauma-related problems, insomnia, etc in the face of a pandemic that strains health care resources (augenstein, 2020; national quality forum, 2017) . especially when face-to-face appointments are risky. 2. federal and state governments should initiate a bill honoring the telemental health services to manage present and future pandemic psychological implications. 3. healthcare stakeholders needed to collaborate with psychotherapists in the management of pandemic or disease outbreak to regulate residents' emotions and promote people's psychological wellbeing in society. 4. experts should start an awareness campaign on basic means of overcoming psychological distress on media and in communities generally in nigeria to foster mental healthiness. opportunities to expand telehealth use amid the coronavirus pandemic 2019-ncov epidemic: address mental health care to empower society is there a case for quarantine? perspectives from sars to ebola. disaster medicine and public health preparedness validation of the insomnia severity index as an outcome measure for insomnia research posttraumatic stress symptoms and attitude toward crisis mental health services among clinically stable patients with covid-19 in china the psychological impact of quarantine and how to reduce it: rapid review of the evidence women are suffering domestic violence because of covid-19 the consequences of the covid-19 pandemic on mental health and implications for clinical practice mental health problems and social media exposure during covid-19 outbreak children are dying of preventable diseases all the time in africa the 1995 kikwit ebola outbreak: lessons hospitals and physicians can apply to future viral epidemics. general hospital psychiatry 10 of the deadliest natural disasters ebola fight in africa is hurt by limits on ways to get out the mental health of medical workers in wuhan, china dealing with the 2019novel coronavirus validity of a brief depression severity measure gender differences influence over insomnia in korean population: a cross-sectional study the impact of community psychological responses on outbreak control for severe acute respiratory syndrome in hong kong prevalence and predictors of ptss during covid-19 outbreak in china hardest-hit areas: gender difference matter ecological disasters and mental health: causes, consequences, and interventions creating a framework to support measure development for telehealth. 1030 15th street, nw, suite 800 a preliminary assessment of novel coronavirus (covid-19) knowledge and perceptions in nigeria development of a comprehensive, sustained community mental health system in a coronavirus: the psychological effects of quarantining a city how covid-19 affects women's sexual and reproductive health public responses to the novel 2019 coronavirus (2019-ncov) in japan: mental health consequences and target populations psychosocial and coping responses within the community health care setting towards a national outbreak of an infectious disease a brief measure for assessing generalized anxiety disorder why fewer men are beating their wives accessed 28 sleep problems: an emerging global epidemic? findings from the indepth who-sage study among more than 40,000 older adults from 8 countries across africa and asia prevalence and risk factors of acute posttraumatic stress symptoms during the covid-19 outbreak in wuhan covid-19 could lead to an epidemic of clinical depression, and the health care system isn't ready for that cultural beliefs fuel domestic violence. archived from the original on september un backs global action to end violence against women and girls amid covid-19 crisis immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china psychologist advocates increased palliatives to cushion lockdown effect the impact of event scale: revised advice and guidance from who on covid-19 timely mental health care for the 2019 novel coronavirus outbreak is urgently needed sex differences in insomnia: a meta-analysis supplementary data to this article can be found online at https:// doi.org/10.1016/j.ssaho.2020.100052. key: cord-315591-5ttn8beu authors: xie, yaofei; ma, mengdi; wu, wenwen; zhang, yupeng; zhang, yuting; tan, xiaodong title: dose–response relationship between intergenerational contact frequency and depressive symptoms amongst elderly chinese parents: a cross-sectional study date: 2020-09-15 journal: bmc geriatr doi: 10.1186/s12877-020-01751-0 sha: doc_id: 315591 cord_uid: 5ttn8beu background: given the high prevalence of depressive symptoms amongst the elderly chinese population and the significance of intergenerational contact in this demographic group, the purpose of this study was to examine the association and dose–response relationship between the frequency of intergenerational contact and depressive symptoms. methods: data were obtained from the third wave of the china health and retirement longitudinal study. a total of 5791 participants at age 60 or older were included in this study. depressive symptoms were defined by the 10-item version of the centre for epidemiologic studies depression scale. intergenerational contact included in-person meeting and remote connecting, and they were analysed separately. intergenerational contact frequency was classified into ten categories and then treated as a continuous variable for analysis. we performed univariate and multivariate logistic regressions to identify risk covariables. restrictive cubic spline analysis was used to examine the dose–response relationship between intergenerational contact frequency and the outcome of depressive symptoms. results: both the frequency of meeting and the frequency of connecting with children were independently associated with depressive symptoms in the elderly, and the odds ratios for depressive symptoms increased with decreasing frequencies (p < 0.01). there was a negative dose–response relationship between intergenerational contact frequency and depressive symptoms. the odds of depressive symptoms steadily decreased with increasing frequency of meeting with their children. following an initial increase, the odds rapidly decreased as the frequency of connecting with children increased with an inflection point at once a monthly. both associations were nonlinear (p < 0.001). conclusions: our findings revealed a negative dose–response relationship between intergenerational contact frequency and depressive symptoms in the elderly chinese population. thus, future health interventions should consider cultural norms in shaping the mental well-being of chinese elderly persons. depressive disorders amongst the elderly population is a worldwide public health problem [1] . the global health estimates reported by the world health organization (who) indicate that the prevalence of depressive disorders has peaked amongst the elderly [2] . in contrast to depressive disorders in younger populations, late life depression (major depressive disorders) is a risk factor for many chronic medical conditions [3, 4] . in addition, depression can result in significantly lower quality of life and increase mortality in the elderly population [5] [6] [7] . depressive symptoms are the major manifestations of depressive disorders. the prevalence of depressive symptoms varies between regions and populations. a study of elderly latinos in the united states reported a 25.5% prevalence of depressive symptoms [8] . another study reported a 14.0% prevalence in elderly americans of chinese descent [9] . two population-based studies conducted in germany [10] and greece [11] reported 28.7 and 32.3% prevalence of depressive symptoms amongst elderly, respectively. about 19 .0% of elderly koreans had depressive symptoms [12] . the 2008 chinese elderly mental health survey revealed that over 39% of the elderly participants self-reported depressive symptoms [13] . the 2011 china health and retirement longitudinal study (charls) also reported that approximately 40% of older adults had depressive symptoms [14] . china is facing a rapidly aging society; the proportion of elderly has grown from 13.3% [15] to 17.9% [16] of the population between 2010 and 2018. thus, there is a corresponding growth in the number of older people displaying depressive symptoms. previous studies have found that contact frequency with offspring is inversely associated with depressive symptoms amongst older parents [17] [18] [19] . one explanation is that older parents expect support from their children, and when their adult children do not meet expectations, depressive symptoms may arise [20] . it has been suggested that intergenerational contact is a critical aspect of social support for the elderly [21] , and the lack of which has been implicated in an increased risk of depressive symptoms [22] . indeed, intergenerational contact provides an opportunity for companionship, sharing of interests and opinions, and for expression of emotions. for the elderly, these opportunities foster a sense of belonging to the family, and they also enable family members to offer help and care [23] . children may provide a sense of meaning and order to life, and they may even be a source of self-esteem and prestige for the elderly [24] . intergenerational contact is important for elderly chinese people. chinese confucian cultures emphasises family and filial piety, and the practice of intergenerational contact is a part of filial piety. the absence of filial piety in the lives of chinese elderly is connected with depressive symptoms [25] [26] [27] . one study in elderly chinese-american also reported that those experiencing greater than expected filial piety had a lower risk of depressive symptoms [28] . more than ever, elderly chinese people experience less contact with their adult children. according to the china health and retirement report published by the charls team in 2019, the number of elderly people not living in the same city as any of their children rose from 8 to 11% between 2011 and 2015. in the same period, there was also an increase from 19 to 24% in adult children living in different cities from their parents, and increasing distance between children and parents was associated with less intergenerational contact [29] . in addition, the proportion of 'empty nesters' (i.e., parents who do not live with their adult children) have increased remarkably and now includes nearly half of the elderly population in the country [30] . it is estimated that the proportion of empty-nester households could reach 90% by 2030 [31] . several studies reported a high prevalence of depressive symptoms amongst empty nesters [32] [33] [34] . however, to our knowledge, no study has investigated the direct association between intergenerational contact frequency and depressive symptoms in the elderly chinese population. to address this gap in knowledge, the present study in elderly chinese participants aims to: (a) examine the association between intergenerational contact frequency and depressive symptoms, and (b) explore its dose-response relationship. data were obtained from the 2015 third wave survey data from the charls study. charls is an ongoing longitudinal study that collects demographic, social and economic data as well as the health status of nationally representative samples of middle-aged and elderly chinese residents. charls uses a four-stage sampling method. at the county and village levels, a probabilityproportional-to-size sampling method was used, and a total of 450 villages or communities were included. at the household and individual levels, the charls researchers designed a software package named char ls-geographic information system (charls-gis) to determine each sampling frame on the map. furthermore, a sample of 80 households was randomly selected from a list of all households in each sampling frame. in every household sample, a family member over 45 years old was randomly selected as the main interviewee. face-to-face interviews were then conducted by trained investigators to collect study data. the response rate was over 85% [35] . all the survey data are publicly available online. a total of 5791 participants were retained in the present study after removing the participants younger than 60 years and the participants with missing values on any of the main variables. the sample size was considered sufficient. depressive symptoms were determined using the 10item version of the centre for epidemiologic studies depression scale (ces-d-10) [36] . the cronbach's alpha of the chinese version of this scale was 0.813 [37] . the ces-d-10 contains three items addressing depressive affect, five addressing somatic symptoms, and two specifying positive affect. each item has four options: option 1, "rarely or none of the time (< 1 day)", option 2, "some or a little of the time (1 − 2 days)", option 3, "occasionally or a moderate amount of the time (3 − 4 days)", option 4, "most or all of the time (5 − 7 days)". participants are asked to recall the frequency of specific feelings and behaviours during the past week and to choose the most appropriate response. each item was rated from 0 to 3, corresponding to the first through fourth options. exception include 'item 5' and 'item 8', which are reverse-scored from 3 to 0. the total score of the ces-d-10 scale ranged from 0 to 30, and participants who scored ≥10 points were considered to have significant depressive symptoms [38] . two intergenerational contact types were analysed: inperson "meetings" and remote "connections" made either by phone, text message, postal mail or email. the frequency was categorised into ten numbered items, 1 = almost never, 2 = less than once a year, 3 = once a year, 4 = once every 6 months, 5 = once every 3 months, 6 = once a month, 7 = every 2 weeks, 8 = once a week, 9 = 2-3 times a week and 10 = almost every day. the participants were allowed to select the number closest to the actual frequency. the contact frequency of all adult children was recorded and co-resident children were included under the category of "almost every day". we collected basic demographic characteristics including gender, age, marital status, education level, and residence that have been reported to be associated with depressive symptoms amongst the elderly chinese population as control variables [39] [40] [41] . previous studies reported that the presence of chronic disease was significantly related to depressive symptoms in the elderly [42, 43] . conversely, old parents in poor physical health may stimulate increased contact with their children. so we used the variable of "number of chronic diseases suffered" to reduce the possibility of reverse causation. we analysed the intergenerational contact frequencies of all children in a family using the variable of "number of children" as a covariate to control for the effect of having multiple children. we first conducted a descriptive analysis of all the study variables. pearson chi-square tests and variance analyses were performed to assess differences in ces-d-10 scores and the prevalence of depressive symptoms in the subgroups. next, univariate and multivariate logistic regression models were used to calculate the unadjusted and adjusted odds ratios (ors) of the covariates to identify risk factors for depressive symptoms. finally, we used restrictive cubic splines with four knots at the 25th, 50th, 75th, and 95th centiles to explore the dose-response relationship between intergenerational contact frequency and depressive symptoms. in the restrictive cubic spline analysis, the significant risk factors identified earlier were adjusted in the model. the frequency of "meetings" and the frequency of "connections" were mutually adjusted. a likelihood ratio was used to test for non-linearity [44, 45] . missing values were accounted by using regression interpolation. statistical significance was set to p < 0.05, and all p-values were two-sided. table 1 displays the demographic characteristics, ces-d-10 scores, and the prevalence of depressive symptoms. among the 5791 participants, males accounted for about 56%, the average age was 69 years old, and over 60% were from 60 to 69 years old. nearly two-thirds of the participants were living with their spouse, and more than 70% lived in villages. uneducated participants accounted for about 30% of the sample, and nearly half of them completed education no further than elementary-level. nearly 60% of their household consumption expenditures per capita fell within 0-2000 rmb. more than 80% of participants reported that they were diagnosed with at least one type of chronic disease. over 90% of participants had more than one child. in terms of intergeneration contact frequency, participants that met with their children either at least once a week or 1-2 times a month accounted for approximately 30% of the sample each. over a quarter of participants met with their children 1-2 times every 6 months, and about 12% reported a frequency of ≤1 time per year. the participants who connected with their children either ≥2 times or 1 time a week accounted for approximately one-third of the sample each. about 15% of participants connected with their children 1-2 times a month, while others reported the frequency at ≤1 time every 3 months. the mean ces-d-10 score of all the participants was 8.83 ± 6.68. using ≥10 as the cut-off score, depressive symptoms were identified in 37.52% of the participants. the variance analysis and chi-square test results revealed that gender, marital status, residence, education level, number of chronic diseases, number of children, frequency of meeting with children, and frequency of connecting with children were each associated with differences in ces-d-10 scores and in the prevalence of depressive symptoms (p < 0.001). table 2 presents the results of the logistic regression models for the associated factors of depressive symptoms. the unadjusted ors for significant variables were calculated. we tested for collinearity on all independent variables using tolerance and variance inflation factors (vifs) before multivariate analyses. all values for tolerance were over 0.1 and all vifs were less than 10.0, therefore, there was no collinearity among independent variables. adjusted regression analysis showed that depressive symptoms were more likely to be identified in women (or: 1.69, 95% ci: 1.49-1.92); those who were divorced, widowed, never married, or cohabitated (or: 1.29, 95% ci: 1.13-1.47); those who lived in villages (or: 1.78, 95% ci: 1.47-2.14); those with a low education level; those who met up with their children less than once weekly; and those who connected with their children less than twice weekly. the odds of depressive symptoms increased with an increasing number of chronic diseases: 44, 74, and 234% for one, two, and three or more conditions, respectively. there was no significant association between the number of children and depressive symptoms. multiple logistic regression results demonstrated that intergenerational contacts were independently associated with depressive symptoms amongst the elderly chinese population. figure 1 illustrates the changes in ces-d-10 scores and prevalence of depressive symptoms in conjunction with (a) meeting with children in-person and (b) connecting with children remotely through different methods. overall, it shows that lower ces-d-10 scores and fewer depressive symptoms tend to trend with increasing frequency of intergenerational contact. figure 2 shows the dose-response relationship between depressive symptoms and intergenerational contact frequency resulting from restricted cubic splines analyses. the analyses were adjusted for the factors associated with depressive symptoms in multivariable logistic regression. both models were nonlinear (p < 0.001 for the non-linearity test). figure 2 (a )illustrates the steadily decreasing ors for depressive symptoms with an increasing frequency of meeting with children. remarkably, the odds of depressive symptoms show a significant inverse association with contact frequency when it falls below once monthly (frequency of meeting with children = 6). meanwhile, fig. 2(b) shows the ors for depressive symptoms increased slightly followed by a sharp decrease as the frequency of connecting with children increases. the inflection point for the changes in ors occurs at oncemonthly connections. (frequency of connecting with children = 6). the increasing social-structural constraints on resources and time have reduced intergenerational contact between the elderly chinese population and their adult children. considering china's traditional family culture and the special importance of intergenerational contact for this group, the present study investigated the relationship between intergenerational contact and depressive symptoms. we found overall prevalence of depressive symptoms in the participants was 37.5% as defined by a ces-d-10 score of ≥10, which is higher than the prevalence reported in the elderly japanese population of 11.5%. that study defined depressive symptoms using the geriatric depression scale (gds) with a cut-off score of ≥6 [46] . our result is also higher than the prevalence of 31.5% reported in elderly europeans; the results there were measured using the euro-d scale with a cut-off score of ≥4 [47] . by contrast, the prevalence for institutionalised elderly persons in brazil was 45.8% [48] and it was 60.6% in elderly nepalese [49] . depressive symptoms in these studies were also defined by the gds with a cutoff score of ≥6. the differences in these findings may be attributed to the economic and cultural differences amongst different regions. depressive symptoms amongst the elderly chinese are associated with low levels of education, unmarried status, and location setting of residence, which are consistent with several previous studies [39, 40, 50] . amongst the elderly chinese, intergenerational contact frequency is independently and inversely associated with depressive symptoms; it exhibits a negative dose-response relationship with the odds of depressive symptoms. for in-person interactions, the ors for depressive symptoms did not increase significantly with a decrease of frequency of interaction until they reached a frequency of ≤1 time monthly compared with those who have almost daily contact. the results suggest that children should meet up with their older parents at least once a month to possibly prevent them from developing depressive symptoms. this result is similar to a study in the u.s. that reported that the frequency of in-person interactions with children was inversely associated with the development of depressive symptoms in older parents [51] . for contact by telephone, postal mail, or email, relative to connecting almost everyday, the ors for depressive symptoms rapidly increased with a decrease in the frequency of connection. they reached an inflection point where connections were made once a month, whereby the ors decreased slightly with a decrease in contact frequency. we suggest that other forms of contact are more easily accessible, therefore parents expect a greater frequency of interaction with their children, and they develop depressive feelings more easily when there is a minor decrease in contact frequency. but when the frequency drops to once monthly, their depressive feelings reach a stable level but do not get worse. during the coronavirus disease 2019 (covid19) pandemic, quarantines were implemented to prevent disease transmission, but concurrently, they had a fig. 1 changes in ces-d-10 scores and in the prevalence of depressive symptoms relative to intergenerational contact frequency. frequency: 1 = almost never, 2 = less than once a year, 3 = once a year, 4 = once every 6 months, 5 = once every 3 months, 6 = once a month, 7 = every 2 weeks, 8 = once a week, 9 = 2-3 times a week and 10 = almost every day negative psychological impact [52] [53] [54] . our findings suggest that children should keep close connections with their older parents during periods of quarantine, which may help reduce the risk of depressive symptoms. the associations of depressive symptoms and intergenerational contact frequency might be related to three aspects. first, infrequent intergenerational contact leads to loneliness in older adults, thereby resulting in increased depressive symptoms. loneliness is a subjective and negative feeling that occurs when individuals experience diminished social relationships [55] . on the one hand, infrequent contact with family can heighten the risk for loneliness [56] , because loneliness is usually conceptualized as perceived social isolation [57] , and infrequent social contact is an objective measure of perceived social isolation [58] . moreover, chinese family culture attaches great importance to the happiness of a family union. thus, the elderly chinese are prone to loneliness when they are unable to receive sufficient companionship from their adult children. on the other hand, depressive symptoms were regarded as a logical consequence of loneliness [59] . previous studies have shown that loneliness is consistently and strongly associated with depressive symptoms [60] [61] [62] . therefore, loneliness may be an intermediate step between reduced intergenerational contact and depressive symptoms. second, infrequent intergenerational contact limits the availability of family support for the elderly. social support for many elderly adults comes from family members. specifically, intergenerational support is a primary component that may improve the psychological wellbeing of elderly parents [63] . poulin et al. [64] argued fig. 2 dose-response association between intergenerational contact frequency and the odds for depressive symptoms. frequency: 1 = almost never, 2 = less than once a year, 3 = once a year, 4 = once every 6 months, 5 = once every 3 months, 6 = once a month, 7 = every 2 weeks, 8 = once a week, 9 = 2-3 times a week and 10 = almost every day. or: odd raio; lb.: lower limit; ub: upper limit that family support from adult children can prevent depressive symptoms in elderly chinese people. conversely, loss of support from children is a key reason for the high prevalence of depressive symptoms in this population [13] . furthermore, part of intergenerational contact is the provision of home care, and it has been reported that the chinese elderly who worry about the lack of caregivers tend to have higher levels of depressive symptoms [65] . hence, decreased intergenerational contact may be related to reduced caregiving, thereby leading to increased depressive symptoms. third, infrequent intergenerational contact is not conducive to maintaining a good parent-child relationship. poor relationships are associated with depressive symptoms in the elderly. intergenerational contact is considered a critical indicator of the strength of the parent-child relationship [19] . frequent contact provides opportunities for companionship and socialising, thus promoting the parent-child relationship. li et al. [66] reported that parent-child relationships may directly affect depressive symptoms amongst the elderly chinese population. in addition, a study in elderly people living in the rural areas of the u.s. similarly concluded that parent-child relationships were inversely associated with depressive symptoms [67] . several limitations of this study should be addressed. we attempted to consider all children of survey participants who had multiple children. however, having infrequent contact with one child may matter less if other children maintain relatively more frequent contact. also the effects of contact frequency on depressive symptoms may be different between each child. thus, our use of the average frequency of intergenerational contact for parents with multiple children may produce bias. investigating these potential effects is beyond the scope of our study, but it is important for future studies to investigate each parent-child relationship or factors that contribute to differences between each child. next, we did not have study variables that described qualities stemming from intergenerational contact, such as loneliness, social support and parent-child relationships. therefore, comprehensive and structural relationships for these variables were not obtained. finally, the data were cross-sectional, which allowed us to analyse associations between variables, but a causal relationship between intergenerational contact and depressive symptoms could not be determined. to address these issues, future longitudinal analyses that feature additional variables should be conducted to enhance our understanding of the relationship between intergenerational contact and depressive symptoms. the present study demonstrates that lower intergenerational contact frequency with children is independently associated with greater depressive symptoms amongst the elderly chinese population. the ors for depressive symptoms show an increasing trend with decreasing frequency of contact with children of the participants. our results suggest that provision of depression prevention services should be considered for older chinese people. a number of demographic characteristics are related to depressive symptoms and should be taken into account during screening. scholars and policy makers should pay attention to family cultural norms when health interventions are considered in the elderly chinese population. depression in late life: review and commentary world health organization. depression and other common mental disorders: global health estimates. geneva: world health organization body mass index moderates the relationship between c-reactive protein and depressive symptoms: evidence from the china health and retirement longitudinal study changes in depression among older adults in china: a latent transition analysis depression among older adults: a 20-year update on five common myths and misconceptions family relationships and depressive symptoms among chinese older immigrants in the united states course of late-life depression in china is chronic and unremitting neighborhood language isolation and depressive symptoms among elderly u.s. latinos face-saving and depressive symptoms among u. s. chinese older adults age-and gender-specific prevalence and risk factors for depressive symptoms in the elderly: a population-based study nutritional status is associated with the degree of cognitive impairment and depressive symptoms in a greek elderly population correlation between depressive symptoms and subjective mastication ability and ability to pronunciation among korean elderly prevalence and correlates of depressive symptoms in chinese older adults: a population-based study challenges of population aging in china: evidence from the national baseline survey of the china health and retirement longitudinal study (charls) health promoting lifestyles and influencing factors among empty nesters and non-empty nesters in taiyuan, china: a cross-sectional study age composition and dependence ratio of population, national data: national bureau of statistics of china receiving instrumental support in late parent-child relationships and parental depression social support and depressive symptoms in the elderly intergenerational contacts and depressive symptoms among older parents in eastern europe depression among older parents: the role of intergenerational exchange how families still matter : a longitudinal study of youth in two generations. cambridge loneliness, social support networks, mood and wellbeing in communitydwelling elderly life-course changes and parent-adult child contact children's impact on the mental health of their older mothers and fathers: findings from the survey of health, ageing and retirement in europe risk factors for depression in older adults in beijing relationship between self-rated filial piety and depressive symptoms among the elderly systematic literature review and metaanalysis of filial piety and depression in older people the association between filial discrepancy and depressive symptoms: findings from a community-dwelling chinese aging population china health and retirement report. china health and retirement longitudinal study does an empty nest affect elders' health? empirical evidence from china depression and social support between china' rural and urban empty-nest elderly risk factors of mental disorders among empty and non-empty nesters in shanxi, china: a crosssectional study prevalence and related influencing factors of depressive symptoms for empty-nest elderly living in the rural area of yongzhou, china risk factors for depression in empty nesters: a cross-sectional study in a coastal city of zhejiang province and china screening for depression in well older adults: evaluation of a short form of the ces-d (center for epidemiologic studies depression scale) reliability and validity of 10-item ces-d among middle aged and older adults in china cross-validation of a short form of the ces-d in chinese elderly depressive symptoms in the mid-and old-aged people in china trajectory pathways for depressive symptoms and their associated factors in a chinese primary care cohort by growth mixture modelling factors that related to the depressive symptoms among elderly in urban and rural areas of china exploring individual, family, and extrafamilial factors associated with depression among elderly residents of care settings health status and lifestyle factors as predictors of depression in middle-aged and elderly japanese adults: a seven-year follow-up of the komo-ise cohort study flexible regression models with cubic splines comparing smoothing techniques in cox models for exposure-response relationships prevalence of depression and depressive symptoms among older japanese people: comorbidity of mild cognitive impairment and depression course of depressive symptoms and associated factors in people aged 65+ in europe: a two-year follow-up depressive symptoms and associated factors in institutionalized elderly prevalence of depressive symptoms and its associated factors in older adults: a cross-sectional study in kathmandu prevalence of depressive symptoms and factorial invariance of the center for epidemiologic studies (ces-d) depression scale in a group of mexican indigenous population does mode of contact with different types of social relationships predict depression in older adults? evidence from a nationally representative survey the psychological impact of quarantine and how to reduce it: rapid review of the evidence mental health outcomes of quarantine and isolation for infection prevention: a systematic umbrella review of the global evidence the psychological impact of quarantine on coronavirus disease 2019 (covid-19) loneliness, depression and sociability in old age perceived social isolation makes me sad: 5-year cross-lagged analyses of loneliness and depressive symptomatology in the chicago health, aging, and social relations study social isolation, loneliness and health among older adults being all alone makes me sad": loneliness in older adults with depressive symptoms social support deficits, loneliness and life events as risk factors for depression in old age. the gospel oak project vi the prevalence and predictors of severe depression among the elderly in malaysia associations between loneliness, depressive symptoms and perceived togetherness in older people does intergenerational social support influence the psychological well-being of older parents? the contingencies of declining health and widowhood perceived family and friend support and the psychological well-being of american and chinese elderly persons worry about not having a caregiver and depressive symptoms among widowed older adults in china: the role of family support intergenerational relationship, family social support, and depression among chinese elderly: a structural equation modeling analysis effects of parental rejection and relationship quality on depression among older rural adults publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the research team of charls are acknowledged for their work. authors' contributions yx conducted data analysis and is a major contributor in writing the manuscript. mm contributed in raw data processing, software application, and writing the manuscript. ww performed part of raw data processing, revised the manuscript. ypz and ytz revised the manuscript. xt designed and was responsible for the study. all authors read and approved the final manuscript. none. the datasets analysed during the current study are available in the charls repository: http://charls.pku.edu.cn/index/en.html. the authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the helsinki declaration of 1975, as revised in 2008. not applicable. the authors declare that they have no competing interests. key: cord-333808-deifddar authors: mcgregor, bradley a; vidal, gregory a; shah, sumit a; mitchell, james d; hendifar, andrew e title: remote oncology care: review of current technology and future directions date: 2020-08-31 journal: cureus doi: 10.7759/cureus.10156 sha: doc_id: 333808 cord_uid: deifddar cancer patients frequently develop tumor and treatment-related complications, leading to diminished quality of life, shortened survival, and overutilization of emergency department and hospital services. outpatient oncology treatment has potential to leave cancer patients unmonitored for long periods while at risk of clinical deterioration which has been exaggerated during the covid19 pandemic. visits to cancer clinics and hospitals risk exposing immunocompromised patients to infectious complications. remote patient reported outcomes monitoring systems have been developed for use in cancer treatment, showing benefits in economic and survival outcomes. while advanced devices such as pulmonary artery pressure monitors and implantable loop recorders have proven benefits in cardiovascular care, similar options do not exist for oncology. here we review the current literature around remote patient monitoring in cancer care and propose the use of reliable devices for capturing and reporting patient symptoms and physiology. cancer is a leading cause of morbidity and mortality in the united states, with over 1.8 million new cancer diagnoses and more than 600,000 cancer deaths estimated for 2020 [1] . furthermore, cancer care significantly impacts the overall healthcare system through high rates of emergency department utilization, hospital admission, and costly treatments whose toxicities have potential to diminish quality of life [2] [3] [4] . cancer patients frequently experience local and systemic symptoms causally related to their malignancy. local symptoms are due to direct complications of the primary tumor or metastases and can include pain, neurological deficits, respiratory symptoms (cough, shortness of breath, hemoptysis) and obstruction (bowel, biliary, airway). systemic complications include cachexia, paraneoplastic syndromes, electrolyte abnormalities, metabolic alterations, and hematologic changes. these symptoms are a frequent cause of hospitalization. in a series reported by numico et al., 74% of hospitalizations of cancer patients were for conditions related to tumor involvement, with a minority for workup or treatment-related complications. the most common symptoms at the time of admission were dyspnea, pain, neurological (not specified by authors), fever, and gastrointestinal (vomiting, jaundice) [5] . identifying and addressing cancer symptom burden prior to the need for admission is recognized as a critical need and has led to increased utilization of patient-reported outcome (pro) tools discussed in detail below. in addition to tumor-related morbidity, cancer patients suffer treatment-related complications. given the myelosuppressive nature of radiation and chemotherapy, anemia, neutropenia, and thrombocytopenia with associated malaise, infection, and bleeding can occur. one of the most serious complications, neutropenic sepsis, is associated with up to 50% mortality rate, average hospital cost of over $49,000, and total expenditures of $1.1 billion per year in the us [6, 7] . less severe though far more prevalent toxicities such as nausea, vomiting, and diarrhea can have a large negative impact leading to volume depletion, metabolic and electrolyte imbalances and renal failure. newer immunotherapies are associated with immunerelated adverse events with unpredictable timing and vagueness of symptoms, making identification and management especially challenging [2] [3] [4] . modern technology can increase patients' connectivity to the healthcare system through mobile communications and remote physiologic monitoring [8] . monitoring systems have been used most extensively for cardiovascular diseases such as congestive heart failure (chf) and arrhythmia detection. for patients that require long-term monitoring for either of these, implantable devices like cardiomems™ and implantable loop recorders (ilr) have been shown to decrease rates of hospitalization, improve arrhythmia detection, and lower costs compared with usual care [9, 10] . in oncology, while implantable devices are not available, studies have shown that monitoring patient-reported outcomes reduces visits to the emergency department, decreases follow-up costs and improves overall survival [11] [12] [13] [14] . since the outbreak of a novel sars-cov-2 in 2019 (covid-19), the term "social distancing" has entered the common lexicon. however, social distancing has been a mainstay of oncologic care for decades as immunosuppressed cancer patients take precautions to minimize risk of infections. patients are instructed to eliminate interactions with sick contacts and avoid large gatherings. yet at the same time, patients attend frequent visits to outpatient cancer centers for clinical evaluations. for a neutropenic patient, each visit poses a risk for infectious exposure. the latter is further magnified since the onset of the covid-19 pandemic. as a result, the centers for medicare and medicaid services (cms) has broadened its coverage of telehealth services under the 1135 waiver authority and coronavirus preparedness and response supplementation appropriation act, which has significantly expanded the volume of patients receiving care via telemedicine [15] . though this has reduced oncology patients' infectious exposure, it has created the dilemma for laboratory and vital sign monitoring for patients at risk for drug-induced toxicities. tools that facilitate social distancing while maintaining connectivity to the healthcare system and providing objective data for ongoing management are urgently needed [16, 17] . representative prospective randomized studies of remote and/or electronic pro in cancer care are summarized in table 1 . pro-ctcae™ (patient-reported outcomes version of the common toxicity criteria for adverse events) is a validated tool used to monitor and report toxicities related to cancer treatment in clinical trials. basch et al. reported results from a prospective randomized study from memorial sloan kettering cancer center evaluating the efficacy of an online symptom reporting tool [13, 14] . a total of 766 patients with advanced solid tumors undergoing systemic cytotoxic chemotherapy were randomized to either an online symptom reporting platform or usual care. in the experimental arm, patients received weekly email prompts to report on 12 common treatment-related toxicities through a web-based portal called symptom tracking and reporting (star). a severe or marked change in symptom reporting prompted an email alert to an oncology nurse; summary reports were made available to the treating physician at the time of clinical visits. over the course of the study, the star platform was associated with an improvement in health-related quality of life scores (34% vs 18%, p < 0.001), with fewer visits to the emergency department (34% vs 41%, p = 0.02) compared to standard of care. median overall survival was also 20% longer in the pro arm (31.2 months vs 26.0 months, p = 0.04). the authors proposed that the mechanism of improved survival was related to early interventions including active remote symptom management, supportive medications, chemotherapy dose modifications, and referrals for specialty consultation that prevented downstream consequences. additionally, the pro group was able to tolerate continuation of chemotherapy for a longer duration (8.2 months vs 6.3 months, p = 0.002). [12] . one of the earliest uses of patient-driven technology to monitor outcomes was the cancer care monitor used by the west clinic, memphis, tn, in 2003 [27] . prior to each scheduled oncology visit, patients would report their symptoms on computers and later digital tablets (patient care monitoring) [28] . this validated survey was used to support a web and mobile-based application prospectively applied to postmenopausal women starting new anti-hormonal therapy to assess whether this tool would improve symptom burden and medication adherence [29] . of significance, this application was able to increase medication adherence at eight weeks, when complimented with weekly reminders (100% vs 75%, p < 0.05). additional ongoing prospective randomized trials evaluating remote patient monitoring and patient reported outcomes in oncology are summarized in table 2 . in the united states, the symptom management implementation of patient reported outcomes in oncology (simpro) study aims to enroll 18,000 patients with thoracic, gastrointestinal, and gynecologic malignancies. patients randomized to the intervention arm will enter symptom data into the mobile electronic symptom management system (esym). the primary outcome is 30-day emergency department treat and release rate as measured through medical record abstraction [30] . an additional ongoing us study, the thrive study, is a prospective, randomized trial evaluating a web-enabled application to improve adherence to hormonal therapy in women with breast cancer. the study will randomize 300 patients into three separate arms: 1. a group that receives weekly reminders through the application, 2. a group that receives weekly reminders and tailored feedback, and a usual care group. the primary endpoint is medication adherence as determined using an electronic pillbox [31] . [32] . the primary outcome is measurement of symptom burden, with secondary outcomes including quality of life, supportive care needs, anxiety, self-care self-efficacy, work limitations, cost effectiveness, and changes in clinical practice in response to pro data. a similar study is being undertaken in australia for hematologic malignancies utilizing the patient remote intervention and symptom management system (prisms), a computer tablet-based software system that prompts patients to enter twice daily data regarding physical and emotional symptoms [33] . the prisms study aims to enroll 222 patients undergoing chemotherapy for chronic lymphocytic leukemia (cll), hodgkin's lymphoma, and non-hodgkin's lymphoma (nhl) in two australian hospitals. the primary outcome focuses on symptom burden due to nausea, mucositis, constipation, and fatigue. ubiquitous smartphones and miniaturization of sensor and communication technology has led to enormous data gathering enterprises in consumer and healthcare markets. smartphone accelerometers, gps tracking, and high-resolution cameras are critical to fitness and wellness applications but also as diagnostic tools such as remote skin cancer detection. these same devices when combined with subjective pro feedback can be used to guide patient care or provide prognostic data. performance status (ps), commonly measured using the karnofsky or eastern cooperative oncology group (ecog) ps scale, is one of the strongest predictors of cancer survival outcomes and risk of treatment toxicity. patients with a compromised ps have higher risks of morbidity and mortality, but current clinical ps assessments, despite their critical role in clinical trials, are limited by subjectivity and high rates of interobserver variability [39] [40] [41] . many consumer and medical wearables contain three-axis accelerometers and three-axis gyroscopes, providing continuous readings of individual movement which holds significant promise as a means of overcoming the current limitations of physician identified performance status. gresham et al. evaluated the feasibility of using activity data from fitbit charge hr® wearable devices as a surrogate for ps in 37 patients with cancer, 92% of whom had stage iv disease [42] . they reported high correlations between average daily step counts and ecog-ps (r = 0.63); each increase in daily step count by 1000 was associated with a significant decrease in adverse events, hospitalization, and hazard for death. strong correlation was also reported between these activity metrics and pro data. subsequent systematic review of published studies evaluating the use of activity tracking in cancer care identified 41 trials including active cancer patients and those undergoing follow-up and survivorship care [43] . most trials included breast cancer patients (65%) and focused on exercise (54%) or behavioral (29%) interventions. twelve trials evaluated daily step counts, and the reported steps per day were slightly lower in patients on active cancer therapy (2885 to 8300 steps/day) compared to survivors (4660 to 11,000 steps per day). no studies included implantable monitoring devices. while pro platforms and wearable technology have potential to improve care, implementation in the clinic faces many challenges. web-based pro platforms rely on patient engagement, which can be increasingly problematic in an aging cancer population with less familiarity with technology. furthermore, waiting for patients to report symptoms lacks a proactive preventative solution. with regards to wearable technology, most studies demonstrate feasibility, however patient adherence remains a major limitation. seventeen of the studies included in the gresham systematic review reported adherence data, but adherence was defined differently in most studies [43] . the most commonly reported adherence metric was three consecutive days of activity tracking (range: 3-7 consecutive days), with a valid wear time as 5 to 10 hours per day. these definitions of adherence leave large gaps in time where no data is gathered or reported, limiting the ability to produce high fidelity analytics and accurate diagnostic tools. additionally, for cancer patients facing several months of therapy, three to seven consecutive days of activity tracking does not represent reliable monitoring through the duration of treatment and follow-up. dreher et al. demonstrated similar adherence limitations in a study of fitbit® use in breast cancer patients, stating, "adherence to wearing the fitbit was low, with 16.9% of patients never syncing their device." for patients who did sync their devices, the median number of valid activity tracking days (defined as > 10 hours of use) during the 9-month duration of the study was only 44.5% (median = 39.6%, range 0% -100%) [44] . even the much-publicized apple watch® atrial fibrillation study, a population consisting of apple watch® owners, showed poor adherence with only 21% of those who received an irregular pulse notification initiating the first indicated visit [45] . the studies utilizing wearable technology in oncology care demonstrate the importance of objective data gathering, but also highlight the limitations of systems that rely on patient adherence. alternatively, the studies involving cardiac referenced in the introduction show significant benefits associated with the reliable and continuous monitoring from implantable sensor technology, including disease control, survival, and economic endpoints. representative ongoing early phase or pilot studies evaluating emerging digital technology in cancer care are summarized in table 3 . emerging research shows benefits in outcomes and costs of cancer care through use of remote monitoring technology especially electronic patient reported outcomes (epro). however, broad clinical adoption has been limited by a lack of commercially available oncology specific solutions, concerns about reimbursement, and limitations associated with low patient adherence. a preferred solution would securely and reliably gather digital physiologic data without requiring patient activation, much like pulmonary artery pressure monitors and implantable loop recorders in cardiology. additionally, such a system would contain mobile patient engagement and epro tools that could be tied to existing reimbursement framework facilitating rapid adoption. powerful analytic tools including machine learning and artificial intelligence could then be applied to identify early signs of common complications and provide individual patient health and risk profiles, allowing oncologists to make more informed and personalized treatment recommendations. the use of an implantable device in oncology has already been explored, as oncologic cardiologists at md anderson cancer center have utilized implantable loop recorders and cardiomems® to monitor patients at high risk of complications from cardiotoxic systemic therapy, but data regarding safety and efficacy is lacking [46] . to our knowledge, oncodisc, a san francisco-based medical technology start-up, is the only company developing implantable monitoring technology and mobile epro solutions for oncology. the oncodisc device, an intelligent implantable vascular access port, takes advantage of existing oncology workflow and a common minimally invasive procedure with established reimbursement. the current covid-19 pandemic has highlighted the need for reliable connected systems to facilitate home care while reducing hospitalizations and clinic visits, especially in immunocompromised cancer patients. early studies show significant benefits to pro-based systems, including lower costs and prolongation of survival. further advances in sensor technology and mobile communications hold great promise for improving cancer outcomes while at the same time reducing costs. however, widespread adoption has been hampered by a lack of commercially available solutions. to that end, implantable physiologic sensor systems and associated data analytic tools, akin to those used in cardiovascular care, should be researched for oncology. cancer stat facts: cancer of any site hospitalizations during systemic therapy for metastatic lung cancer: a systematic review of real world vs clinical trial outcomes impact of observation status on hospital use for patients with cancer hospitalisations and emergency department visits in cancer patients receiving systemic therapy: systematic review and metaanalysis hospital admission of cancer patients: avoidable practice or necessary care mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients treatment-related complications of systemic therapy and radiotherapy the future of wearable technologies and remote monitoring in health care sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the champion randomised trial cryptogenic stroke and underlying atrial fibrillation two-year survival comparing web-based symptom monitoring vs routine surveillance following treatment for lung cancer cost-effectiveness of web-based patient-reported outcome surveillance in patients with lung cancer overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment symptom monitoring with patient-reported outcomes during routine cancer treatment: a randomized controlled trial cancer patient care during covid-19 managing cancer care during the covid-19 pandemic: agility and collaboration toward a common goal coronavirus: what people with cancer should know automated home monitoring and management of patient-reported symptoms during chemotherapy: results of the symptom care at home rct enhancing patient-provider communication with the electronic self-report assessment for cancer: a randomized trial automated symptom alerts reduce postoperative symptom severity after cancer surgery: a randomized controlled clinical trial a randomized trial of the electronic lung cancer symptom scale for quality-of-life assessment in patients with advanced non-small-cell lung cancer the effect of real-time electronic monitoring of patient-reported symptoms and clinical syndromes in outpatient workflow of medical oncologists: e-mosaic, a multicenter cluster-randomized phase iii study (sakk 95/06) electronic self-report assessment for cancer and selfcare support: results of a multicenter randomized trial effects of an internet support system to assist cancer patients in reducing symptom distress: a randomized controlled trial a mobile app to stabilize daily functional activity of breast cancer patients in collaboration with the physician: a randomized controlled clinical trial web-based collaborative care intervention to manage cancer-related symptoms in the palliative care setting validation of the cancer care monitor items for physical symptoms and treatment side effects using expert oncology nurse evaluation the patient care monitor-neutropenia index: development, reliability, and validity of a measure for chemotherapy-induced neutropenia use of a webbased app to improve breast cancer symptom management and adherence for aromatase inhibitors: a randomized controlled feasibility trial symptom management implementation of patient reported outcomes in oncology (simpro) thrive study protocol: a randomized controlled trial evaluating a web-based app and tailored messages to improve adherence to adjuvant endocrine therapy among women with breast cancer the esmart study protocol: a randomised controlled trial to evaluate electronic symptom management using the advanced symptom management system (asyms) remote technology for patients with cancer the patient remote intervention and symptom management system (prisms) -a telehealth-mediated intervention enabling real-time monitoring of chemotherapy side-effects in patients with haematological malignancies: study protocol for a randomised controlled trial the hope trial: helping our patients excel home telemonitoring for patients with lung cancer (htplc) self-monitoring and reminder texts to increase physical activity after cancer ii (smartpaceii) electronic patient self-reporting of adverse-events: patient information and advice (erapid): a randomised controlled trial in systemic cancer treatment effects of an interactive mhealth innovation for early detection of patient-reported symptom distress with focus on participatory care: protocol for a study based on prospective, randomised, controlled trials in patients with prostate and breast cancer extent and determinants of error in doctors' prognoses in terminally ill patients: prospective cohort study observer error in grading performance status in cancer patients performance status score: do patients and their oncologists agree? wearable activity monitors to assess performance status and predict clinical outcomes in advanced cancer patients wearable activity monitors in oncology trials: current use of an emerging technology fitbit usage in patients with breast cancer undergoing chemotherapy large-scale assessment of a smartwatch to identify atrial fibrillation implantable devices track cardiac events in cancer patients in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. key: cord-354702-hi4nxf67 authors: laszkowska, monika; faye, adam s.; kim, judith; truong, han; silver, elisabeth r.; ingram, myles; may, benjamin; ascherman, benjamin; bartram, logan; zucker, jason; sobieszczyk, magdalena e.; abrams, julian a.; lebwohl, benjamin; freedberg, daniel e.; hur, chin title: disease course and outcomes of covid-19 among hospitalized patients with gastrointestinal manifestations date: 2020-09-30 journal: clin gastroenterol hepatol doi: 10.1016/j.cgh.2020.09.037 sha: doc_id: 354702 cord_uid: hi4nxf67 background & aims our understanding of outcomes and disease time course of covid-19 in patients with gastrointestinal (gi) symptoms remains limited. in this study we characterize the disease course and severity of covid-19 among hospitalized patients with gastrointestinal manifestations in a large, diverse cohort from the unites states. methods this retrospective study evaluated hospitalized individuals with covid-19 between march 11 and april 28, 2020 at two affiliated hospitals in new york city. we evaluated the association between gi symptoms and death, and also explored disease duration, from symptom onset to death or discharge. results of 2,804 patients hospitalized with covid-19, the 1,084 (38.7%) patients with gi symptoms were younger (aor for age≥75 0.59, 95% ci 0.45-0.77) and had more co-morbidities (aor for modified charlson comorbidity score ≥2 1.22, 95% ci 1.01-1.48) compared to those without gi symptoms. individuals with gi symptoms had better outcomes, with a lower likelihood of intubation (ahr 0.66, 95% ci 0.55-0.79) and death (ahr 0.71, 95% ci 0.59-0.87), after adjusting for clinical factors. these patients had a longer median disease course from symptom onset to discharge (13.8 vs. 10.8 days, log-rank p=0.048; among 769 survivors with available symptom onset time), which was driven by longer time from symptom onset to hospitalization (7.4 vs. 5.4 days, log-rank p<0.01). conclusion hospitalized patients with gi manifestations of covid-19 have a reduced risk of intubation and death, but may have a longer overall disease course driven by duration of symptoms prior to hospitalization. the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is the viral pathogen responsible for causing coronavirus disease 2019 (covid19) , a pandemic that has spread rapidly, infecting over 14 million people globally and causing over 600,000 deaths to date. 1, 2 while the hallmark of this infection is severe respiratory illness, involvement of other organ systems, including the gastrointestinal tract, has been documented. reports have been mixed, showing anywhere from 11 to 63% of hospitalized patients have at least one gastrointestinal (gi) symptom. [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] furthermore, sars-cov-2 nucleic acid has been identified in stool samples and on endoscopic biopsies, and absorptive enterocytes in the ileum and colon have been found to highly express angiotensin converting enzyme 2 receptors, which are critical for viral cell entry. [13] [14] [15] [16] [17] [18] [19] these findings indicate that the gi system may be a route for transmission and a moderator of both symptom manifestation and outcomes. nonetheless, our understanding of the prognostic implications of gi manifestations, particularly diarrhea, on outcomes has been inconsistent. 20 some studies suggest gastrointestinal symptoms may convey increased risk of poor outcomes, 4, 21 while others show no association or a potential protective association. [6] [7] [8] [9] these studies vary in their inclusion criteria, ascertainment of gi symptoms, and definitions of severity of disease course. 18, 22, 23 a recent case-control study from our center showed that patients hospitalized with gi manifestations had lower rates of death and were more likely to have a length of stay over 1 week; however, like other early reports of gi symptoms, it did not account for the potential impact of factors such as age and comorbidities on mortality, and did not assess the overall time course of disease from symptom onset to death or discharge. [6] [7] [8] [9] most reports on outcomes j o u r n a l p r e -p r o o f globally have assessed the impact of gi symptoms on incidence of severe disease, rather than mortality. 4, 21 furthermore, small studies from china have assessed how time-course of disease is impacted by presence of gastrointestinal symptoms, and some suggest presence of diarrhea may be associated with prolonged symptoms. 4, 11, 19, 24 here, we aimed to further characterize the duration and severity of covid-19 among hospitalized patients with gastrointestinal manifestations in a large, diverse cohort from new york city. we hypothesized that the presence of gastrointestinal symptoms could portend a milder disease phenotype, but longer disease time course, potentially due to differences in inflammatory response. this retrospective study at two affiliated academic hospitals (columbia university irving medical center, allen hospital) includes consecutive hospitalized patients who underwent testing for covid-19 from march 11, 2020 (when institution-based testing began) to april 28, 2020, and includes a small percentage of patients described in our center's prior report (<8%). 6 demographic data, clinical symptoms, laboratory findings, comorbidities, treatment, and outcome data were collected from electronic medical records. data on symptoms at the time of presentation were obtained using natural language processing algorithms applied to chart documentation, implemented in python. presence and absence of various iterations of specific symptoms including fever, fatigue, dizziness, headache, cough, sore throat, congestion, rhinorrhea, shortness of breath, nausea, vomiting, diarrhea, and abdominal pain were systematically identified in emergency room evaluation and admission notes, including in the history of present illness, chief complaint, review of systems, and assessment. the algorithm parsed relevant full text notes and was systematically refined based on chart review to include variations on spelling and phrasing of individual symptom keywords to ensure accurate capture of data. algorithm extraction was then validated by investigators blinded to the outcomes of the study, who performed manual review of 1,053 charts of the total 2,804 covid-19 positive patients. data for symptom documentation between algorithm extraction and manual review was >90% concordant for individual gi symptoms. exposure to covid-19 treatments during the j o u r n a l p r e -p r o o f course of the hospitalization were also recorded, including steroids (prednisone, methylprednisolone, and dexamethasone), hydroxychloroquine, azithromycin, remdesivir, and tocilizumab. patients were considered exposed if they received at least one dose of a given treatment. continuous variables were expressed as medians and interquartile ranges, with wilcoxon rank-sum test used to assess differences in distributions between the groups. categorical variables were summarized as counts and percentages, with chi-square or fisher's exact tests used for comparison. univariable and multivariable regression analyses were done to compare characteristics of patients with and without gi symptoms in covid-19. a modified charlson comorbidity index was utilized in multivariable models, which incorporated weighted values of all components of the index (myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, connective tissue disease, peptic ulcer disease, diabetes mellitus, chronic kidney disease, hemiplegia, leukemia, lymphoma, solid tumor, liver disease, and aids) but excluded age since it was included separately in our model. cox proportional hazard models were used to assess the association between gastrointestinal symptoms and 30-day rate of intubation and death, adjusting for age, sex, body mass index, co-morbidities, and presence of respiratory and constitutional symptoms. in a subgroup of patients with available data on timing of symptom onset, kaplan-meier analysis was used to assess overall duration of illness, as well as time from symptom onset to admission and time from admission to discharge or death, stratified by the presence of gi symptoms. patients with unknown symptom onset time as well as one outlier with a reported j o u r n a l p r e -p r o o f symptom duration over 3 months were excluded for this part of the analysis. symptom onset prior to hospitalization was censored at 14 days to limit recall bias and ensure symptoms were likely associated with having covid-19. for all analyses, an alpha of 0.05 was considered statistically significant, with calculations performed in stata 16 (stata corp, college station, tx). this study was approved by the institutional review board of columbia university medical center. from march 11 th to april 28 th , there were a total of 4,670 individuals who were hospitalized and tested for the sars-cov-2 virus, including 2,804 (60.0%) who tested positive. among these, 1,084 (38.7%) reported any gastrointestinal (gi) symptoms on presentation, including diarrhea (n=657, 23.4%), nausea/vomiting (n=648, 23.2%), and abdominal pain (n=334, 11.9%; supplemental table 1 ). on univariable analysis ( table 1) , patients with gi symptoms were more likely to be younger (p<0.01) and have a higher bmi (p<0.01), though there were no significant differences in sex/gender (p=0.18), race/ethnicity (p=0.63), or in underlying comorbidities, other than a slightly higher proportion of patients with a history of stroke presenting without gi symptoms (9% compared to 6%, p=0.01; all other p values>0.05). more patients with gi symptoms had diverticular disease compared to those without (2% compared to 0.5%, p<0.01), though there was no difference among individuals with inflammatory bowel disease or irritable bowel syndrome on univariable analysis. on multivariable analysis ( table 2) , age ≥75 years (aor 0.59, p<0.01) was associated with a lower odds of gi symptoms at presentation, whereas an increased number of co-morbidities (aor 1.22, p=0.04 for modified charlson comorbidity score j o u r n a l p r e -p r o o f ≥2) was associated with a higher odds of having gi symptoms at presentation. furthermore, presence of an underlying gi disease including diverticular disease, irritable bowel syndrome, and inflammatory bowel disease was associated with a significantly higher odds of presenting with gi symptoms (aor 3.04, p<0.01). male sex (p=0.08) and bmi (all p values>0.49) were not associated with gi symptoms at presentation on multivariable analysis. of note, some of these differences such as extent of lymphopenia probably have limited clinical relevance despite being statistically significant. patients presenting with gi symptoms had better outcomes than those without gi symptoms, including significantly lower rates of intubation (17% vs. 22%, p<0.01) and lower rates of death (15% vs. 23%, p<0.01; table 1 ). on kaplan-meier survival analysis, those presenting with gastrointestinal symptoms had a significantly longer median time to death (7.5 vs. 4.9 days, p<0.01) and lower rate of death than those without (log-rank p<0.01; figure 1 ). this persisted on cox proportional hazards analysis (ahr 0.71, p<0.01; table 3 table 2 ). next, we explored whether the presence of gi symptoms was associated with differences in disease time course among 945 covid-19 patients with known symptom onset time. we conducted a time to event analysis looking at how the duration of time between symptom onset and discharge varied. those who survived (n=769) with gi symptoms had a significantly longer median disease course than those surviving without gi symptoms (13.8 vs. 10.8 days respectively, log-rank p=0.048; figure 2a) . this was largely driven by longer median time from symptom onset to admission (7.4 vs. 5.4 days, log-rank p<0.01; figure 2b ), rather than median length of stay (5.7 vs. 4.8 days, log-rank p=0.25; figure 2c ). although patients with gi symptoms who died also had a longer course of disease as compared to patients without gi symptoms who died, the result was not statistically significant (13.5 vs. 9.1 days, p-value=0.08). in this study, we found that hospitalized individuals with covid-19 who presented with gastrointestinal symptoms of diarrhea, nausea, vomiting, or abdominal pain were younger but had more co-morbidities than those presenting without gi symptoms. individuals with gi symptoms had better outcomes than those without gi symptoms, including lower rates of intubation and death, even after adjusting for other relevant predictors such as age and comorbidities on multivariable analysis. patients with gi symptoms also had a longer time-course of disease from symptom onset to discharge, which was largely driven by longer pre-hospital duration (from symptom onset to admission) rather than length of stay. one possible explanation for this longer but more indolent disease course in individuals with gi symptoms is that such patients may have less systemic inflammation secondary to covid-19. we demonstrated that patients with gi symptoms had lower inflammatory markers on laboratory testing, including significantly lower c-reactive protein, d-dimer, and lactate dehydrogenase, and trends towards lower erythrocyte sedimentation rates. these individuals were also less likely to have a leukocytosis. while further research is needed to elucidate the role of specific biomarkers in predicting severity of disease, we hypothesize that a lower degree of inflammation may modulate rates of adverse outcomes such as intubation and death, but the impaired immune response may result in a longer time to clear the virus, resulting in prolonged duration of illness. in contrast, some prior studies have suggested gastrointestinal symptoms may convey increased risk of poor outcomes. 4, 21 this discordance in findings may be due to differences in inclusion criteria, small size of prior studies, as well as differences in the symptoms that were assessed. for example, a study by wan et al only assessed the impact of diarrhea, but not other gastrointestinal symptoms. 21 furthermore, patients were admitted with symptoms such as fever, cough, or dyspnea or ct scan abnormalities, but not necessarily a requirement for supplemental oxygen which was included in admission criteria at our institution during the height of the pandemic. data regarding inflammatory markers corresponding to gastrointestinal symptoms have also been discordant. as such, individuals with diarrhea in the study by wan et al (n=84) had higher esr but no difference in crp or d-dimer, whereas no difference in inflammatory markers was seen in a small us study by redd et al (n=318) . 7, 21 it is possible that we were able to detect this difference given the larger size of our study. additionally, in this study we demonstrated that individuals with gi symptoms have a longer disease course, which is largely driven by the duration of symptoms prior to j o u r n a l p r e -p r o o f hospitalization. while this may raise concerns about a delayed diagnosis of disease in this population, the fact that they have better outcome suggests that gi symptoms may instead be a marker of more indolent disease, or disease more localized to the gi tract. while these individuals may not need to present earlier for admission, it may be important to recognize and test them early in their disease course given concerns of potential outpatient fecal transmission and infectious spread. 25, 26 in addition, other studies have shown more familial clustering of disease among individuals with gi symptoms. 4 this further emphasizes the importance of early recognition and testing in this population, which remains symptomatic at home longer, to limit spread. to date, this is the largest study in the us to assess outcomes in covid-19 positive patients with gi symptoms. our findings complement the findings of several other recent publications. a prior case-control study from our institution suggested that patients hospitalized with diarrhea, nausea, and vomiting had lower rates of death. 6 another study from a large center in new york city found that individuals with gi symptoms of diarrhea, abdominal pain, and nausea/vomiting had significantly lower rates of death on univariable analysis (but not on multivariable analysis, though this analysis was for the composite outcome of intensive care unit admission and death). 8 studies from china have also shown that patients with digestive symptoms have a longer time of symptom onset to admission, and have a longer duration between symptom onset and viral clearance, supporting our findings. 24 notably, other studies have reported conflicting implications of gi manifestations for disease severity. inconsistencies in these reports are likely due to the heterogenous nature in which gastrointestinal manifestations and disease severity have been defined and ascertained. 7, 9, 23 for example, studies may have been j o u r n a l p r e -p r o o f confounded by use of antivirals with gastrointestinal side effects, and many utilized different variations of composite outcomes without examining mortality specifically. 4, 21 our study has many strengths. first, it is the largest study characterizing outcomes in individuals with gi manifestations of covid-19. we utilized a large dataset from an academic institution at the epicenter of the covid-19 pandemic in new york city, which represents a diverse population with robust data across many demographic and clinical variables. this is the first study to assess the impact of gastrointestinal symptoms on mortality after adjusting for other relevant clinical factors such as age and comorbidities. furthermore, this study was the first to document the timeline from symptom onset to hospitalization in a us cohort. these data provide key insights into the clinical presentation of an indolent phenotype of disease, and further research to understand the mechanisms driving this phenotype will help identify those at highest risk for complications of this disease. our study does have limitations. first, symptom reporting is limited by recall bias of individual patients, as well as ascertainment bias among providers. to mitigate this, we utilized a natural language processing algorithm to flag symptom reporting across provider documentation between diarrhea and severe outcomes. in addition, details regarding attributes of specific symptoms, such as frequency and consistency of diarrhea, were not reliably recorded which is a limitation of the data. another limitation is that this analysis only involved hospitalized patients. further research of outpatients with and without gi manifestation may give additional insights into the broader population afflicted with covid-19. finally, our analysis did not account for impact of various investigational treatments on outcome. in conclusion, our study demonstrates that individuals with gastrointestinal symptoms including diarrhea, nausea, vomiting, and abdominal pain have lower rates of intubation and death than those without gi symptoms. these individuals have a more indolent disease course, driven largely by longer time from symptom onset to admission. given the lower inflammatory marker profiles in these patients, it is possible that gi manifestations convey a phenotype of disease with a dampened immune response -potentially improving outcomes but delaying viral clearance. further research is needed to better understand the mechanisms underlying these differences, which may lead to an improved understanding of the natural history and time course of covid-19. covid-19 dashboard world health organization coronavirus disease 2019 (covid-19) situation report -51 clinical characteristics of covid-19 patients with digestive symptoms in hubei, china: a descriptive, cross-sectional, multicenter study epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (covid-19) with gastrointestinal symptoms don't overlook digestive symptoms in patients with 2019 novel coronavirus disease (covid-19) gastrointestinal symptoms and covid-19: case-control study from the united states prevalence and characteristics of gastrointestinal symptoms in patients with sars-cov-2 infection in the united states: a multicenter cohort study gastrointestinal and hepatic manifestations of novel coronavirus disease in a large cohort of infected patients from new york: clinical implications high prevalence of concurrent gastrointestinal manifestations in patients with sars-cov-2: early experience from california prevalence of gastrointestinal symptoms and fecal viral shedding in patients with coronavirus disease 2019: a systematic review and meta-analysis manifestations and prognosis of gastrointestinal and liver involvement in patients with covid-19: a systematic review and meta-analysis don't overlook digestive symptoms in patients with 2019 novel coronavirus disease (covid-19) digestive system is a potential route of covid-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process covid-19 and the gastrointestinal tract: more than meets the eye first case of 2019 novel coronavirus in the united states gastrointestinal symptoms of 95 cases with sars-cov-2 infection evidence for gastrointestinal infection of sars-cov-2 diarrhoea may be underestimated: a missing link in 2019 novel coronavirus diarrhea is associated with prolonged symptoms and viral carriage in corona virus disease diarrhea during covid-19 infection: pathogenesis, epidemiology, prevention, and management enteric involvement in hospitalised patients with covid-19 outside wuhan covid-19 in gastroenterology: a clinical perspective gastrointestinal symptoms associated with severity of coronavirus disease 2019 (covid-19): a pooled analysis. internal and emergency medicine digestive symptoms in covid-19 patients with mild disease severity: clinical presentation, stool viral rna testing, and outcomes. the american journal of gastroenterology transmission of sars-cov-2 via fecal-oral and aerosols-borne routes: environmental dynamics and implications for wastewater management in underprivileged societies sewage monitoring is the uk's next defence against covid-19 j o u r n a l p r e -p r o o f key: cord-342246-tnjtd9n3 authors: özçelik korkmaz, müge; eğilmez, oğuz kadir; özçelik, muhammet ali; güven, mehmet title: otolaryngological manifestations of hospitalised patients with confirmed covid-19 infection date: 2020-10-03 journal: eur arch otorhinolaryngol doi: 10.1007/s00405-020-06396-8 sha: doc_id: 342246 cord_uid: tnjtd9n3 purpose: the aim of our study is to evaluate the incidence and characteristics of otolaryngology symptoms in covid 19 patients. methods: 116 patients with positive pcr test results for covid-19 and followed up by otolaryngologists at a tertiary referral center/covid-19 pandemic hospital were questioned in terms of otolaryngology symptoms associated with covid-19 infection. data including demographics, disease severity, concomitant diseases, previous otolaryngologic diseases,incidence and duration of new onset symptoms were collected and categorically analyzed. in addition, the severity of loss of smell and taste was evaluated by visual analogue score (vas). results: a total of 58 men and 58 women participated. the mean age of the patients was 57.24 ± 14.32 (19–83). the most common otolaryngological findings were hyposmia/anosmia (37.9%) and hypogeusia/ageusia (41.37%), respectively. these complaints were followed by headache (37.1%), and nausea/vomiting (31%). the most common oropharyngeal symptoms were sore throat (32.7%) and dysphagia (20.6%). the rate of otological/vestibular symptoms was dizziness (31.8%), tinnitus (11%), true vertigo (6%), and hearing impairment (5.1%), respectively. the most of symptoms were more frequent in > 60 years and women. there was a significant correlation between nasal itching and smell disturbance in patients with allergic rhinitis. considering the duration of symptoms, the longest were hyposmia/anosmia and hypogeusia/ageusia. the mean vas’s in patients with hyposmia/anosmia and hypogeusia/ageusia were 5.52 ± 2.08 and 5.79 ± 2.21, respectively. conclusion: the most common otolaryngologic symptoms of covid-19 infection are known as sore throat, smell and/or taste disturbances. however, our study showed that these patients can be seen with different symptoms in otological or laryngeal areas. therefore, a more careful evaluation should be made in terms of otolaryngologic symptoms when covid 19 infection is suspected. the coronavirus disease 2019 (covid19) , which is caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), is an ongoing viral pandemic that emerged from the city of wuhan, china and quickly spread to the rest of the world [1] . this outbreak has been responsible for nearly 935,000 deaths worldwide and more than 29 million people have been confirmed as infected so far [2] . the virus is transmitted from human to human via droplet transmission and direct contact with oral, nasal, and eye mucous membranes [3] . studies suggest that covid-19 may become airborne through aerosol-generating clinical procedures [4] . coronaviruses are known to cause diseases of varying severity affecting respiratory, neurological, gastrointestinal, and hepatic organs in animals and humans [4] . the patients with the classical symptoms of covid-19 are easily diagnosed; however, it can be difficult to recognize those without characteristic findings and pose a risk for transmission, thereby causing the disease to last longer and be persistent [5] . according to the clinical reports from asia, the most frequently observed symptoms are cough, fever, sputum production, dyspnea, arthralgia, myalgia, rhinorrhea, sore throat, headache, and diarrhea [6, 7] . since the virus is first transmitted to the body through the upper respiratory tract with droplets, it is unavoidable to encounter otolaryngologic symptoms. the above-mentioned symptoms have been reported and they are the most common findings for covid-19; however, several studies, particularly from europe, have also reported certain chemosensory dysfunction symptoms such as anosmia and ageusia, which are common in covid positive patients [8] . hyposmia can generally be caused by upper respiratory tract infections; however, these symptoms can be present in covid-19 patients without any nasal symptoms, suggesting the direct viral damage to the chemosensory system [9] . considering the neural effects of the virus, it is likely to affect other cranial nerve pairs, including the vestibular and acoustic nerve, and can cause associated symptoms. however, there are not enough publications in the literature on this subject yet. because of the paucity of diagnostic tests in many european countries, data regarding epidemiological factors and clinical presentation of covid-19 positive patients are limited; the reported studies were generally carried out by anamnesis and symptom inquiry [10] . the aim of this study is to evaluate specifically the otolaryngologic symptomatology of covid-19 positive patients followed up in the otolaryngology clinic, to reveal the findings encountered and their frequency, and to investigate whether there are different findings in the turkish population other than those reported in other countries. the present study is a prospective observational cohort study. the study protocol was approved by the ethics committee of one hundred and sixteen patients with covid-19 infection with a positive reverse transcription-polymerase chain reaction (rt-pcr) test result, who were followed up and treated by ear-nose-throat (ent) specialists in a tertiary and pandemic hospital between april and may 2020, were included in the study. the inclusion criteria were being between the ages of 18-90, having no mental or physical defects preventing communication, no previous history of nasal, oropharyngeal or laryngeal surgery, no serious neurological deficit, or no history of the nervous system disease. in addition, patients, who used drugs affecting the vestibular or central nervous system (e.g., sedative and hypnotic drugs such as benzodiazepines, antihistaminic drugs such as betahistine and dimenhydrinate, and anticonvulsant drugs such as phenytoin and carbamazepine), were not included in this study. an informed consent form was obtained from all patients before participating in the study. all of the patients included in this study had positive results of the covid -19 rt-pcr test, which was studied with nasopharyngeal/oropharyngeal swab samples. in addition, clinical findings of all patients, thoracic computed tomography (ct) and / or laboratory tests (hemogram, urea, creatinine, albumin, alanine aminotransferase (alt), aspartate aminotransferase (ast), c-reactive protein (crp), sedimentation, lactate dehydrogenase (ldh), d-dimer, cardiac troponins (tnt / tni), creatine kinase (ck / ck-mb), albumin ferritin) were evaluated to be compatible with sars-cov 2 infection. during the study, the patients, who were transferred to the intensive care unit due to deterioration in their health status were excluded from the study. patients, who continued their current symptoms while discharged from hospital, were then contacted by telephone, and the duration of their symptoms was followed up. in addition to demographic data such as the age and gender of the patients, general data including the concomitant systemic diseases, previous otolaryngologic diseases (perennial/allergic rhinitis, nasal septal deviation, chronic sinusitis, nasal polyps, hearing loss, tinnitus, vestibular disorders), the use of medications, and the length of hospital stay were also recorded. in addition, clinical data (fever, pulse, arterial blood pressure, and oxygen saturation), laboratory tests, and thorax ct results were recorded. the clinical severity was evaluated based on laboratory, radiologic and clinical data. patients were classified as mild (1) or moderate (2) according to the latest who joint report [11] . a questionnaire form that included the otolaryngologic and general manifestations and aimed at questioning the new-onset symptoms was filled in individually for every patient. the onset times of all available symptoms and their durations were questioned and recorded; therefore, the average times for each symptom were calculated (supplemental questionnaire). to evaluate the loss of sense of smell and taste, the visual analogue scale (vas) was used, taking the sample of the american academy of otolaryngology-head and neck surgery covid-19 anosmia reporting tool [12] . individuals were asked to evaluate their ability to smell and taste scoring between 0 (i cannot smell / taste) and 10 (normal). vas score averages of those with loss of smell/taste sensation were then calculated. patients were evaluated in five different categorical groups in terms of age, gender, disease severity, concomitant systemic, and otolaryngologic diseases. they were examined in two subgroups, which were < 60 years and ≥ 60 years in terms of age, mild and moderate in terms of disease severity, yes or no in terms of having a history of concomitant otolaryngologic (nasal, otologic, etc.) disorder, yes or no in terms of concomitant systemic diseases (dm, ht, renal failure, cardiac diseases,respiratory diseases, others). the presence of differences in symptoms and the vas score averages of those with loss of smell/taste sensation were compared in terms of categorical groups. we used descriptive statistics, such as mean, standard deviation (sd), and distribution to analyze patient characteristics. the categorical data were given as numbers (n) and percentages (%). the kolmogorov-smirnov test was performed for the normality distribution analysis; and according to the results, nonparametric tests were conducted. independent sample t test was used for comparing the mean between groups. comparisons between continuing data were analyzed with the mann-whitney test. fisher's exact test and pearson chi square tests were used for the comparison of categorical variables, where p values less than 0.05 were accepted as significant. all statistical analyses were performed using commercial software (ibm spss statistics. version 23.0. armonk. ny: ibm corp). a total of 116 patients consisting of 58 males (50%) and 58 females (50%) were included in the study. the mean age of the patients was 57.24 ± 14.32 (min 19-max 83). the patients were grouped in terms of age, where 62 people (53.4%) were under the age of 60, 54 people (46.6%) were in the group over 60. there was no statistical difference in terms of gender and mean age between groups (p > 0.05 for both). the average length of hospital stay was 14.36 6.42 days. thorax ct scans with unilateral or bilateral findings compatible with covid 19 pneumonia such as consolidation, frosted glass opacities, crazy paving patterns, and linear opacities were found in 48% of the patients. while 59 (50.9%) of the patients did not have any concomitant systemic diseases, 57 (19.8%) people had one or more concominant diseases. the severity of covid-19 infection was mild in 83 (71.5%) and moderate in 33 patients (28.4%). while 89 (76.7%) patients had no previous otolaryngologic disease, 14 (12. 1%) had perennial/seasonal allergic rhinitis, 8 (6.9%) had sinonasal problems, 3 (2.5%) had hearing loss/ tinnitus, and 2 (1.7%) had vestibular problems (table 1) . information on the frequency of symptoms is given in fig. 1 . the most common general findings were dry cough (53.4%), dyspnea (38.8%), headache (37%) and nausea/ vomiting (31%). in terms of otolaryngological symptoms these complaints were followed by hypogeusia/ageusia (41.3%) and hyposmia/anosmia (37.9%). symptoms related to pharynx/larynx such as sore throat, dysphagia, voice impairment and globus sensation were detected in 32.7%, 20.6%, 19.8%, and 13.7%, respectively. nasal symptoms were the least often symptoms encountered by the patients. nasal obstruction was observed in 27.5% of the patients, rhinorrhea in 13.7%, and sneezing/nasal itching in 12.9%. considering the distribution of otologic / vestibular symptoms, the rates were as follows; dizziness (31.8%), tinnitus (11.2%), hearing impairment (5.2%) and true vertigo (6.1%). ocular complaints were present in 17.2% of patients. high fever occurred in 27.5% of the patients. the relation of symptoms in terms of age, gender, the severity of the disease, concomitant systemic diseases, previous otolaryngologic diseases (perennial/seasonal allergic rhinitis) are given in table 2 . when the patients were grouped in terms of age, it was found that many symptoms such as tinnitus, true vertigo, headache, smell/taste impairment, sore throat and voice impairment were statistically significant common in patients under 60 years of age (p < 0.05 for each). dyspnea and cough were more common in patients over 60 years. in terms of gender distribution, the rate of dizziness, headache, smell/taste impairment, sore throat, and voice complaints were statistically significant higher in women. when evaluated according to the clinical severity of covid-19 infection, there was no statistically significant difference between other findings except nausea/ vomiting, cough and dyspnea which were higher in the moderate group. the symptoms of nasal itching and hiposmia/ anosmia were statistically significantly higher in patients with concomitant otolaryngologic diseases (p < 0.05). ten of 15 patients with nasal itching and 12 of patients with smell loss had a history of seasonal allergic rhinitis. in terms of comorbidities, the incidence of headache was higher in patients with hypertension / hypertension + diabetes mellitus. again, dyspnea was higher in patients with chronic respiratory disease. no statistically significant difference was found between patients with and without concominant systemic disease in terms of other symptoms (table 3) . when the vas scores regarding the sense of smell and taste were examined, the mean vas was 5.52 ± 2.08 (min 0-max 8) for those who stated hyposmia/anosmia, and 5.79 ± 2.21 (min 0-max8) for those who stated that they had hypogeusia/ ageusia. accordingly, the average vas scores in the group 60 years and older were found to be statistically significantly lower in the evaluation of the vas averages among the categories in patients with hyposmia/anosmia and hypogeusia/ ageusia (p < 0.05). in other groupings, no statistically significant difference was found in terms of vas averages. data on the maximum, minimum and median duration of the symptoms over a period of 30 days are shown in fig. 2 . accordingly, the longest-onset otolaryngologic symptom was found to be symptoms related to taste and smell. there was no statistically significant difference between the other symptom duration averages. to identify the questions that tend to be correlated, factor analysis was used with the assumption of the correlation between factors or subgroups of questions. in fig. 3 , the results are shown only for factors with eigen values greater than one. it was found that symptoms were loaded in six different factorial subgroups. the complaints about hearing, tinnitus and vertigo constituted the first subgroup (otological); difficulty in swallowing, sore throat, globus sensation and voice impairment constituted the second (pharyngeal); smell/taste impairment symptoms constituted the third (smell and taste); nasal congestion, runny nose, and sneezing constituted the fourth (nasal); dizziness, nausea, headache constituted the fifth (neurovegetative); and fever, cough, and dyspnea constituted the sixth (others) subgroup. the main transmission route for sars-cov-2 is known as airborne droplets in addition, the virus can also be transmitted by touching hands to the mouth, nose, or eye mucosa after contact of droplets made by coughs and sneezes from sick people. therefore, it is very likely that the disease will show signs and symptoms in the eyes and upper respiratory tract, which is the first entry point into the body. in some studies, conjunctivitis has also been described [13, 14] . this present study, it was found that pcr positive covid 19 patients had different otolaryngological symptoms, especially loss of smell and taste. symptomatic patients can range from a mild to a heavy clinical status; however, in the vast majority of patients, the situation is not very severe. in a study evaluating the disease severity of approximately 44,500 definitive cases from the china disease control and prevention center, 81% of the patients had mild (no pneumonia or mild pneumonia), 14% had severe (e.g., dyspnea, hypoxia, or developing more than 50% lung involvement in imaging within 24-48 h) and 5% critical disease (e.g., respiratory failure, shock or multiorgan dysfunction) have been reported [15] . since the health status of the patients, who were followed up in the clinic, was in the mild and moderate level, cases that could be considered as severe were not included in our study. as it is known, the most common symptoms of covid-19 are fever, cough, dyspnea, and pneumonia characterized by bilateral infiltrates in the lung imaging [15, 16] . there is no specific clinical feature that can reliably differentiate covid-19 from other viral respiratory infections. in a study examining 138 patients hospitalized with covid-19 pneumonia in wuhan in terms of general clinical features, the most common clinical features at the onset of the disease were fever (99%), fatigue (70%), dry cough (59%), anorexia (40%), myalgia (35%), dyspnea (3%) and sputum production (27%) [17] . in another study, fever was reported in almost all patients; however, about 20% of them were found to have a very low-grade fever. in subsequent studies, it is noteworthy that fever was not frequently observed as a finding [18, 19] . the rate of patients with fever of 37° and above was only 27.5% in our study. the most obvious theory of the neurological involvement of the covid-19 virus is through the angiotensinconverting enzyme 2 (ace2) mechanism. ace2 is defined as a functional receptor for sars cov-2 and the virus reaches host cells in this way. this enzyme receptor is most commonly found in lung type 2 alveoli. however, it is also expressed by many cells, including glial cells and neurons. the expression and distribution of ace2 suggests that sars-cov-2 can cause neurological involvement through direct or indirect mechanisms [20, 21] . in particular, it is mentioned that sars-cov-2 can pass through the cribriform lamina of the ethmoid bone through the ace2 receptor, and transneuronal transportation can be achieved through the olfactory nerve. based on this information, it seems likely that the virus can also affect the functions of other cranial nerves. in a retrospective study by mao et al., neurological involvement or symptoms were reported in 36.4% of 214 patients (mean age 52.7 ± 15.5) with pcr positive for covid-19. while dizziness (16.8%) and headache (13.1%) were the most common symptoms of the central nervous system, hypogeusia (5.6%) and hyposmia (5.1%) have been reported as the most common peripheral nervous system symptoms [22] . in our study, the incidence of headache and dizziness in patients was found to be remarkably higher compared to the literature. although there is no comprehensive study on the prevalence of otolaryngologic symptoms in the literature so far, sore throat and rhinorrhea are the most frequent complaints that have been mentioned [23] . there is an increasing number of studies, which indicate that the most common clinical findings in terms of otolaryngologic symptoms are the smell and taste dysfunction [24, 25] . in a study using a questionnaire method conducted with 59 patients diagnosed with covid-19 in italy, smell or taste disorder was reported in 34%, and both smell and taste disorder in 19% [26] . in another study evaluating whether there was a difference in taste and smell in patients with and without positive rt-pcr test, it was reported that taste and smell disorder was higher in patients with positive rt-pcr test [27] . in our study, the most common otolaryngologic symptoms were the loss of smell and taste, which is important in terms of supporting the literature data on covid-19. again, another important point we determined about the sense of smell and taste is that the incidence and severity of it are higher in individuals under 60 years of age. while the rate of loss of smell / taste disturbance was higher in women, the incidence of smell disturbance was higher in patients with allergic rhinitis. these data contribute to the literature on this subject. when we look at the frequency distribution of nasal symptoms, one of the first findings of covid-19, it is seen that the rate of complaints such as rhinorrhea is lower compared to other symptoms [28] . in this respect, covid-19 differs from other upper respiratory viral infections [29] . in our study, the percentage of nasal obstruction was around 27%, while the rate of complaints such as runny nose and itching was around 14%. another important point in terms of nasal symptoms in our study was that except for loss of smell and itching, there was no significant difference in other findings in patients with sinonasal pathology. in addition, sore throat (32%) was found to be a common complaint in terms of pharyngeal and laryngeal symptoms. it has not been mentioned as a definite symptom in the literature; however, 19% of the patients, who participated in our study, were complaining about voice impairment. in the literature, there is not enough data on the effect of vestibular and acoustic nerve in covid-19 cases yet. in this respect, the most striking data in our study was that the complaint of dizziness was found at a rate of 31%. the percentage of patients with tinnitus complaints was around 11%. in addition the dizziness rate was more common in individuals under 60 years of age and female. in this regard, although there are no comprehensive studies in the literature, only a case of covid-19 complaining of dizziness was reported [30] . audiology laboratories were closed to prevent personnel contamination during the time we followedup the patients and objective tests could not be performed. these datas suggest that otological and vestibular symptoms should also be questioned in covid-19 patients. however, large series of studies with objective tests are required for precise data. in addition to otolaryngological symptoms, gastrointestinal findings (i.e., nausea and diarrhea) have been reported; and these may also be complaints of admission in some patients. in a systematic meta-analysis of studies reporting on gastrointestinal symptoms in patients with confirmed covid-19, the prevalence of gastrointestinal symptoms was 18% overall; diarrhea, nausea/vomiting, or abdominal pain were reported at 13, 10 and 9%, respectively [31] . in our study, the rate of patients who mentioned having nausea/ vomiting was 31%, and it was concluded that nausea/vomiting may be an important finding in terms of the distribution of symptoms as it is part of neurovegetative symptoms. the point that we evaluated differently from the literature in our study was whether the symptoms differed in terms of variables such as age, gender, clinical status, and concominant systemic and otolaryngologic diseases. accordingly, the point that draws attention in terms of age was that many symptoms were statistically significantly higher in the group under 60 years of age. from this point of view, in studies investigating the distribution of symptoms according to age, it was emphasized that, unlike our study, some symptoms were more common in older individuals [32, 33] . similarly, the fact that many symptoms are seen more frequently in women than men may be important in terms of being affected by covid-19 infection. again, as another data, headache was more common in patients with ht and dm. although there is no specific information about the relationship between headache and disease in the literature, it may not be sufficient to provide precise data, since our study group is small. when the data were examined in terms of the duration of the symptoms, the longest-onset symptoms were observed to be related to taste and smell. in a review on olfactory functions in covid-19 cases, it was stated that it may take more than a week to replace olfactory/gustatory functions. it is seen that the data we obtained are compatible with the literature in this respect [32] . therefore, we believe that the data in our study will be useful in terms of including the duration of symptoms. when the symptoms were evaluated by factor analysis, similar complaints were included in the same subgroups, which was an important finding in terms of showing the validity of the data obtained in our study. thus, otological, pharyngeal, nasal, smell, and taste, neurovegetative symptoms were determined to form subgroups among themselves. this situation was interpreted as covid-19 affecting a certain region in the body and causing associated symptoms. it is not always possible to identify patients with sars-cov-2 infection only by clinical presentation due to the unspecific nature of the early symptoms. this is also valid for otolaryngologic manifestations and it should be known that quite different symptoms can be encountered as reported in our study. so far, the most frequently mentioned symptoms of sars cov-2 infection in the literature have initially been referred to as sore throat and mild cough, and later as hyposmia/anosmia or loss of taste. in particular, many studies have focused on olfactory functions. however, it was observed in our study that many otolaryngologic findings such as dizziness, headache, and even voice changes may be related to covid-19. therefore, focusing only on certain symptoms can create errors in the initial diagnosis and referral of patients. it is believed that further studies on these symptoms with objective evaluations would provide more data in terms of involvement and findings for the head and neck region of covid-19. -pcr test result: 2.2. thorax ct findings: 2.3.laboratory findings: 2.4. general clinical findings: fever: pulse: arterial blood pressure: 2.3. clinical severity clinical characteristics of coronavirus disease 2019 in china the evidence of sars-cov-2 infection on ocular surface isolation of a novel coronavirus from a man with pneumonia in saudi arabia covid-19 and anosmia in tehran epidemiologic features and clinical course of patients infected with sars-cov-2 in singapore clinical features and treatment of covid-19 patients in northeast chongqing smell and taste symptom-based predictive model for covid-19 diagnosis a primer on viralassociated olfactory loss in the era of covid-19 clinical and epidemiological characteristics of 1420 european patients with mild-to-moderate coronavirus disease 2019 report of the who-china joint mission' on coronavirus 358 disease 2019 (covid-19). world health organization american academy of otolaryngology head 455 and neck surgery (aao-hns): anosmia reporting tool a family cluster of severe acute respiratory syndrome coronavirus 2 infections review of coronavirus disease-(covid19)-2019 epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (covid-19) during the early outbreak period: a scoping review viral dynamics in mild and severe cases of covid-19 clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china coronavirus disease 2019 (covid-19): a clinical update epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study evidence of the covid-19 virus targeting the cns: tissue distribution, hostvirus interaction, and proposed neurotropic mechanisms clinical manifestations and evidence of neurological involvement in 2019 novel coronavirus sars-cov-2: a systematic review and meta-analysis neurological manifestations of hospitalized patients with covid-19 in wuhan, china: a retrospective case series study covid-19 and anosmia: a review based on up-to-date knowledge a new symptom of covid-19: loss of taste and smell smell and taste dysfunction in patients with covid-19: a systematic review and meta-analysis anosmia and ageusia: common findings in 384 covid-19 patients taste and smell impairment in covid-19: an aao-hns anosmia reporting tool-based comparative study the common cold covid-19 in otolaryngologist practice: a review of current knowledge novel coronavirus pneumonia with onset of dizziness: a case report gastrointestinal manifestations of sars-cov-2 infection and virus load in fecal samples from the hong kong cohort and systematic review and meta-analysis olfactory and taste disorders in covid-19: a systematic review evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-ncov infections study questionnaire and clinical datas. section 1. personal information 1 key: cord-331135-4u99yxw2 authors: arsandaux, j.; montagni, i.; macalli, m.; texier, n.; pouriel, m.; germain, r.; mebarki, a.; kinouani, s.; tournier, m.; schuck, s.; tzourio, c. title: higher risk of mental health deterioration during the covid-19 lockdown among students rather than non-students. the french confins study date: 2020-11-05 journal: nan doi: 10.1101/2020.11.04.20225706 sha: doc_id: 331135 cord_uid: 4u99yxw2 background: covid-19 pandemic and its consequences have raised fears of its psychological impact. the objective of this study was to estimate the effect of student status on mental health conditions during covid-19 general lockdown among adults in france. methods: using cross-sectional data of the confins cohort, we estimated the effect of student status on depressive and anxiety symptoms, suicidal thoughts and perceived stress using multivariate logistic regression analyses. stratified models for college students and non-students were performed to identify associated population-specific factors. results: among the 2260 included participants, students represented 59% (n=1335 vs 925 non-students) and 78% of the total sample were female. student status was more frequently associated with depressive symptoms (adjusted or(aor)=1.58; 95%ci 1.17;2.14), anxiety symptoms (aor=1.51; 95%ci 1.10;2.07), perceived stress (n=1919, aor=1.70, 95%ci 1.26;2.29) and frequent suicidal thoughts (n=1919, aor=1.57, 95%ci 0.97;2.53). lockdown conditions that could be potentially aggravating on mental health like isolation had a higher impact on students than non-students. limitations: participants were volunteers, which could limit generalisation of the findings. the cross-sectional design did not allow determining if lockdown impacted directly mental health or if there is another cause. however, we adjusted analyses with the history of psychiatric disorders, and factors related to lockdown conditions were associated with mental health disturbances. conclusions: college student's mental health is of great importance in the context of the general lockdown set up during the pandemic. follow-up and interventions should be implemented especially for those at high-risk (younger people and those with history of psychiatric disorders). young adults are particularly exposed to psychiatric disorders which often start in young adulthood. college students have been identified as a vulnerable population and have higher prevalence of psychiatric symptoms (e.g. depressive symptoms, anxiety symptoms and suicidal risk) than other adults (kessler et al., 2007; kovess-masfety et al., 2016; verger et al., 2010 verger et al., , 2009 . in this population, and particularly in the first years at university, a high level of stress related to academic achievement, a low self-esteem, and depressive symptoms are frequently reported (augesti et al., 2015; beiter et al., 2015; cheung et al., 2020) . the unprecedented context of 2020 with the major sars-cov-2 pandemic and its consequences have raised fears of its psychological impact in the population and more particularly in the fragile population of college students (galea et al., 2020) . in february 2020, the sars-cov-2 epidemic, causing the covid-19 disease, hit europe and france, one of the most affected countries in the world in number of cases and deaths ("who coronavirus disease dashboard | who coronavirus " n.d.) . to contain the spread of the epidemic, france established a general lockdown from march 17 to may 11, 2020. it has been shown in previous lockdown situations (e.g. sars epidemic in 2013) that quarantine can have an impact on mental health (depression, post-traumatic stress symptoms, confusion, anger as well as suicide) by itself (barbisch et al., 2015; brooks et al., 2020) . little information is available about the psychological impact of lockdown on college students and its risk of exacerbating their isolation and their psychological vulnerability (beck et al., n.d.; husky et al., 2020) . a few studies have reported high prevalence of depressive symptoms, anxiety symptoms and stress during the covid-19 lockdown among college students (cao et al., 2020; husky et al., 2020; odriozola-gonzález et al., 2020; tang et al., 2020) but it is unkown whether the impact was different in this population compared to non-students adults. the objectives of this study were to estimate the effect of lockdown on mental health conditions (depressive symptoms, anxiety symptoms, suicidal thoughts and perceived stress) in college students and to compare their frequency and associated factors to a sample of non-students recruited in the same study. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 this study is based on the confins e-cohort (www.confins.org), a prospective online population-based cohort study of adults in france set up since april 2020 during covid-19 national lockdown and still ongoing. the objectives of the confins cohort were: (1) to investigate the impact of the covid-19 pandemic and the general lockdown, established in france between march and may 2020, on the well-being and mental health of the population; and (2) to explore opinions and beliefs of the population about the pandemic, its treatment and vaccines. a large communication campaign was deployed in france on social media and press, with a focus on specific populations (i.e. college students, health workers) reached also by emailing. the eligibility criteria were to be more than 18 and locked down in the french territory until the end of the general lockdown in france (may, 11, 2020) . enrolled participants signed in a secured web-site and complete questionnaires online. the baseline questionnaire collected socio-demographic information, medical history, lockdown conditions, mental health parameters, as well as opinions and beliefs. thanks to the confins cohort, direct comparison between students and non-students is possible (same recruitment and data collection for both populations). this study is based on baseline data collected during the general lockdown in france (until may, 11, 2020) . depressive symptoms. depressive symptoms were measured using the patient health questionnaire-9 (phq-9) (kroenke et al., 2001; pfizer, n.d.) modified to assess symptoms within the last seven days (instead of the last 14 days) for close monitoring purpose. items are rated from 0 to 3 according to increased frequency of experiencing difficulties in each area covered. scores are summed and can range from 0 to 27. higher scores represent higher depressive symptoms. we used the validated french version of the phq-9 (arthurs et al., 2012) . since, distribution of the score was not normal, we used a validated cut-off of 10 to define the presence of depressive symptoms (kroenke et al., 2001; manea et al., 2012) . anxiety symptoms. anxiety symptoms were measured using the generalized anxiety disorder-7 (gad-7) (spitzer et al., 2006) modified to assessed symptoms within the last seven days (instead of the last 14 days). items are rated from 0 to 3 according to increased frequency of experiencing difficulties in each area covered. scores are summed and can range from 0 to 21. higher scores represent higher anxiety symptoms. we used the validated french version of the all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10.1101/2020.11.04.20225706 doi: medrxiv preprint gad-7 (micoulaud-franchi et al., 2016) . since, distribution of the score was not normal, we used a validated cut-off of 10 to define the presence of anxiety symptoms (kroenke et al., 2001) . suicidal thoughts. participants reported if they experienced suicidal thoughts during the last seven days ("during the past 7 days, have you ever thought about killing yourself (suicidal ideas)": with the responses "no, never" and "yes sometimes" or "yes, on multiple occasions" considering together for analysis purpose). perceived stress. participants rated their current stress on a 10 points-scale ("how worried or stressed are you right now on a scale of 0-10"), with 0 representing the lowest level of stress and 10 the highest. since, distribution of the score was not normal, we used a cut-off of 7 to defined high perceived stress (corresponding approximately to the third quartile of the distribution). participants declared if they were currently college students or not and were asked about specific information according to their academic situation (e.g. cursus, university year) if they were students and their professional situation otherwise (having a high professional position and having a stable professional situation like time-undetermined work contract). sociodemographic information included sex and age (in years), familial situation (in a relationship or not) and education level collected differently for students and non-students and transformed for analysis into three categories: minor than a second-year university level or currently in their 1 st or 2 nd year for students ; holding a second-year university level or currently in their 3 rd year for students ; holding more than a second-year university level or currently in their 4 th or more year for students. other variables possibly influencing on mental health were also recorded like working or studying in the medical field, having an history of psychiatric disorder (among depression, bipolar disorders, generalized anxiety), history of another disease at risk for severe forms of covid-19 (among cardiovascular, respiratory, chronic digestive disease, cancer and diabetes). other covariates/exposures were collected according to the student status or not. for students: having a paid activity (student job) and self-rated financial situation during childhood (correct, difficult or very difficult vs comfortable or very all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10.1101/2020.11.04.20225706 doi: medrxiv preprint comfortable). for non-students: having a high professional position and having a stable professional situation (time-undetermined work contract). information related to the covid-19 pandemic or lockdown were also recorded: week of inclusion (w14-15 corresponding to march 30 to april 12, w16-17 corresponding to april 13 to 26 and w18-19 corresponding to april 27 to may 11), being in lockdown in a high-risk region (defined by region that registered more than 10 death during the week 14), having acquaintance or family with covid-19 or covid-19 suspicion, being alone in lockdown accommodation, being in lockdown at home (in the same place than before lockdown), lockdown accommodation with an outdoor space (like a balcony or a garden), lockdown accommodation surface (in m 2 ), having a pet, doing physical exercise during lockdown. nonstudents declared if they were working remotely during lockdown or not. first, we described the study sample overall and in both student and non-student categories. second, we estimated the effect of student status on each mental condition (i.e. depressive symptoms, anxiety symptoms, suicidal thoughts and perceived stress) using separated logistic regression models. three multivariate models were built using a different adjustment: model 1 adjusted for age and sex, model 2 adjusted for age, sex and variables not related to the covid-19 pandemic or lockdown (i.e. being in a relationship, education level, working or studying for the medical sector, history of psychiatric disease, history of other disease at risk for and model 3 adjusted for age, sex, pre-cited variables not related to the covid-19 pandemic or lockdown and variables related to the covid-19 pandemic or lockdown (i.e. week of inclusion in the cohort, being in lockdown in a high-risk region, acquaintance or family with or covid-19 suspicion, being in lockdown alone, lockdown accommodation with an outdoor space, having a pet, lockdown accommodation surface, physical activity during lockdown). we estimated odds ratio (or), their 95% confidence interval (95% ci) and the p-value of the wald test (and p-value of the type 3 test for categorical variables) related to the effect of student status. we performed secondary analysis restricting the sample to young adults (≤ 30 years old) to better take into account potential confusion by age. third, we computed a general model for each mental health conditions among students and non-students separately to investigate associated factors of these two populations. we performed the same model than primary analysis extending the list of exposure with all factors all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10.1101/2020.11.04.20225706 doi: medrxiv preprint (model 3) and entering specific variables for students (i.e. paid activity and financial situation during childhood) and for non-students (i.e. high professional position, stable professional position, teleworking). to test the robustness of the findings, we conducted sensitivity analyses using alternative cutoff for depressive, anxiety symptoms and perceived stress: (a) cut-off that represents severe depressive symptoms (phq-9 ≥ 15), severe anxiety symptoms (gad-7 ≥ 15) and mild perceived stress (≥ 5), (b) cut-off that represents the full spectrum of depressive (minimal: 0-9; mild: 10-14; moderate: 15-19; severe: 20-27) and anxiety symptoms (minimal: 0-4; mild: 5-9; moderate: 10-14; severe: 15-21). we also performed sensitivity analyses among the complete case population to test the robustness of results regarding the imputation process. our missing data analysis procedures used missing at random assumptions. we used the multivariate imputation by chained equations (mice) method of multiple multivariate imputation in sas software (proc mi and mianalyze) (janssen et al., 2010; rubin and schenker, 1991; schafer, 1997) . we independently analysed 10 copies of the data, each with suitably imputed missing values, in the multivariate linear or logistic regression analyses. we averaged estimates of the variables to give a single mean estimate and adjusted standard errors according to rubin's rules. we imputed only data from covariates using covariate data and completed the imputation process with other data collected in the confins cohort (having a child, housing type before and during the lockdown, self-rated health and self-rated quality of life before the lockdown). we performed additional imputations for the student subsample since paid activity and financial conditions during childhood had missing data. we performed all analyses using the sas statistical software (sas v9.3). of the 2344 participants enrolled in the confins cohort, 2309 were eligible for the study and 2260 were ultimately included in the primary analysis for depressive and anxiety symptoms and 1919 for suicidal thoughts and perceived stress (fig1). table 1 and table s1 provided in supplementary material describe the study sample. students represented 59% of the total sample (n=1335 vs 925 non-students). mean age in the student sample was about 16 years lower (mean=23.3 vs 40.1) whereas sex ratio was similar (3/4 female) in both samples. students had less frequently a partner (48.1% vs 76.3%) and were more frequently at risk for severe forms all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10.1101/2020.11.04.20225706 doi: medrxiv preprint for covid-19 (35.4% vs 24.0%). however, both populations were similar regarding history of psychiatric disorders (about 23%), education level (with a majority of more than a second-year university level) and proportion of individual working or studying in health domains (about 40%). although non-students spent the lockdown more frequently in their usual place than students (88.2% vs 63.4%), the quality of lockdown accommodation (e.g. surface, outdoor space) was similar for both. students were fewer than non-students to be in a high-risk region (11.3% vs 31.2%) and they were enrolled in the cohort later (mostly during weeks 16-17). during lockdown period, mental health conditions were different between the two populations. students presented more frequently depressive symptoms (32.5% vs 16.2%), anxiety symptoms (24.0% vs 14.7%), suicidal thoughts (11.7% vs 7.6%) and perceived stress (33.1% vs 22.1%) than non-students (table 2 ). in multivariate models, student status was associated with an increased probability to report depressive symptoms (or fully adjusted=1.58; 95%ci=1.17;2.14), anxiety symptoms (or fully adjusted=1.51; 95%ci=1.10;2.07), and perceived stress (or fully adjusted=1.70, 95%ci=1.26;2.29), independently from covariates related or not to the covid-19 pandemic or lockdown (table 3) . for suicidal thoughts, the oddratios were in the same range (or fully adjusted=1.57; 95%ci=0.97;2.53) but did not reach significance. sensitivity analyses showed consistent results when analyses were performed among the complete case population and with different cut-offs (results presented in table s2 in supplementary material). when both samples were restricted to young adults (≤ 30), students still had a higher risk of depressive symptoms (or fully adjusted=1.54; 95%ci=1.03;2.29), anxiety symptoms (or fully adjusted=1.60; 95%ci=1.04;2.45) and perceived stress (or fully adjusted=1.59; 95%ci=1.07;2.34) (results presented in table s3 supplementary material). students reported consistently more frequently depressive symptoms whatever the strata: female, male, with a history of psychiatric disorders, or according to various lockdown conditions (e.g. being in lockdown alone) (fig2). in explicative models for mental health conditions, we found shared factors between students and non-students: past history of psychiatric disorders (e.g. for depressive symptoms: or=2.80, 95%ci=2.06;3.82 among students and or=3.10, 95%ci=1.99;4.81 among non-students) and physical exercise during lockdown which was associated with less frequent mental health disturbances (e.g. for all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. in this large sample of adults observed during the general lockdown, high level of mental health disturbances was observed. students had a much higher prevalence of mental health problems (more depressive symptoms, anxiety symptoms and perceived stress) than non-students. in multivariate models adjusting for a large variety of potential confounding factors, students had a more than 50% increased risk of mental health problems compared to non-students. this increased risk was also observed in participants with or without a past history of psychiatric diseases, in the various strata of lockdown situations, or when both samples were restricted to young adults. finally, lockdown conditions that could be potentially aggravating on mental health like isolation had a higher impact on students. high frequency of mental health disturbances found in our study corroborates previous research conducted separately among students and other adults. among the general non-student population, several studies reported a prevalence between 17% and 28% for depressive symptoms, between 14% and 45% for anxiety symptoms and between 8% and 27% for stress (bäuerle et al., n.d.; choi et al., 2020; gonzález-sanguino et al., 2020; gualano et al., 2020; mazza et al., 2020; ozamiz-etxebarria et al., 2020; wang et al., 2020) . among college students, several studies reported a prevalence during the lockdown ranging between 9% and 21% for depressive symptoms, between 25% and 34% for anxiety symptoms and 28% for stress (cao et al., 2020; odriozola-gonzález et al., 2020; tang et al., 2020) . our study directly compared students and non-students in the same cohort and brings strong evidence for a higher risk of mental health disturbances among students rather than non-students during general lockdown. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10. 1101 /2020 mental health during lockdown was associated with lockdown conditions, especially among students. indeed, estimated frequency of mental health disturbances are higher during the general lockdown (in our study and in above-mentioned studies) compared to previous research conducted before covid-19 pandemic and lockdown among students (between 11% and 20% of depressive symptoms, 15% of anxiety symptoms, and 11% of stress) (beiter et al., 2015; ibrahim et al., 2013; rotenstein et al., 2016) . furthermore, lockdown conditions were associated with mental health among students in our study, showing that lockdown represents a high-risk period for students. lockdown conditions were yet partially explored in the literature with an association found between mental health and having relative or acquaintance who got covid-19 (cao et al., 2020; tang et al., 2020) . to explain this higher mental health risk for individuals during general lockdown, several mechanisms could be discussed: disturbance in mood homeostasis during lockdown (i.e. failure to stabilize mood via mood-modifying activities) (taquet et al., 2020) , lack of social and familial support (gariépy et al., 2016; kmietowicz, 2020; pössel et al., 2018) or specific vulnerability of young adults and students already explored in the literature that could be exacerbated by pandemic and lockdown (e.g. worries about the future and employment) (hunt and eisenberg, 2010; tang et al., 2020; twenge et al., 2017) . the strengths of our study include the large sample, the standardised assessment tools used for mental health conditions and broad adjustment for other factors (related or not the covid-19 pandemic or lockdown). this study profits recruitment of these two populations in the same cohort as well as similar data collection that allow direct comparison. some limitations should however be taken into consideration. first, a sampling bias could have arisen since participants were volunteers, which could limit generalisation of the findings. regarding mental health disturbances, the consequences appear however limited as frequencies were consistent with existing literature. second, the cross-sectional design did not allow determining if lockdown impacted directly mental health or if there is another cause. however, we considered the history of psychiatric disorders that is an important confounder, and factors related to lockdown conditions were associated with mental health disturbances, suggesting that lockdown should have an impact on mental health especially for students. longitudinal studies have been set up in the general population and have showed a deterioration of mental health during lockdown all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10.1101/2020.11.04.20225706 doi: medrxiv preprint (pierce et al., 2020) . similar studies are needed among students to establish clearly if lockdown can impact mental health in the short and in the long term. from a public health perspective, this study confirms that students were a vulnerable population for mental health disturbances during pandemic period and lockdown, suggesting that screening might be useful to offer adapted support. besides, for preventive purpose in case of a new lockdown perspective, support and interventions adapted to students should be created and evaluated. especially psychological support could be provided by university health student services both online and through crisis hotlines. peers could also organize self-help groups and detect students with particular distress. from a research perspective, we recommend to explore two priority areas. first, research is warranted in order to clarify causality of the relationship between lockdown and mental health disturbances among students. to this end, longitudinal mental health data covering a period before, during and after lockdown would be necessary. second, it appears relevant to better understand the mechanisms underlying the specific vulnerability of students, i.e. identifying intermediate factors and especially those that can be modified. besides, qualitative studies or mixed design (i.e. mix of quantitative and qualitative data) may be useful to better understand both psychologic disorders students experienced during this period and solutions some of them put in place to better cope with depression, anxiety, stress and suicidal thoughts. the i-share and confins team are currently supported by an unrestricted grant of the nouvelle-aquitaine regional council (conseil régional nouvelle-aquitaine) (grant n° 4370420) and by the bordeaux 'initiatives d'excellence' (idex) program of the university of bordeaux (anr-10-idex-03-02). the team has also received grants from public health france (santé publique france, contract n° 19dppp023-0) and the nouvelle-aquitaine regional health agency (agence régionale de santé nouvelle-aquitaine). m. macalli was supported by a phd grant of the nouvelle-aquitaine regional council (grant n° 17-eure-0019). the funding bodies were neither involved in the study design, or in the collection, analysis, or interpretation of the data. all rights reserved. no reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10.1101/2020.11.04.20225706 doi: medrxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in the copyright holder for this this version posted november 5, 2020. ; https://doi.org/10. 1101 /2020 are scores on english and french versions of the phq-9 comparable? an assessment of differential item functioning differences in stress level between first year and last year medical students in medical faculty of lampung university increased generalized anxiety, depression and distress during the covid-19 pandemic: a cross-sectional study in germany covid-19 health crisis and lockdown associated with high level of sleep complaints and hypnotic uptake at the population level the prevalence and correlates of depression, anxiety, and stress in a sample of college students the psychological impact of quarantine and how to reduce it: rapid review of the evidence. the lancet the psychological impact of the covid-19 epidemic on college students in china depression, anxiety and stress in different subgroups of first-year university students from 4-year cohort data depression and anxiety in hong kong during covid-19 the mental health consequences of covid-19 and physical distancing: the need for prevention and early intervention social support and protection from depression: systematic review of current findings in western countries covid-19) in spain effects of covid-19 lockdown on mental health and sleep disturbances in italy mental health problems and help-seeking behavior among college students stress and anxiety among university students in france during covid-19 mandatory confinement a systematic review of studies of depression prevalence in university students missing covariate data in medical research: to impute is better than to ignore age of onset of mental disorders: a review of recent literature rules on isolation rooms for suspected covid-19 cases in gp surgeries to be relaxed mental health of college students and their non-college-attending peers: results from a large french cross-sectional survey the phq-9 optimal cut-off score for diagnosing depression with the patient health questionnaire (phq-9): a meta-analysis a nationwide survey of psychological distress among italian people during the covid-19 pandemic: immediate psychological responses and associated factors rapid detection of generalized anxiety disorder and major depression in epilepsy: validation of the gad-7 as a complementary tool to the nddi-e in a french sample psychological effects of the covid-19 outbreak and lockdown among students and workers of a spanish university psychological symptoms during the two stages of lockdown in response to the covid-19 outbreak: an investigation in a sample of citizens in northern spain patient health questionnaire (phq) screeners [www document mental health before and during the covid-19 pandemic: a longitudinal probability sample survey of the uk population associations between social support from family, friends, and teachers and depressive symptoms in adolescents prevalence of depression, depressive symptoms, and suicidal ideation among medical students: a systematic review and meta-analysis multiple imputation in health-are databases: an overview and some applications analysis of incomplete multivariate data a brief measure for assessing generalized anxiety disorder: the gad-7 prevalence and correlates of ptsd and depressive symptoms one month after the outbreak of the covid-19 epidemic in a sample of home-quarantined chinese university students mood homeostasis before and during the coronavirus disease 2019 (covid-19) lockdown among students in the netherlands increases in depressive symptoms, suicide-related outcomes, and suicide rates among u.s. adolescents after 2010 and links to increased new media screen time psychological distress in first year university students: socioeconomic and academic stressors, mastery and social support in young men and women covid-19) epidemic among the general population in china having a pet, n (%) 1002 health conditions during lockdown key: cord-307930-5jwtykqg authors: almomani, a. a. r.; bollt, e. m. title: informative ranking of stand out collections of symptoms: a new data-driven approach to identify the strong warning signs of covid 19 date: 2020-04-30 journal: nan doi: 10.1101/2020.04.25.20079905 sha: doc_id: 307930 cord_uid: 5jwtykqg we develop here a data-driven approach for disease recognition based on given symptoms, to be efficient tool for anomaly detection. in a clinical setting and when presented with a patient with a combination of traits, a doctor may wonder if a certain combination of symptoms may be especially predictive, such as the question, "are fevers more informative in women than men?" the answer to this question is, yes. we develop here a methodology to enumerate such questions, to learn what are the stronger warning signs when attempting to diagnose a disease, called conditional predictive informativity, (cpi), whose ranking we call cpir. this simple to use process allows us to identify particularly informative combinations of symptoms and traits that may help medical field analysis in general, and possibly to become a new data-driven advised approach for individual medical diagnosis, as well as for broader public policy discussion. in particular we have been motivated to develop this tool in the current environment of the pressing world crisis due to the covid 19 pandemic. we apply the methods here to data collected from national, provincial, and municipal health reports, as well as additional information from online, and then curated to an online publically available github repository. as healthcare systems around the world copes with the covid-19 crisis, concerns about the ongoing spread of the disease remain, in part because of an as yet uncertain size and spreading role concerning asymptomatic and low symptomatic population, and also the true false negative rate [14] of available tests. such a clear threat to humanity demands our best informative ability to recognize its traits across populations. clinical diagnosis remains a major line of defense, especially while direct tests remain uncertain and not widely available. we develop in this work a conditionally predictively informative ranking (cpir) method, that adopts data-driven principles of information theory, as an extension of the principle of causation entropy [11] , to give a reliable ranking that reflects the direct informativity of each symptom, after considering the underlying relationships between the symptoms. see fig. 1 . in brief, this approach contrasts directly to the commonly used concept of correlations [8, 2, 7, 10] , that associates a score to describe how strongly measurements go together, whereas, cpir associates a score to describe how strongly atypical is a new observation, given that a collection of symptoms has already been observed. often it is the presence of atypical observations that allow the clinician to decide how worrying should be considered the constellation of symptoms presenting in a given patient. likewise, understanding atypical associations can be especially informative when characterizing a disease across the population. 1 figure 1 : (left) venn diagram of symptoms, typical, and atypical sets of patients. this figure illustrates how some patients share different symptoms, which represent mutual information shared between different symptoms. (right) graph representation of symptoms that shows the shared information between symptoms and the disease, and between symptoms themselves. our interest is to discover the direct information between symptoms and the disease. we define a conditional predictive informativity (cpi) measure in terms of conditional mutual information (i) to describe how much information is to be inferred if a given patient has certain symptoms, given already stated other symptoms are observed. that is, in answering the question, "is a cough especially informative if a fever has already been observed in a patient," would be stated with the cpi as the following and relating to conditional mutual information, cp i(cough associates to a patient if a fever is already observed) = i (cough of a patient given fever), referring to the available covid-19 dataset, and as shown in fig. 1 , it turns out those with a fever is about 80% of those already have a cough, so while correlation picks that association it is exactly not this association we wish to identify with cpi. another example, that we may ask, "are chills especially informative if a headache has already been observed in a patient?" for that question, we write: cp i(chills associates to a patient if a headache is already observed) = i (chills of a patient given headache). referring to the available covid-19 dataset, we find that less than 20% of patients who have chills also have a headache. so the answer to the question is yes, observing chills is informative given a headache. moreover, chills is crucially informative. as we show in fig. 1 , patients can be seen as typical and atypical patients. both groups have tested positive for the disease, however, while the majority of the patients shares the same set of symptoms and reaction to the disease, a subgroup will have different reactions that may appear as severe pain and symptoms, and even death. in covid-19 statistics, we see that more than 80% of the patients have mild symptoms, or they may even be asymptomatic, while a small group have severe pain and risky symptoms, and the global mortality rate of covid-19 is less than 7% of confirmed cases. even while the number of patients who have chills is much lower than patients who have fever, see in fig. 1 , this symptom turns out to be more informative than fever, meaning that chills specially appears in atypical patients, but not in typical patients. however, a fever appears in both groups, and furthermore, it is highly associated with other diseases. this paper is devoted to developing and describing how to compute these kinds of classifications and conclusions. ranking on this conditional measure allows us to learn the markers of the disease. to state one such example outcome, our analysis shows that chills combined with pneumonia is especially informative when it occurs in young women, more so than in other patients. it is a standout collection of symptoms. another fig 7-fig. 10 , we summarize the outcome of exaustive search of combinations of demographic information and symptoms that maximize the cpi, the most striking of which we highlight here. in green boxes, we show the symptoms associated with typical patients, and in red, we show the critical and risky symptoms that are associated with the atypical set of patients. example is that headaches and body aches are highly informative of atypical patients when they appear in men. more results of this type are shown in fig. 2 . with such examples in mind, our methods here will allow us a data-driven method to define an informativity ranking of symptoms toward a reliable prediction of disease presence based on the specific combination of informative symptoms. the knowledge gained when observing a specific combination of symptoms relative to the further predictability of the status of other symptoms founds the essential ability to understand how to understand observations in the clinical setting. with the idea of informative collections of symptoms, then we offer the cpir, as a ranking of these informative symptoms, sorted so as to describe those symptoms that when occurring together, make for unmistakable signs of the disease. stated another way in terms of an example, a patient who is observed to have a dry cough and a fever is not so indicative of the disease since so often the fever and a dry cough go together. just as even more so in the extreme, observing a dry cough and then the presence of a left foot, then furthermore observing the presence of a right foot is not so informative as a further observation. however, as it turns out we find, a cough may be indicative, but then a fever may be more informative if furthermore the patient is female. individual-level epidemiological data from the covid-19 outbreak, are publically available from the international resource [15] . these are collected from national, provincial, and municipal health reports, as well as additional information from online, and these data are collectively curated for general use. this data is continually updated, as described in the paper associated with the github repository. as of april 16, the dataset has more than 267,000 entries for individual-level data. fig. 2 is a table of the more striking combinations of informative symptoms and traits, that we have found in this study, the methods of which to rank the cpi are developed below. in our previous work, [1] , we introduced the method of entropic regression, which adopts the principle of causation entropy, [11] , for the discovery of underlying dynamics based on the influence of a set of candidate functions to the outcome dynamics. however, in the case of boolean outcomes, and mixed datasets, where the outcome depends on a combination of variables that could be real numbers, boolean variables, or descriptive data, we must extend principles of causality inference and minimal description. let y ∈ {0, 1} be the outcome that a patient has a disease, or not, such that: the patient data, or the variables that influence the outcome, are mostly mixed variables with different data types. see fig. 3 . further, define the i th patient variables to be, (i.e. a row in the table shown in fig. 3 ). here, {s i,j } ns j=1 are symbolic variables that each has independent sets of labels (i.e. symbols, category,...,etc.) {l 1 , l 2 , . . . , l kj }, and n s is the number of symbolic variables. similarly, {b i,j } n b j=1 ∈ {0, 1} are boolean variables, and n b enumerates the boolean variables. {r i,j } nr j=1 are real valued variables, and n r is number of real valued variables. for example, and as preliminary introduction to our approach, assume that the variable s :,2 is an ndimensional vector, representing the number of observations or diagnosis states of symptoms of a given patient. symptoms are labeled; for example l 1 represents presence of a fever, l 2 represents presence of a cough, and l 3 represents a headache, or possibly even the degree of these. here we illustrate with example that k 2 = 3 is the number of labeled descriptions, or the number of symptoms that will be observed in patients. for sake of clarity we will drop the subscript and we write the vector of symptoms for all patients as s. for a given patient i, who for example has a fever and a headache, we write the entry s i = {l 1 , l 3 }, representing occurrence of a fever and a headache. then, we can translate the vector descriptive variable s, to multi-vector (matrix, see fig. 3 ) boolean variabless = b(s), such that: so, the function b(s) converts the column vector s of n descriptive entries, to an n × k boolean matrix s, where the k th column, k = 1, ..., k, of the boolean matrix describes the occurrence of the labeled description l k on s. fig. 3 shows a schematic illustration for this local "booleanization" process. with variables booleanized, we now describe in the next section how to construct a conditionally predictively informative ranking (cpir) for the symptoms. it is clear that real valued variables can be converted to a set of boolean variables by thresholding and then these translated to labels and then to a boolean matrix as discussed above. now we describe how certain boolean factors may be predictive of other factors, given the status of yet other factors. this is a variation on the theme of our previous work in causation entropy [3, 11, 12, 13] , cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april 30, 2020. . figure 3 : booleanization of non-boolean variables illustrative example. by this example, we illustrate how to convert standard descriptive variables, such as the commonly named symptoms, into a boolean matrix as this is a required initial stage for our analysis. see eqs. (1)-(3). but here given the nature of the expected data and the corresponding difference of the underlying questions, the role of time is less relevant than the notion of indicative and predictive. our goal here is to define an informativity ranking of symptoms toward reliable prediction of disease presence based on the combination of informative symptoms. the conditionally predictive information (cpi) described here as the conditional mutual information between one boolean variable s k and the outcome y is given by: where k * is the set of boolean variables indices {1, ..., k} − {k}. that is the mutual information between the k th boolean variable and the outcome y , conditioned on all other boolean variables. while this is therefore just a conditional mutual information [5] , it is the way the conditioning set is designed, and how these are ranked that make this approach especially relevant to our needs here. thus, it is a measure of knowledge one gains in observing some of the variables to further the possibility to predict the status of other variables, which is a crucial when the goal is to uncover a minimal and most informative set of variables. eq. 4 quantifies the information added by observation of the boolean variable s k , given the state of all other symptoms. however, this does not inform the directionionality of influence between s k and the outcome y . for example, the boolean variables a = [111000] and b = [000111] have high mutual information with the outcome y = [111000]. however, while the event occurrence in y is associated with the event occurrence in a. we see that the event occurrence in y is associated with non-occurrence of the event in 5 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april 30, 2020. . figure 4 : in a statistical sense, we see that l 1 and l 3 have the same probability of appearing when the outcome y = 1. however, we see that the variable l 3 has the exact state as y . meaning that if we consider y = l 3 as our prediction map, we will have perfect accuracy, regardless of the values of l 1 and l 2 . then, we see that although l 1 and l 3 have the same probability, l 3 is more informative variable, and in the sense of conditional mutual information, we will see that i(y ; l k |l 3 ) = 0, for all k = 3. that is, no variable has additional information other than the information provided by l 3 . b. then, the mutual information i(a; y) = i(b; y) may result, but this reveals no information about the directionality of the relationship. to address this issue, we re-write eq. 4 as: where γ is a sign function that is given by: where p r(y |s k ) is the conditional probability of y given s k , and ( ¬ ) is the logical not operator of a boolean variable. that is, if the occurrence of (y = 1) associates with occurrence of (s k = 1) more than it is associates with s k = 0, then this describes a positive relationship. otherwise it is negative relationship, that occurrence of y is associated with non-occurrence of s k . here, we want to emphasize a major difference between our approach and the commonly used methods from statistical analysis by correlations from data. statistical analysis based on correlations [8, 2, 7, 10] has a different goal than we have here. correlations describe variables and outcomes in terms of probability of occurrence, but it is well known that correlation does not imply causation [9] . for example, suppose that 80% of the patients (y = 1) have a fever, and 50% of them have a cough. then, fever and cough are the dominant symptoms. however, this analysis neglects the correlation among the symptoms themselves, but most important to our interests here, it does not reveal if the symptoms are informative or not. see fig. 4 for a detailed example. we are less interested in the cause in this work, and instead, we are interested in developing an informativity rank (ir) of the symptoms. that is, for a set of symptoms, what are the symptoms that are conditionally predictively informative (cpi) of an underlying condition such as the presence of a disease. assume an example in the extreme for discussion, that 99% of the patients who have a cough also have the fever. then clearly there is (almost) no further useful information provided by observing the cough that was not already provided by observing the fever. thus, the cough on its own can not stand as an informative symptom if not combined with the fever. seeking informative variables is our main objective, and the conditional mutual information, carefully conditioned as stated and with the optimized conditioning set, can reveal this informative set by discovering the set of direct influences between the variables and the 6 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april 30, 2020. . outcomes. finding the conditional mutual information in eq. 4. in other words, this translates to asking, "what is the direct influence (information) provided by the symptom s k , given the information from all other symptoms, s k * ?" by this local analysis, we will infer the dominant variables are most informative. furthermore, we will show this analysis in terms of the covid-19 dataset discussed above. first, however we must explain an important issue associated with uni-state outcomes. in the available covid-19 data, we must cope with a common and well known problem called selection bias, [4] ; this problem realizes itself here in that we generally only have the data acquired from actual diseased patients, meaning that we only have the data for the people who have already tested positive. we call this the problem of a uni-state outcome variable, y = 1, for all the patients. considering the covid-19 dataset, we found about 26 commonly reported symptoms (fever, cough, ..., etc.), including the asymptomatic cases to be within the possible combinations of symptoms. this means that for each patient i, we have a binary string s i of 26-bits that represents the symptoms that patients have. for simplicity of discussion, we will consider an example of 4 symptoms ordered as follows: {asymptomatic, fever, cough, abdominal pain}, but of course we use all the available data in our analysis. further, if certain of the symptoms for the patient are not reported, then we have s i = [0, 0, 0, 0]. if it is reported that the patient has no symptoms, we have s i = [1, 0, 0, 0]. if the patient has a fever and a cough, we have s i = [0, 1, 1, 0], and so on. for a 26-bit binary string, there exists the possibility of up to 2 26 or more than 67 million possible combinations of symptoms. however, we found that in the actual data set, there were expressed in fact only n u = 124 unique binary strings s u for the actual symptoms observed. in fig. 5 , we show the histogram of s u derived from the data. observe that not only do we have a low count of unique states, moreover, most of the unique states have a very low frequency of occurrence f = 1, f = 2. low frequency events, associated with a low probability or otherwise rare events, may be especially interesting to be studied individually as these outliers may in fact be specifically informative. however, our intention here is to rank the symptoms based on their informativity of the disease on the majority of patients. note that we seeks to infer the cpi that describes the outcome of most patients, and hence, we assume that the outcome y , is equal to 0, if the patient has a binary string s i that has low probability. mathematically we write: where p r(s i ), is the probability of occurrence of the binary string s i , and δ is a probability tolerance. in order to choose δ, assume that f is the ordered frequency (histogram) of the unique set of symptoms s u , such that f 1 ≤ f 2 ≤ . . . f nu . to investigate how each state in s u provides additional information, we consider to analyze the entropy of the histogram sequentially. let the entropy e i be the entropy of the probability distribution of the frequency entries, given by: where fj i k=1 f k represents the probability of the j th entry in f with respect to the assumption that only the first i states are available. in another words, at each i we are asking what is the entropy of s u if we were to assume that we have only have the first i states?. this allow us to track, starting from the low frequency states, how the large frequency states affects the information (entropy) of s u . fig. 6 shows the entropy curve from eq. 8. it will be a subject for our future work to connect this approach to the theory stemming from the asymptotic equipartition property (aep) [5] , and in so doing, to discuss the optimality of the value of δ, whereby in analogy to aep, we are classifying the patients as associated with typical and atypical sets. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april 30, 2020. thus, most of the information is interpreted to be associated with the typical set of patients. for our current analysis, we consider δ =f /n , wheref is the frequency at the maximum entropy, and n is the sample size. for our dataset, we found δ = 2.69 × 10 −5 . now, given δ, we have the outcome y from eq. 7, and the set of boolean variables s that describes the symptoms. we apply eq. 5 to find the conditional mutual information (cmi) of each symptom. the cpir is the scaled cmi, ∼ [0, 1], to indicate the rank of each symptom and it is shown in fig. 7. in fig. 8 , we show the cmi between the symptoms themselves, which are the cmi between each pair of symptoms, given the information from all others. this mutual information in fig. 8 between the symptoms, can practically lead to a fuzzy classification of the critical symptoms since it is hidden for the commonly used statistical techniques. the conditional mutual information associated with the cpi, eq. (4), requires that we review the conditional mutual information [5] , and remark how the associated probabilities may be estimated. let x, y , and z be jointly distributed random variables with associated probability density function p(x, y, z). the conditional mutual information between x,y given z according to eq. 4, is given by: where h is the entropy function, and h(··) is the joint entropy of two variables. the entropy of a discrete random variable x with pmf p x (x), and n possible states is given by for a boolean random variable x, letp be the probability that x = 1. we do not emphasize here how to efficiently estimatep other than to note that typically this may be done by counts of relative occurence. then, the probability that x = 0 is 1 −p, and the entropy of x is then given by: for the joint entropy of discrete variables in eq. 9, we can think of the joint variable xz, for example, as a new variable with a two dimensional outcome state (concatenation of the two variables as two columns), for which we call the joint space of x and z. then, the entropy can be found by the probability distribution of the unique states in xz (unique rows), using eq. 10. now, we can algorithmically obtain our conditionally predictively informative ranking (cpir) by the following loop through all symptoms: and the ranking cpir is then given by cp ir i = cip i / max(|cp i|). in fig. 7 , we show the results with plotting the absolute value of cpir after descending sorting, which gives more clear view and readability for the figure. now we are in a position to answer very simple but important questions, such as, "are fevers more informative in women than men?" clearly there are many comparably, important, and simple to state questions 8 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april 30, 2020. . (hist-histogram) . we see to the left that most of the unique symptoms combinations have very low occurrence in the dataset, and to clarify that, we consider the histogram of the frequencies to the right, which shows that most of the frequencies have low values, which means that the majority of symptoms combination s u , have only one or two occurrence in the 260000 entries of the dataset. figure 6 : entropy of the unique states. we see that as we adding states with low frequency, the entropy increase. however, at some point where the frequency of the state is significantly larger than previous frequency, the entropy decrease. the point of maximum entropy can be seen as a critical point, and the states before and after this point have different information and belong to different categories. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april 30, 2020. . that become clinically relevant when a doctor may be presented with a specific patient presenting specific symptoms. one interesting question to ask is that if the symptoms have different cpir depending of specific demographic variable such as sex or age. there are different ways to answer this question with the conditional mutual information. we may for example, add the boolean vector of gender to the conditioning set, and track the reduction of cpir for each symptom. however, another approach that overcomes the need to increase the size of the conditioning set is to replace the outcome set with the gender vector. let, y i,1 = 1, if the patient i is female, and y i,1 = 0 otherwise. similarly, let y i,2 = 1, if the patient i is male, and y i,2 = 0 otherwise. note that due to missing data and other factors, y :,1 = ¬ y :,2 , where (¬) is the logical operator (not). then, we repeat the process for y :,1 , y :,2 , by using the symptoms matrix s, and eq. 5. fig. 9 shows the results of symptoms demographic informativity. given δ, we have the outcome y from eq. 7, and the set of boolean variables s that describes the symptoms. we apply eq. 5 to find the cpi of each symptom. the cpir is the scaled cpi, as discussed in the computations section, to indicate the rank of each symptom, and it is shown in fig. 7 . the fever and cough are widely known as the main symptoms of covid-19, and in our dataset, we found that 75% of patients have a fever, and 45% of them have a cough. however, fig.7 shows that the most informative symptom is chills, and it is specifically informative that the patient is from the atypical set of patients. the fever, placed the second informative symptom of the typical patients, while the most informative symptom of the typical patients was the respiratory symptoms, which include respiratory infection, acute respiratory viral infection (arvi), and acute respiratory distress syndrome (ards). clinically, breathing difficulty can be listed under respiratory symptoms. analyzing breathing difficulty individually, we found it to be the second informative symptom of atypical patients. clinically, fatigue and weakness are two different symptoms, where the weakness is defined as a failure to generate the required or expected force on first testing or attempted performance, and fatigue is defined as a failure to generate the required or expected force during sustained or repeated contraction [6] . both symptoms are informative symptoms of covid-19, however, weakness is more critical, since it is informative of atypical patients. interestingly, since they are often mistakenly used alternatively, especially by the patients when they describe them, if we consider them to be equivalent, say both of them are fatigue, then it will be the most informative symptom among all of the other symptoms of covid-19. in fig. 8 , we show the cmi computed between pairs of symptoms, given the information from all others. this mutual information in fig. 8 between the symptoms, can practically lead to a fuzzy classification of the critical symptoms since it is hidden for the commonly used statistical techniques. for example, in a statistical sense, we say that fever and cough are the most symptoms to appear in covid-19 patients, and this analysis lack any consideration of the dependency between cough and fever, and that most of the patients who have cough are already have a fever. fig. 8 shows this dependency as high direct information shared between cough and fever, and in our cpi approach, addressing these interactions between symptoms is embedded in eq. 5, and we obtain the direct informativity between each individual symptom and the outcome. to the question, are fevers more informative in women than men? the answer, according to the cpir, is yes. in fig. 9 , we see that while fever is informative for the typical male patients, it is associated with the atypical female patients. in order to read fig. 9 fully and correctly, we say that fever is an informative symptom of atypical patients of women, which means that it is more surprising to see women who have a fever, and hence, it can be a more critical or risky symptom to be taken especially seriously when it appears in women. we must interpret that fig. 9 helps in recognizing differences in symptoms informativity between men and women, but it does not replace the general audience discussion of fig. 7 , but rather it compiments it. for example we see that chills, which is the most informative symptom in fig. 7 , has zero cpri in men and women but that does not mean it is not informative. instead it means that chills have no difference in informativity between men and women. finally we show in analogy to fig. 9 , a comparable assay of results for symptoms informativity in younger and older patients. as a summary of our results querying for the most striking combination of symptoms and traits, see a tabular summary fig. 2 . . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april 30, 2020. . figure 7 : conditionally predictively informative ranking (cpir). although statistically, fever is the highest occurrence symptom, several other symptoms was more informative than fever. the most reliable five informative symptoms are: chills, breathing difficulty, respiratory symptoms, joint pain, and fever. to understand how to read this curve, consider the cough, which is statistically known to be from the main symptoms of covid-19. however, we see here that the cough is a weak informative symptom, meaning that the cough by itself is not a reliable indication of covid-19 unless it jointed with a stronger symptom such as fever. see fig. 1 for more details. on the other hand, if a patient has only chills, that is a more reliable indication than cough or fever alone. we can conclude then that the high informative symptoms jointly, can be a solid indication that the patient has covid-19, such as having headache and sputum together, or headache and fatigue together, and so on. moreover, symptoms appear to the right (red dots), are more critical, since they indicate informative symptoms of atypical set of patients. in this paper we introduced a conditionally predictively informative ranking (cpir) approach. in partciular we used this method to analyze covid-19 symptoms, and to give a ranking of informative symptoms. in analogy to the symptoms example, other descriptive (labeled) variables can be analyzed to extract the informative descriptions in each variable that contains labeled descriptions. in our future work, we will extend the idea to consider symptoms-disease causality-driven networks, to construct informative networks that can give a signature of symptoms combinations. we hope this can be helpful as a data-driven approach for disease recognition based on given symptoms, and it can be efficient tool for anomaly detection. from the presented mathematical methods applied to the data, the results are as shown in fig. 7 , fig. 9 and fig. 10 . summarizing from these figures, we highlight in fig. 2 our main perhaps most striking combination of symptoms and traits as our results. while we have highlighted the covid 19 in this discussion, for the obvious critical nature of this crisis, it is our hope that this tool, in particular the cpir, may find utility for other disease analysis, and indeed for other questions of medical, social, and scientific importance. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april 30, 2020. . figure 8 : symptoms influence network. in this figure, we show the mutual information directly shared between symptoms. we see that some symptoms have high mutual information between them, which makes the additional information provided by one of them, given the other, is low. our results are based on the dataset [15] , which is continually updated online, and we will update our results based on the new data available, and the results will be updated continually in our online (covid-19 repository), together with the matlab code to process the data and perform cpir analysis. this work was funded in part by the army research office, and also darpa. the authors declare no conflict of interest. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april 30, 2020. . figure 9 : symptoms demographic informativity (gender). it is important to note that this figure is independent of the order and analysis that are shown in fig. 7 , since here we have a different outcome, and we are investigating the mutual information between symptoms and demographic variables. low (or zero) cpir in this figure does not mean that the symptom is not informative, but it means that the symptom has no different (bias) informativity between women and men. (top) we see the results for symptoms informativity bias in women, and we see the dominant informativity in this figure is that fever and cough, are informative for the atypical set of patients in women, while they are associated with the typical set in fig. 7 . this indicates that fever and cough are more surprising to appear in women. then, they are more critical in women, where their presence in women increases the probability that the patient is from the atypical set. (bottom) similarly, we see the results for symptoms informativity bias in men, and we see the dominant informativity in this figure is that fever and cough are associated with the typical set of patients. although that reduces the risk in men who have fever and cough, however, since 75% of patients have a fever, then that indicates that men have a higher probability of infection with covid-19. we note that our dataset has some missing or unreported information about gender, and that is why we see the difference between the graphs. if we have complete data about the gender, with only male and female entries, then we will see the cpir for men as rotation (left-right) of the women graph, and that can be seen clearly in fig. 10 . . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april 30, 2020. . https://doi.org/10.1101/2020.04.25.20079905 doi: medrxiv preprint figure 10 : symptoms demographic informativity (age). we see the results for symptoms informativity bias based on the age of the patients. we see that fever, cough, sore throat, and fatigue are more informative in younger patients (< 60), while pneumonia is more informative in older people. 14 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april 30, 2020. . https://doi.org/10.1101/2020.04.25.20079905 doi: medrxiv preprint how entropic regression beats the outliers problem in nonlinear system identification an introduction to medical statistics causation entropy from symbolic representations of dynamical systems sample selection bias correction theory elements of information theory physiological analysis of skeletal muscle weakness and fatigue. clinical science and molecular medicine an introduction to statistical learning essential medical statistics correlation still does not imply causation introduction to statistics and data analysis. cengage learning causation entropy identifies indirect influences, dominance of neighbors and anticipatory couplings identifying the coupling structure in complex systems through the optimal causation entropy principle causal network inference by optimal causation entropy covid-19 testing: the threat of false-negative results epidemiological data from the covid-19 outbreak, real-time case information key: cord-293655-2ab7wdsk authors: mandic-rajcevic, s.; masci, f.; crespi, e.; franchetti, s.; longo, a.; bollina, i.; veloci, s.; amorosi, a.; baldelli, r.; boselli, l.; negroni, l.; za, a.; orfeo, n. v.; ortisi, g.; colosio, c. title: contact tracing and isolation of asymptomatic spreaders to successfully control the covid-19 epidemic among healthcare workers in milan (italy) date: 2020-05-08 journal: nan doi: 10.1101/2020.05.03.20082818 sha: doc_id: 293655 cord_uid: 2ab7wdsk objective to study the source, symptoms, and duration of infection, preventive measures, contact tracing and their effects on sars-cov-2 epidemic among healthcare workers (hcw) in 2 large hospitals and 40 external healthcare services in milan (italy) to propose effective measures to control the covid-19 epidemic among healthcare workers. design epidemiological observational study. setting two large hospitals and 40 territorial healthcare units, with a total of 5700 workers. participants 143 hcws with a sars-cov-2 positive nasopharyngeal (nf) swab in a population made of 5,700 hcws. main outcome measures clinical data on the history of exposure, contacts inside and outside of the hospital, nf swab dates and results. a daily online self-reported case report form consisting of the morning and evening body temperature and 11 other symptoms (cough, dyspnoea, discomfort, muscle pain, headache, sore throat, vomiting, diarrhoea, anosmia, dysgeusia, conjunctival hyperaemia). results most workers were tested and found positive due to a close contact with a positive colleague (49%), followed by worker-initiated testing due to symptoms (and unknown contact, 28%), and a sars-cov-2 positive member of the family (9.8%). 10% of nf swabs performed in the framework of contact tracing resulted positive, compared to only 2.6% through random testing. the first (index) case caused a cluster of 7 positive hcws discovered through contact tracing and testing of 250 asymptomatic hcws. hcws rarely reported symptoms of a respiratory infection, and up to 90% were asymptomatic or with mild symptoms in the days surrounding the positive nf swab. during the 15-day follow-up period, up to 40% of hcws reported anosmia and dysgeusia/ageusia as moderate or heavy, more frequently than any other symptom. the time necessary for 95% of hcws to be considered cured (between the positive and two negative nf swabs) was 30 days. conclusion hcws represent the main source of infection in healthcare institutions, 90% are asymptomatic or with symptoms not common in a respiratory infection. the time needed to overcome the infection in 95% of workers was 30 days. contact tracing allows identifying asymptomatic workers which would spread sars-cov-2 in the hospital and is a more successful strategy than random testing. there are more than 3 million sars-cov-2 positive cases and more than 200,000 deaths attributed to coronavirus disease (covid19) worldwide. commonly reported symptoms of covid-19 include fever, cough, dyspnea, sore throat, muscle pain, discomfort, and many prevention strategies are based on identifying these symptoms of infection. the virus can be spread even by asymptomatic patients or patients with mild symptoms, and healthcare workers (hcws) represent 10% of overall cases and often more than 10% of hospital personnel are commonly infected. hcws represent both a vulnerable population and an irreplaceable resource in the fight against this epidemic and further analysis is needed to show how and why they get infected and introduce successful prevention measures. the first (index) case in our study was infected by a family member, but due to close contacts with colleagues managed to infect other 7 hcws. contrary to a common expectation that hcws get infected from patients, they regularly get infected by other hcws. up to 90% of hcws were asymptomatic or had only mild symptoms. random testing for sars-cov-2 was not efficient. active search for suspect cases through contact tracing is the strategy of choice to identify most of the positive hcws. most hcws remained asymptomatic during the 15-day follow-up period, and even in the days prior to the positive nf swab. anosmia and ageusia/dysgeusia were reported more commonly than classic symptoms of a respiratory infection. contrary to the recommended quarantine of 14 days, 30 days were necessary for 95% of the workers to be declared cured (two negative nf swabs) on the 30th of january 2020, the world health organization (who) declared the outbreak of the novel coronavirus disease 2019 (covid-19) as a public health emergency of international concern. at the time of the writing of this paper, almost 3 million cases and almost 200,000 deaths have been reported worldwide (1). most prominent symptoms include fever, dry cough, headache, sore throat and sneezing, although a growing number of reports underline asymptomatic and patients with mild symptoms having the same viral load as symptomatic patients and spreading the infection in the general population and among healthcare workers (hcw) (2) (3) (4) (5) . most published reports on covid-19 patients underline that hcws get infected regularly and they represent one of the most vulnerable groups during this pandemic (6, 7) . the safety of hcws is key not only to fight this international biological threat through their care for the critically ill patients, but also to prevent them from transmitting the virus. who and european centre for disease control (ecdc) recommendations for the rational use of personal protective equipment agree on the use of: a) a medical (surgical) mask, eye protection, long-sleeved water-resistant gown, gloves, and keeping 1 m distance when dealing with suspected or confirmed covid-19 cases; b) a respirator (n95 or ffp3), eye protection, waterresistant gown and gloves during aerosol generating procedures; c) a medical (surgical) mask to be worn by suspected or confirmed covid-19 patients, or any patient with respiratory symptoms. good hand hygiene should be kept using 70% alcohol based disinfectants or soap and water (washing at least 20 seconds) (8) (9) (10) . who definitions of suspect cases require at least mild symptoms, although contact tracing and adjustment of suspect case definition is encouraged (11) . inclusion of contact tracing and testing of asymptomatic patients can help identify potential spreaders of sars-cov-2 in hospitals, but with a high logistic burden (12) . having in mind that around 10% of infected persons are hcws, and that most hospitals report 10% of staff getting infected (13) , the additional burden might be worth it. additional challenges are posed by the removal from workplace and return-to-work procedures which depend on the expected duration of the disease and a negative nasopharyngeal swab, which can be false negative (14) . in this frame, we developed our own experience in the territorial socio-sanitary public company of the saints paolo and carlo of milano, italy (tssc). the first sars-cov-2 infected hcw in our structure was confirmed on february 27 th , 2020. since that moment, we applied a protocol based on five main steps: 1. to identify a case (or cases) which could be diagnosed by any of our hospitals or reported by any other affordable source (patients and workers); 2. to identify symptomatic workers and to verify the existence of an infection; 3. to conduct an internal epidemiological survey addressed at identifying all close contacts of the infected subjects; 4. to "biologically" isolate these contacts, in the hospital and in the private life, and immediately perform a nasopharyngeal swab; 5. to decide, based on clinical and laboratory data, the return-to-work policy safe for the hcws and their colleagues. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 8, 2020. our tssc is composed of two public hospitals of milan and 40 territorial healthcare institutions (providing various services such as vaccination, preventive care, administration), which are part of the region of lombardy (northern italy) public healthcare system. the two hospitals employ a total of 4142 workers (healthcare workers and non-healthcare workers in a healthcare setting, all referred to as hcws in our report). there are around 1500 workers in 40 territorial healthcare institutions. out of 5,700 workers, 70% are female, with a mean age of 46 years. it is estimated that around 150,000 patients are examined in our emergency rooms of the two hospitals every year, with an average of 50 admissions per day in around 800 hospital beds available. the hospitals provide all diagnostic and medical procedures covering most existing medical specialties. san paolo hospital is also the home of the department of health sciences of the university of milano, which integrates it into the university of milan academic system. workers of the whole groups of structures are provided with occupational health services in the healthcare setting. since at the beginning of the epidemic, most administrative workers started smart working, with only a few exceptions. during our routine occupational health surveillance of workers, we transferred the most vulnerable subjects (the elderly, those affected by chronic diseases) from the most risky departments (i.e. emergency room) to "safer" departments. most vulnerable workers got the possibility to remain home, without any impact on their earnings. our study is addressed at the health care personnel who continued their activities during the crisis. all data presented in this paper were extracted from the health surveillance files, and no experimental activity has been carried out. nevertheless, all our workers are informed about our health surveillance procedures and have signed an informed consent regarding the data collection and analysis. no ethical approval was deemed necessary by the ethical committee of the saints paolo and carlo hospitals. it was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research figure 1 outlines the procedure and treatment of close contacts, quarantine and return-to-work procedure. a "close contact" was defined as a person who had a face-to-face dialogue or who spent at least 15 minutes in an indoor environment with a covid-19 patient, without wearing a personal protective device (ppd, e.g. surgical mask). the epidemiological survey was performed by the health care management of the structure and close contacts were reported to our occupational health unit. symptomatic workers were those with any respiratory symptoms (defined at the beginning as fever, sore throat, cough, difficulty breathing, or diarrhoea). asymptomatic workers were asked to adopt "source control" and isolation measures to reduce the viral charge and risk of infecting another colleague or a family member. viral charge reduction or "source control" was performed by asking the worker, even if asymptomatic, to wear a surgical mask both while working, traveling and in the private life. the worker was to take meals separately from the family, live in a separate room and use a dedicated bathroom or at least carefully wash the only bathroom available after use. each close contact was required to do a nf swab. workers absent from work due to respiratory symptoms were asked to come to the hospital for a nf swab when their symptoms would allow it (fever below 37.5°c and other symptoms not preventing to travel). if the swab was positive, the affected worker was placed in mandatory quarantine for a 14-day period. for symptomatic workers the quarantine period lasted for at least 14 days from the full termination of all symptoms, even if the symptoms were reported later during the disease (after the swab). workers with symptoms were asked to immediately leave the workplace and to go home, adopting the same rules of source control and isolation given to the asymptomatic workers. in case of a negative nf swab, the worker would come back to work after the cessation of symptoms. to reduce the potential impact of false negative nf swabs, all close contacts, even if the swab . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20082818 doi: medrxiv preprint resulted negative, maintained precautionary source control measures (surgical mask) for a 14-day period after the contact. during their absence or isolation (negative nf swab but confirmed close contact) all workers were asked to fill in and submit a daily symptoms report which was collected by phone and in paper for the first 5 workers, and then transformed into an online questionnaire to allow an overview and tracking of the whole population of hcws under observation. this collection was performed in order to point out any sign or symptom indicative of a possible worsening of the health conditions of the worker. we set up a specific procedure to manage safe return to work of the workers absent for covid-19 or suspected of covid-19. in particular, a symptomatic covid-19 worker was considered cured 14 days after the resolution of respiratory infection symptoms and two consecutive negative tests for sars-cov-2 at least at 24 hour distance one from the other (15) . the definition of "clearance" of the virus indicates the disappearance of detectable sars-cov-2 rna in nasopharyngeal swabs. in case of a positive swab after the 14-day period, another 7 days was added to the quarantine, and then the two swabs were repeated. we faced an additional problem of readmitting to work hcws who were absent from work but did not undergo a nf swab during this period. if the worker was absent for 14 days or more (same as covid-19 positive workers) and/or showed typical symptoms, she or he was treated as a covid-19 patient. if the period of absence was shorter than 14 days, or the presence of typical symptoms was not recorded, the worker was treated as "close contacts" (followed the "source control" procedure, underwent a nf swab, and symptoms were followed). since the 25 th of march, a new regulation recommended random testing of hcws (16) . we also report the results of hcws found positive using this approach. our study presents the results and analysis of 143 hcws with a positive nf swab who filled the online symptoms report in the period from the 9 th of march until the 8 th of april 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. hcws with a positive nf swab, symptomatic hcws, as well as those under surveillance for a close contact with a positive hcw or a family member were asked to fill in a daily symptoms report. the symptoms report has evolved to improve tracking and adjust for clinical findings during the period in four phases. these phases are described shortly to better explain what data was collected and when: 1. initially, from the 27 th of february until the 8 th of march, the daily symptoms report was in paper form and was given to (a few initial) hcws to fill and submit in writing after the quarantine; 2. from the 9 th of march, the symptoms report was put online, and all workers were given a link to an electronic sheet where they would fill and submit the daily report, and their data became available right away. the report included the morning and evening body temperature and there was a free-text field available to add any other symptoms; 3. from the 12 th of march, the free-text field for symptoms was converted into specific questions regarding the symptoms (cough, dyspnoea, sore throat, headache, muscle pain, discomfort, vomiting), based on the current knowledge of covid-19 symptoms; 4. finally, based on clinical experience, additional symptoms (anosmia, dysgeusia, and conjunctival hyperaemia) were added. nasopharyngeal specimen is the gold standard for swab-based sars-cov-2 testing. nasopharyngeal swab was performed by inserting the flexible wire shaft minitip swab through the nares parallel to the palate until resistance was encountered or the distance is equivalent to that from the ear to the nostril of the patient, indicating contact with the nasopharynx. then the person performing the swab would gently rub and roll the swab and leave it in place for several seconds to absorb secretions. the swab was then slowly removed while rotating it. all hcws in charge of taking this sample did a standardized course which allowed all samples to be taken in the same way. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. real-time reverse transcription-polymerase chain reaction (rrt-pcr) assay is currently the most reliable and the only available direct method to detect sars-cov-2 virus; it is the gold standard method for laboratory diagnosis of covid19 (17, 18) . test was positive if rdrp and e or n or both genes were detected; repeated to confirm positive if only rdrp or n were detected. we present a case series of 143 out of 185 sars-cov-2 positive hcws in the study period. each hcw was connected to their daily reports. the reports were centred around the date of the positive swab, making that day's report the follow-up day 0 (zero). days following the positive swab are denoted with positive integers (from 1 to 15), and days leading to the positive swab are denoted with negative integers (from -5 to -1). the morning and evening temperature were collected as numeric variables. the absence or intensity of each symptom was collected as: absent, light, moderate, and heavy. categorical variables (i.e. symptom intensity) are presented in tables as the absolute count (n) and proportion among the grouping variable (e.g. number and percentage of hcws reporting absent, light, moderate, and heavy for each symptom). data management, processing, analysis and visualization were done using r language and environment for statistical computing (19) . . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . from the 27 th of february until the 8 th of april, 2485 nf swabs (some of which repeated) were performed? for hcws in our two hospitals and the territory, of which 460 nf swabs were done at random. these nf swabs resulted in a total of 185 sars-cov-2-positive workers, of which 12 were found through random swabs. the positive rate in non-random samples was around 10%, while the positive rate among randomly sampled hcws was around 2.6%. table 1 shows the characteristics of the hcws included in our study. the study group was made of 143 covid-19 positive hcws employed in the different healthcare structures of our tssc. the data for san paolo hospital also include the territorial healthcare institutions since their occupational health surveillance is done by the san paolo hospital. the majority of hcws were female (57.3%), and the most prevalent job title was nurse (48.3%), followed by medical doctors (26.6%), and assistant nurses (9.8%). most workers were tested due to a close contact with a positive colleague (49%), followed by worker-initiated testing due to symptoms and unknown contact (total 28%), and a sars-cov-2 positive member of the family (9.8%). close contact with covid-19 positive patients was the reason for testing in 7.7% of cases hcws, while 5.6% were tested on random bases. the hcws under study submitted an average of 9 daily symptoms reports during their quarantine, ranging from 1 to 26. most hcws started submitting daily symptoms reports on the day following the nf swab (66%). the highest percentage of filled reports was noted in the first week, going from 73% on the 2 nd day, down to 58% on the 7 th day. the gradual drop of daily reports submitted continued in the second week, going from 48% down to 33%. figure 4 shows the steep rise and gradual decline in the percentage of hcws submitting the daily health report. table 2 shows the respiratory and other commonly reported symptoms in the day prior to the positive nf swab (day -1) , on the day of the swab (day 0), and in the following day (day 1). on average, the sars-cov-2-infected hcws were afebrile, with no or light respiratory symptoms. cough and dyspnoea were absent or light in around 90% of the workers, while general symptoms, such as discomfort, muscle pain, and headache were reported more often, although by no more than 30% of the workers. most symptoms were absent in more than 50% of the hcws in the first week of the disease. anosmia and dysgeusia were the only specific symptoms which were commonly reported, in light, moderate or heavy form by almost 50% of the workers. figure 5 shows the body temperature of hcws on the day of the positive nf swab (day 0) and in the 15 days following the swab. figure 6 shows commonly reported symptoms associated with covid-19, their intensity, from absent to heavy, as reported by the hcws during the 15 days following the nf swab. the most common symptoms of a respiratory infection, such as cough, dyspnoea, or sore throat, were present in a heavy or moderate form in less than 15% of the study group in the first days of the infection. between 70% and 90% of hcws reported no or mild respiratory symptoms. the only two symptoms reported more commonly as moderate and heavy by between 30% and 40% of hcws were anosmia and ageusia/dysgeusia. there was a gradual . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20082818 doi: medrxiv preprint reduction of most symptoms in the second week, with persisting anosmia and dysgeusia in around 30% of hcws. for a smaller group of workers who reported their symptoms also in the 5 days leading to the positive nf swab, figure 7 shows the body temperature and figure 8 shows other reported symptoms (days -5 to 0). these workers were defined as close contact but were unable to perform a nf swab, so they submitted symptoms reports until the moment of the swab. although based on a smaller number of reports (see table 2 ), most hcws report normal body temperature or light fever, and those with fevers above 37.5°c or 38°c can be considered outliers. hcws reported cough (in light and moderate forms), and non-specific symptoms such as discomfort, muscle pain, sore throat, and headache most commonly in the days leading to the positive nf swab. we noted a gradual increase in the number of hcws reporting anosmia, as well as the gradual worsening of this symptom from light and moderate forms to the heavy form. the median time elapsed from the positive swab to two consecutive negative swabs was 21 days (minimum: 14 days; maximum: 34 days) for san carlo hospital, and 25 days (minimum: 15 days; maximum: 46 days) for san paolo hospital (including territorial healthcare institutions). since the data was not normally distributed, we also report the median values of 20 and 25 in san carlo and san paolo hospitals, respectively. 95% of hcws was considered cured and was able to return to work after 27 days and 36 days in san carlo and san paolo hospitals, respectively. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. according to the latest data of the italian institute of health (istituto superiore sanita', april 23 rd 2020), there were more than 177 thousand persons positive for sars-cov-2 and more than 23 thousand covid-19 related deaths in italy. healthcare workers represent more than 10% of cases (just below 20,000 infected), with a median age of 48 years and 33% male (20) . our results represent one of the first reports on the development of the sars-cov-2 epidemic among healthcare workers in large hospital. our data has shown the number of newly diagnosed sars-cov-2-positive hcws from only one (index case). at the peak of the epidemic in our hospitals and territorial units, up to 12 workers were being diagnosed positive every day, and the source of the infection were other hcws. most hcws had no or only light symptoms which at the beginning never led them or others to doubt they were infective. common respiratory symptoms, such as fever, cough, dyspnoea, or sore throat were much less reported than recently discovered symptoms such as anosmia and ageusia/dysgeusia. finally, the time which passes from the positive nf swab to the cessation of symptoms and two consecutive negative nf swabs is more than double of the 14 days initially proposed, which should be taken into account when deciding the duration of the quarantine, even for asymptomatic workers. the epidemic in our hospitals started with one hcw who was infected outside of the hospital setting. in the first 7 days of the epidemic, we traced more than 250 contacts among hcws related to this first positive case, which finally resulted in at least 7 positive hcws. this has been the largest cluster of cases found in our hospital. during the period of around 40 days presented in this report, the occupational health unit of saints palo and carlo hospital performed around 2500 swabs, resulting in 185 positive workers (of which 143 were included in this report), with a much higher percentage of positive cases found among workers identified through contact tracing (~10%) than among randomly sampled (2.6%). the 3 rd and 4 th weeks of the epidemic in our hospitals were characterized by 5 to 10 cases/day, of which the majority were related to other positive colleagues. transfer and removal of high-risk workers from high-risk hospital environments, reduction of visiting hours, and avoiding close contacts among patients and colleagues (distance, use of ppd) reduced the potential of sars-cov-2 transmission. during the 5 th and 6 th week of the epidemic in our hospitals, the number of positive hcws connected to other colleagues declined rapidly, reducing the both the overall number of daily new cases and . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . the size of the clusters surrounding each positive hcw. in the 6 th week of tracking, most hcws who were found positive were tested because they had a positive family member, noticed symptoms, or were tested at random. the shape of the epidemic curve in our hospital follows the sharp increase of the number of covid-19 cases in italy, the lombardy region, and milan. the sharp decline which has followed afterwards in our hospitals does not follow that of italy as a whole, which was observed several weeks later. we attribute this difference to organizational and protective measures non-pharmacological measures were underlined as leading to a decline in the effective reproductive number in wuhan from 3.8 to 0.3, ultimately stopping the epidemic in china (21) (22) (23) . similar to the experience in china, our experience underlines the role of asymptomatic patients in driving the epidemic in the hospital but adds workplace transmission between colleagues as a driver of the epidemic among hcws. most hcws in our study reported no or only mild symptoms of a respiratory infection. in fact, on the day of the positive swab, the median body temperature measured by hcws was 36.6°c, while cough and dyspnoea were reported as moderate or heavy by only 12.5% and 0% of hcws, respectively. unspecific symptoms, such as discomfort, muscle pain, and headache were reported more commonly, but only in around 30% of hcws. a recent review article on asymptomatic covid-19 transmission underlined this risk in healthcare setting, although concentrating on the risk arising from asymptomatic patients (24) . our results underline the risk of transmission . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . among asymptomatic hcws. one of the measures implemented in lombardy was a mandatory check of the body temperature before the beginning of the work shift for hcws, and, in case of a temperature above 37.3°c a nf swab is performed and the worker suspended until the results are back (25) . our results show this measure, as any other "symptom-centred" measure, does not guarantee protection of hcws and patients, and could even result in a false sense of safety in a scenario where up to 90% of cases could be asymptomatic. most other experiences and opinions regarding the protection of hcws underline the re-organization of work (e.g. moving triage and pharmacy outside of the hospital), reduction of the density of people (e.g. reducing visiting hours and numbers of visitors), adequate training and use of ppe as the main solutions to protecting hcws (26) (27) (28) . three additional symptoms drew our attention while working with suspected sars-cov-2 positive workers: anosmia, ageusia/dysgeusia, and conjunctival hyperaemia. in fact, since the moment they were added to our daily report in the middle of march, anosmia and ageusia became symptoms most commonly reported as moderate or heavy in sars-cov-2 positive hcws, reported in more than 40% and 30% of cases, respectively. they also represented the most persistent symptoms, as most other symptoms typically connected to respiratory infections exhibited a reduction during the 15-day follow-up. conjunctival hyperaemia, although noted by our doctors at the hospitals while performing the medical examination and nf swab, was not often reported by hcws in the daily symptoms report, which might be connected to the fact that it requires an "outside observer" to notice it. it is also important to note that the duration of the infection (time from the positive nf swab to two negative nf swabs) was between 20 and 30 days with 30 days needed for 95% of workers to be considered cured. this information should be considered when deciding whether the quarantine should last for 28 days instead of 14. a much smaller sample of workers (n=10), commonly found among close contacts but absent from the hospital for other reasons, reported their daily symptoms even in the days leading to the positive nf swab. in the days leading to a positive nf swab, the symptoms and their intensity were similar to those reported during the follow-up period. cough and non-specific symptoms were reported more commonly, fever and other respiratory symptoms rarely, and we noted a gradual increase in anosmia and ageusia leading to the day of the positive nf swab. this is the first report of symptoms in the pre-swab period of sars-cov-2 positive patients. our study was based on the data collected to monitor workers health status while quarantined, the filling of the daily symptoms report was voluntary, and the report itself was adapted several times to answer the needs and field situation, which introduce bias in the presented results. nevertheless, our report is based on a relatively high response rate of around 70% in the first week of follow-up. a limitation is the fact that 42 hcws never filled in even one daily symptoms report. in a telephone survey currently in progress, the most common reasons for not filling the online symptoms report was the lack of a smartphone, computer or internet at home, lack of experience with online forms ("not being technological enough"), being diagnosed in the week prior to the implementation of the online report, and taking care of a sick family member ("lack of time for the reports"). five hcws did not fill the report because they were hospitalized. their reports would certainly differ from the rest of our workers with a mild clinical picture, but heir percentage (less than 5% of 185), similar to that in madrid where 29 out of 791 required hospitalization, leads us to believe that the data presented are representative of the majority sars-cov-2-positive hcws and the selection bias in our report is negligible. future studies should analyse in more detail the circumstances surrounding the infection of hcws, symptoms, and the overall outcome of their disease. new symptoms, such as anosmia and dysgeusia which were frequently reported by our hcws could help clinicians arrive to a diagnosis sooner and reduce the time available for worker-to-worker and worker-to-patient transfer of sars-cov-2. another step forward will be understanding whether hcws have developed specific immunity, even among those with negative swab results. this could help us understand whether the presence of specific igg could be an expression of effective immunity, as well as whether it is temporary or permanent. finally, the lessons learned from controlling the sars-cov-2 epidemic among hcws could be applied to other occupations/sectors at risk, such as transport workers, services and sales workers, and public safety workers. hcws represent one of the most important resources in the fight against covid-19, but they are also one of the most vulnerable groups which is commonly infected. our study has shown that at the peak of the epidemic in italy the reorganization of work, physical distancing, use of ppds (even for source control), and contact tracing and testing of asymptomatic hcws were able to stop the worker-to-worker infection in the hospital and reduce the overall incidence of infection . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20082818 doi: medrxiv preprint among hcws. most hcws were asymptomatic or with mild symptoms, which means they would most likely go undetected by symptom-centred preventive strategies. most reported specific symptoms were anosmia and ageusia, and their role in arriving to a clinical diagnosis sooner should be further confirmed. finally, our data suggest that the duration of the infection is longer than previously anticipated, and that a patient should not be considered recovered only 14 days after the positive swab. readmitting such a patient or worker into the social or work life without a further swab assessment might create additional risk. the authors would like to acknowledge the kind help and support from our dear colleagues rosamaria bentoglio, donatella visentin and all workers of the occupational health unit of the saints paolo and carlo hospital of milan without whose selfless effort this work would not be possible. authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20082818 doi: medrxiv preprint laboratory analyses; cc: study design, data collection, manuscript revision, supervision, data interpretation, manuscript revision. this study received no funding. all authors are employed in the institution (see affiliation) where the study was conducted. the corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit the publication. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 8, 2020. . . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 8, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20082818 doi: medrxiv preprint -ncov) : situation report, 99 protecting health-care workers from subclinical coronavirus infection sars-cov-2 viral load in upper respiratory specimens of infected patients epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with 2019 novel coronavirus in wuhan updated rapid risk assessment from ecdc on the novel coronavirus disease 2019 (covid-19) pandemic: increased transmission in the eu/eea and the uk. euro surveill bull eur sur les mal transm eur commun dis bull hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china rational use of personal protective equipment for coronavirus disease 2019 ( covid-19 ) updated rapid risk assessment from ecdc on the outbreak of covid-19: increased transmission globally guidance for wearing and removing personal protective equipment in healthcare settings for the care of patients with suspected or confirmed covid-19 global surveillance for covid-19 caused by human infection with covid-19 virus: interim guidance the efficacy of contact tracing for the containment of the 2019 novel coronavirus (covid-19) sars-cov-2 infection in health care workers comparative accuracy of oropharyngeal and nasopharyngeal swabs for diagnosis of covid-19. cent evidence-based med nuff dep prim care heal sci univ oxford parere del consiglio superiore di sanità: definizione di paziente guarito da covid-19 e di paziente che ha eliminato il virus sars-cov-2 circolare del ministero della salute del 25/03/2020 "aggiornamento delle linee di indirizzo organizzative dei servizi ospedalieri e territoriali in corso di emergenza covid-19 the laboratory diagnosis of covid-19 infection: current issues and challenges detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr r: a language and environment for statistical computing aggiornamento nazionale: 23 aprile 2020. task force covid-19 del dipartimento malattie infettive e servizio di informatica, istituto superiore di sanità evolving epidemiology and impact of non-pharmaceutical interventions on the outbreak of coronavirus disease presumed asymptomatic carrier transmission of covid-19 potential presymptomatic transmission of sars-cov-2 can people with asymptomatic or pre-symptomatic covid-19 infect others: a systematic review of primary data regione lombardia: ulteriori misure per la prevenzione e gestione dell'emergenza epidemiologica da covid-19. ordinanza ai sensi dell'art. 32, comma 3, della legge 23 dicembre 1978, n. 833 in materia di igiene e sanità pubbl exploring the reasons for healthcare workers infected with novel coronavirus disease 2019 (covid-19) in china effective strategies to prevent coronavirus disease-2019 (covid-19) outbreak in hospital integrated infection control strategy to minimize nosocomial infection of coronavirus disease 2019 among ent healthcare workers key: cord-350758-oyqq7ltq authors: zhang, xi-ru; huang, qing-mei; wang, xiao-meng; cheng, xin; li, zhi-hao; wang, zheng-he; zhong, wen-fang; liu, dan; shen, dong; chen, pei-liang; song, wei-qi; wu, xian-bo; yang, xingfen; mao, chen title: prevalence of anxiety and depression symptoms, and association with epidemic-related factors during the epidemic period of covid-19 among 123,768 workers in china: a large cross-sectional study date: 2020-08-26 journal: j affect disord doi: 10.1016/j.jad.2020.08.041 sha: doc_id: 350758 cord_uid: oyqq7ltq background: : covid-19 has gained intense attention globally. however, little is known about the covid-19-ralated mental health status among workers. methods: : the cross-sectional online survey with 123,768 workers was conducted from february 2, 2020 to february 7, 2020 on a mega-size labor-intensive factory in shenzhen, china. oral consent was obtained prior to the questionnaire survey. the information collected in the survey included demographic characteristics, psychological symptoms, covid-19-related information, and demands for psychological education and interventions. symptoms of anxiety and depression were measured by the zung's self-rating anxiety scale and self-rating depression scale. logistic regression models were performed to determine the association between related factors and mental health status. results: : the prevalence of anxiety and depression symptoms was 3.4% and 22.8%, respectively. the dominant epidemic-related factors were having confirmed cases in the community (odds ratio [or], 2.75, 95% ci, 2.37–3.19) and having confirmed friends (or, 2.44; 95% ci, 1.69–3.52) for the increased risk of anxiety and depression symptoms, respectively. nevertheless, major traditional risk factors such as general or poor health status and always drinking alcohol were still the dominant factors associated with the increased risk of anxiety and depression symptoms. overall, 67.3% and 26.8% workers reported desire for psychological education and interventions, respectively. limitations: : all assessments were self-reported, resulting in a risk of method bias. conclusions: : our findings show a relatively low prevalence of anxiety symptoms, a relatively high prevalence of depression symptoms, and urgent demand for psychological education and interventions among workers during the covid-19 outbreak. 2020, triggering a return trip peak for workers. due to a low level of education, a relatively weak awareness of infectious diseases prevention and control, a high-intensity workload, and high crowd densities after returning to work, workers were high-risk populations for the spread and rebound of the epidemic. thus, government departments needed to pay more attention to the workers for prevention and control of the covid-19 epidemic. previous studies have shown that a large-scale epidemic disease not only seriously endangers people's life and property safety but also has a negative impact on mental health, such as anxiety, depression, and other negative emotions, and can cause a psychological crisis. for instance, the public became more pessimistic in their life after experiencing the epidemic of the severe acute respiratory syndrome (sars) in 2003 (lau, yang, tsui, pang, & wing, 2006 . other previous studies on large-scale epidemics also showed that the probability of group panic in an outbreak is much higher than the risk of contracting the disease (betancourt et al., 2016; kelly et al., 2019; leung et al., 2005; mohammed et al., 2015; reardon, 2015; shultz, baingana, & neria, 2015) . therefore, the national health commission issued the "guiding principles for emergency psychological crisis intervention for the pneumonia epidemic of new coronavirus infection" (national health commission of china, jan 26, 2020.). emerging studies on the relationship between covid-19 and mental health status have been published (huang & zhao, 2020; ma et al., 2020; nie et al., 2020; xiao et al., 2020) . however, the available studies mainly focused on the general population, medical workers, and infected patients. currently, there is no known information about the mental health status of factory workers during the peak of the covid-19 epidemic. therefore, in a large cross-sectional online study, we investigated the prevalence of anxiety and depression symptoms, as well as related factors, among factory workers during the epidemic period of covid-19. moreover, we also explored the demand for psychological education and interventions. the data used in the present study were derived from a cross-sectional online survey based on a mega-size labor-intensive factory in shenzhen, guangdong province, china, with 180,000 employees from various provinces across the country. the survey was divided into seven modules, including demographic characteristics, lifestyle factors, epidemic-related factors, traffic information, knowledge, attitude, and practice (kap), and demand for psychological education and interventions during the period of epidemic. the present survey was conducted online using an electronic questionnaire. oral consent was obtained from the respondents prior to beginning the survey. the survey was conducted from february 2, 2020 to february 7, 2020. overall, 142,584 respondents completed the survey, yielding a response rate of 79.2%. after excluding respondents who filled out questionnaires with the same ip address (n = 15,035) and those who completed the survey in less than 510 seconds (n = 3781), 123,768 respondents were ultimately included in the analyses, yielding an effective response rate of 68.8% (figure 1 ). the distribution of the respondents by province or region can be found in table s1 in the supplement. the protocol of this study was approved by the biomedical ethics committee of southern medical university. data were collected online via a large free questionnaire platformthe chinese survey website wenjuanxing (https://www.wjx.cn/). workers were asked to complete a self-administered questionnaire, which took approximately 10-15 minutes. to avoid repetition, questionnaires submitted from the same ip address as a previously submitted questionnaire were not accepted. anxiety and depression symptoms were assessed by the wildly used zung's self-rating anxiety scale (sas) and self-rating depression scale (sds) for testing mental health status (zung, 1971; zung, richards, & short, 1965) . the sas and sds consist of 20 self-reporting items about anxiety and depression symptoms, respectively. some of the items were worded symptomatically positive and rated on a 4-1 scale (a little of the time, some of the time, good part of the time, and most of the time), while others were symptomatically negative and rated on a 1-4 scale (a little of the time, some of the time, good part of the time, and most of the time). the tools used in this study are listed in the supplement. a standardized scoring algorithm was used to determine anxiety and depression symptoms, with a total score of 20-80. anxiety symptoms were identified if the sas score was ≥50, while score of 50-59 was -mild‖, 60-69 was -moderate‖, and ≥70 was -severe‖. similarly, depression symptoms were identified if the sds score was ≥ 53, while score of 53-62 was -mild‖, 63-72 was -moderate‖, and ≥ 73 was -severe‖. two variable sets were considered to be stratification variables, including epidemic-related variables and demographic variables. the epidemic-related variables were defined as follows: cumulative number of confirmed cases in the provinces (1-499, 500-999,1000-9999, and ≥10,000); have infected cases in the community or not (no case, suspected cases, confirmed cases, and not clear); having infected relatives or not (no case, suspected cases, confirmed cases, and not clear); having infected friends or not (no case, suspected cases, confirmed cases, and not clear); having passed by, traveled to, or having lived in hubei province in the last two weeks (none, having passed by hubei province, having traveled to hubei province, and having lived in hubei province). the demographic variables were defined as follows: sex (male or female), age groups (≤ 25 years, 26-35 years, or ≥ 36 years), education levels (≤ 6 years, 7-9 years, 10-12 years, or ≥13 years), ethnicities (han or minorities), provinces or regions (hubei province or others), residence (urban or rural), marital status (married or not married), health status (very healthy, well, or general or poor), smoking status (hardly ever, sometimes, or always), and alcohol consumption (hardly ever, sometimes, or always), positions (general worker, line supervisor, group leader, or manager), and seniority (0-6 months, 7-12 months, 13-24 months, or >24months). the -demand for psychological education‖ was assessed with the following question: -do you have a demand for psychological education?‖ with responses of -yes‖ or -no‖. if someone answered yes, they would be asked -what kind of knowledge for psychological education do you need?‖ with responses of -the common symptom of covid-19‖, -ways to alleviate the psychological effects‖, -ways to seek professional psychological help‖, or -others‖. the -demand for psychological interventions‖ was assessed with the following question: -do you have a demand for receiving psychological interventions?‖ with responses of -very‖, -moderate‖, -a little‖ or -no‖. if someone answered very, moderate, or a little, they would be asked -what kind of psychological interventions do you need?‖ with responses of -counselling‖, -promotion of mental health knowledge‖, -mental health training course‖, -psychological assessment‖, -group building and other development activities‖, -psychological salon‖, or -others‖. meanwhile, they also would be asked -when are you willing to receive the psychological interventions?‖ with responses of -morning meeting‖, -after work‖, -at weekend‖, -lunchtime‖, -dinner time‖, and -others‖. all statistical analyses were performed using spss version 25; all tests were 2-sided, and statistical significance was set at p < 0.05. the mean and standard deviation (sd) (continuous variables) or number and percentage (categorical variables) were used to describe the characteristics of the respondents. bivariable logistic regression analyses were applied to test the associations of potential explanatory variables including demographic variables and epidemic-related variables with anxiety and depression symptoms. to measure the associations of epidemic-related variables with anxiety and depression symptoms, multivariable logistic regression models were used to adjust for demographic variables including sex, age group, education level, residence, marital status, health status, smoking status, alcohol consumption, positions, and seniority. of the respondents were general workers, 6.0% were line supervisors, 4.9% were group leaders, and 12.8% were managers. respondents with more than 24 months of service accounted for 50.6%. compared to female respondents, male respondents were more likely to have senior positions and lived in the province with a less cumulative number of confirmed cases (table 1) . overall, 3.4% of respondents reported anxiety symptoms, ranging from 2.9% mild to 0.3% moderate and 0.2% severe; while 22.8% of respondents reported depression symptoms, ranging from 9.6% mild to 13.1% moderate and 0.1% severe. table 2 describes the results of the bivariate analysis. according to the influence on the risk of anxiety and depression symptoms, the epidemic-related exposures ranked as follows: having infected friends, having infected relatives, having infected cases in community, increased cumulative number of infected cases in provinces, and having lived in hubei province in the last two weeks. interestingly, the prevalence of anxiety and depression symptoms was significantly lower among respondents who recently lived in hubei province compared with those who lived in other provinces or regions. associations of demographic characteristics with anxiety and depression symptoms are shown in table 2 and table s2 . of note, health status and alcohol consumption were the most dominant factors influencing the risk of anxiety and depression symptoms. after adjusting for the demographic covariates, the epidemic-related factors with the highest to lowest risk of anxiety symptoms ranked as follows: having infected cases in the community, having infected friends, having infected relatives, and the increased cumulative number of infected cases in the provinces, and having passed by, traveled to, or lived in hubei province in the last two weeks. the most dominant factors influencing the risk of depression symptoms were having infected relatives and infected friends (table 3) . for instance, compared with respondents with no infected friends, the adjusted odds ratios were 2.72 (95% ci, 1.96-3.78) for anxiety symptoms and 1.60 (95% ci, 1.25-2.05) for depression symptoms in those with suspected friends, and 1.93 (95% ci, 1.12-3.32) for anxiety symptoms and 2.44 (95% ci, 1.69-3.52) for depression symptoms in those with confirmed friends. interestingly, the prevalence of anxiety (or, 0.80; 95% ci, 0.70-0.90) and depression (or, 0.81; 95% ci, 0.76-0.85) symptoms were significantly lower among respondents who recently lived in hubei province compared with those who lived in other provinces or regions. association of demographic characteristics with anxiety and depression symptoms was shown in table 3 and table s3 . of note, health status and alcohol consumption were remained the dominant factors influencing the risk of anxiety and depression symptoms. respondents with general or poor health status were more likely to have anxiety (or, 6.34; 95% ci, 5.64-7.13) and depression (or, 2.15; 95% ci, 1.98-2.35) symptoms. the prevalence of anxiety and depression symptoms among respondents who always drank alcohol was almost triple that of those who hardly ever drank alcohol. as shown in table 4 , the prevalence of respondents reporting a demand for psychological education (overall rate: 67.3%) was higher in those with anxiety (78.4% vs 66.9%) and depression symptoms (69.0% vs 66.7%) than in those without. for all respondents, the most needed psychological knowledge was the common symptom of covid-19, followed by the methods to alleviate the epidemic's psychological effects. the prevalence of respondents reporting a demand of psychological interventions (overall rate: 26.8%) was higher in those with anxiety (63.5% vs 25.5%) and depression symptoms (38.2% vs 23.4%) than in those without. for respondents with anxiety or depression symptoms, the most needed psychological intervention was counselling, followed by promotion of mental health knowledge. morning meeting followed by the period after work were the two most desired time to receive psychological interventions. interestingly, the prevalence of respondents who lived in hubei province reporting the demands of psychological knowledge (63.9% vs. 67.6%) and interventions (22.8% vs. 27.1%) was slightly below that of those who lived in the other provinces or regions (table s4 ). the aim of the present study was to investigate the prevalence and the related factors of anxiety and depression symptoms, and the demands for psychological education and interventions among workers during the epidemic period of covid-19 in china. approximately 3.4% and 22.8% of respondents exhibited symptoms of anxiety and depression, respectively. we also revealed the urgent demands for psychological education (67.3%) and interventions (26.8%) among workers. moreover, after adjustment for the demographic covariates, epidemic-related factors especially having confirmed cases in the community and having confirmed friends were found to be significantly associated with the higher risk of anxiety and depression symptoms, respectively, but traditional risk factors such as health status and alcohol consumption remained the dominant factors. interestingly, respondents who recently lived in hubei province were more likely to report a lower risk of anxiety and depression symptoms, and slightly lower demands for psychological education and interventions. compared with previous studies performed on the general population in china before the outbreak, the prevalence of anxiety symptoms in this study was not significantly different, while the prevalence of depression symptoms was roughly 4-5 times or higher (y. huang et al., 2019; phillips et al., 2009) . the prevalence of anxiety symptoms in the present study was lower than previous studies on the general population which reported 28.8% -35.1%. the prevalence of depression symptoms in the present study from february 2, 2020 to february 7, 2020 was consistent with the results of an epidemiological study that was conducted in early february 2020 among the general population in china, which indicated that the overall prevalence of depressive symptoms was 20.1% (huang & zhao, 2020 ). an earlier survey that was performed in late january 2020 found that 16.5% respondents reported moderate to severe depressive symptom (c. wang, r. pan, et al., 2020) . another later survey that was performed in early march 2020 reported that 27.9% of respondents had depression symptoms (shi et al., 2020) . these findings indicated that depression symptoms occurred among the workers during the epidemic period of covid-19 in china and highlighted the importance of preventing and treating mental health problems of workers. the present study was conducted from february 2, 2020 to february 7, 2020, when these workers suspended their work because of the publication of the policy for postponing the resumption of work (general office of the state council, jan 27, 2020). soon afterwards they came back to work on february 10, 2020. therefore, health authorities and factories should pay more attention on the psychological health of workers for improving mental health in workers after returning to work, which potentially improves productivity. this study demonstrated a statistically significant association between epidemic-related exposure and a higher risk of anxiety and depression symptoms. nevertheless, our findings further indicated that major traditional risk factors, such as physical health and alcohol consumption, were still the dominant factors influencing the risk of anxiety and depression symptoms, which was also reported in the previous studies. a study on 3031 migrant workers from 10 manufacturing factories in shenzhen, china, showed that respondents with physical illness in the past two weeks were more likely to report poor mental health (or,1.72; 95% ci,1.43-2.05) (zhong et al., 2018) . another study demonstrated that consuming an average of seven or more alcoholic drinks per day significantly increased the risk of depression compared with consuming an average of one or two alcoholic drinks (or, 2.21; 95%ci, 1.02-4.40) (almeida, hankey, yeap, golledge, & flicker, 2014) . however, the association between alcohol consumption and mental health status might also be explained by -reverse causality‖, in which increased motivation of frequently drinking would occur in the anxiety and depression symptoms (cyders & smith, 2008; dir, karyadi, & cyders, 2013) . this study revealed an urgent need for psychological knowledge and interventions among workers. of note, we found that respondents with anxiety symptoms were more likely to report the demands of psychological interventions (63.5% vs 25.5%), suggesting that health authorities and factories should pay more attention to those populations. moreover, our findings also have several important, immediate implications for health authorities and factories. first, our findings suggested that the common symptom of covid-19 was the most needed psychological knowledge. second, counseling and promotion of mental health knowledge ranked as the top two demands for psychological interventions. third, morning meeting followed by the period after work were the two most desired time to receive psychological interventions. in summary, we have identified the most desired psychological knowledge, interventions, and times to receive them, which could help health authorities to formulate targeted policies for workers to improve their mental health status. interestingly, we found that respondents who recently lived in hubei province (the hardest-hit province of the covid-19 epidemic) had a lower risk of anxiety and depression symptoms, and slightly lower demands for psychological education and interventions during the epidemic period of covid-19. the reason for this finding may be family support (bhugra & van ommeren, 2006) . people in hubei province delayed returning to work due to the epidemic, and they were advised to avoid going to public places. therefore, family members were likely to spend more time together with each other. to our knowledge, the present study is the largest cross-sectional study to investigate the prevalence of anxiety and depression symptoms, as well as associations with epidemic-related factors during the epidemic period of in china. the present study not only revealed the mental health status of workers during the epidemic period of covid-19, but also provided a reference for the mental health of workers in labor-intensive factories in china. the strengths of our study include the large sample size from various provinces or regions across the country, special population groups, a short-cycle survey, and careful measurement of epidemic-related factors and demographic covariates. wenjuanxing. there are cases whose questionnaires were filled out by others instead of by the respondents themselves. to reduce the error caused by this causes, we excluded questionnaires with the same ip address. third, the measurement methods for anxiety and depression symptoms as well as demographic covariates, and epidemic-related factors relied on self-reporting, and therefore raised the possibility of common method bias. finally, the present study used zung's self-rating scales method. the results of anxiety and depression might lack comparability with clinical diagnostic measurements of anxiety and depression. in conclusion, our survey found a relatively low prevalence of anxiety symptoms, a relatively high prevalence of depression symptoms, and the urgent demands for psychological knowledge and interventions among chinese workers. epidemic-related factors were significantly associated with the higher risk of anxiety and depression symptoms, but traditional risk factors, such as health status and alcohol consumption, were still the dominant factors. in addition, we also identified the most desired psychological knowledge, interventions, and times to receive them, which could help health authorities and factories to formulate targeted policies to increase workers' adherence to knowledge and interventions, and thus improve workers' mental health status. outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle prevalence of depression and its association with quality of life in clinically stable patients with covid-19 mental health in emergency response: lessons from ebola guiding principles for emergency psychological crisis intervention for pneumonia epidemic of new coronavirus infection /27/content_5472433.htm anxiety and depression and its correlates in patients with coronavirus disease 2019 in wuhan importation and human-to-human transmission of a novel coronavirus in vietnam prevalence, treatment, and associated disability of mental disorders in four provinces in china during 2001-05: an epidemiological survey ebola's mental-health wounds linger in africa prevalence of and risk factors associated with mental health symptoms among the general population in china during the coronavirus disease the 2014 ebola outbreak and mental health: current status and recommended response a novel coronavirus outbreak of global health concern immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china the psychological impact of covid-19 pandemic on medical staff in guangdong, china: a cross-sectional study novel coronavirus (2019-ncov): situation report-20 who director-general's statement on ihr emergency committee on novel coronavirus psychological impact of healthcare workers in china during covid-19 pneumonia epidemic: a multicenter cross-sectional survey investigation common mental health problems in rural-to-urban migrant workers in shenzhen, china: prevalence and risk factors a rating instrument for anxiety disorders self-rating depression scale in an outpatient clinic. further validation of the sds or, odds ratio. a in general, the people who have lived in hubei for the past two weeks were almost native of hubei province ways to seek professional psychological help 49,751(27.6) 47,700 (27.5) 2051 (28.4) 38,155 (27.5) 11,596 (27, psychological interventions, and intervention period were ranked according to the demand of respondents with anxiety and depression symptoms key: cord-336942-2mvcyvbl authors: liu, cindy h.; zhang, emily; wong, ga tin fifi; hyun, sunah; hahm, hyeouk “chris” title: factors associated with depression, anxiety, and ptsd symptomatology during the covid-19 pandemic: clinical implications for u.s. young adult mental health date: 2020-06-01 journal: psychiatry res doi: 10.1016/j.psychres.2020.113172 sha: doc_id: 336942 cord_uid: 2mvcyvbl this study sought to identify factors associated with depression, anxiety, and ptsd symptomatology in u.s. young adults (18-30 years) during the covid-19 pandemic. this cross-sectional online study assessed 898 participants from april 13, 2020 to may 19, 2020, approximately one month after the u.s. declared a state of emergency due to covid-19 and prior to the initial lifting of restrictions across 50 u.s. states. respondents reported high levels of depression (43.3%, phq-8 scores ≥ 10), high anxiety scores (45.4%, gad-7 scores ≥ 10), and high levels of ptsd symptoms (31.8%, pcl-c scores ≥ 45). high levels of loneliness, high levels of covid-19-specific worries, and low distress tolerance were significantly associated with clinical levels of depression, anxiety, and ptsd symptoms. resilience was associated with low levels of depression and anxiety symptoms but not ptsd. most respondents had high levels of social support; social support from family, but not from partner or peers, was associated with low levels of depression and ptsd. compared to whites, asian americans were less likely to report high levels across mental health symptoms, and hispanic/latinos were less likely to report high levels of anxiety. these factors provide initial guidance regarding clinical management for covid-19-related mental health problems. the covid-19 pandemic that has upended the lives of individuals worldwide escalated in the u.s. beginning in march of 2020. although research on acute and widescale stressors (e.g., natural disasters), demonstrates severe implications for mental health (kessler et al., 2008) , there is no precedent for understanding mental health effects due to covid-19, as prospective studies investigating the effects of a pandemic are virtually non-existent. in particular, the identification of risk factors associated with depression, anxiety, and post-traumatic stress disorder (ptsd) among u.s. young adults (18-30 years) is urgently needed. comprising more than one-third of the current u.s. workforce, young adults (often referred to as -millennials‖ and -generation z‖) will be a dominant workforce group for the next decade, and our societal functioning depends on how they emerge from the pandemic. understanding their health and well-being during the pandemic is crucial as it sets the stage for later outcomes. certain risk and protective factors are likely to be implicated in pandemic-related mental health. covid-19-related worry (e.g., maintaining employment, getting tested for coronavirus) may be linked to mental health symptoms. the early weeks of the pandemic saw rapid changes in daily routines, with students moving following university closures and attending classes remotely, and for other young adults, transitioning to remote work or facing job loss. these disruptions may put an already vulnerable group at greater risk for mental health challenges (conrad, 2020) . furthermore, loneliness may be particularly prevalent and devastating during the pandemic given directives for social distancing and isolation. those under the age of 25 already show elevated levels of loneliness (domagala-krecioch and majerek, 2013) , and the pandemic may exacerbate these feelings. despite the critical role that social support plays in mitigating the risks to mental health problems, directives on social distancing may impede on one's typical means for obtaining such support. individual resilience, which refers to one's ability to cope with stress, and distress tolerance, which describes one's ability to manage and tolerate emotional distress, may be salient characteristics that protect against the mental health symptoms that follow major stressors. individual resilience is a significant protective factor for depression, ptsd, and general health after natural disasters (kukihara et al., 2014) . findings have generally demonstrated distress tolerance to be associated with lower symptoms of depression and ptsd following tornadoes (cohen et al., 2016) . however, the extent to which these factors are associated with mental health symptoms during a pandemic is unknown. this study sought to identify potential factors that contribute to mental health outcomes among young adults during the covid-19 pandemic. the cares 2020 project (covid-19 adult resilience experiences study, www.cares2020.com) was launched to track the health and well-being of young adults in the u.s. across multiple time points in 2020 and 2021. this present analysis assessed depression, anxiety, and ptsd symptomatology, and psychological experiences including distress tolerance, resilience, social support, and loneliness. we included depression and anxiety as these are common mental health symptoms among young adults (blazer et al., 1994; chen et al., 2019; eisenberg et al., 2007; liu et al., 2019; mojtabai et al., 2016) . we assessed ptsd symptoms given documented high rates of trauma by young adulthood (costello et al., 2002; reynolds et al., 2016; vrana and lauterbach, 1994) ; a concern was that the pandemic would either create and/or exacerbate symptoms related to prior trauma (breslau et al., 2008 (breslau et al., , 1999 brunet et al., 2001) . new items that specifically assessed covid-19specific concerns were also included. the objective of this work is to identify salient psychosocial risks for mental health symptoms and to prioritize intervention targets for addressing mental health symptoms among young adults. the present cross-sectional study assessed potential risk and protective factors for mental health outcomes based on preliminary cares 2020 data obtained from wave 1 data collection (n = 898) conducted from april 13, 2020 to may 19, 2020, approximately one month after the u.s. declared a state of emergency due to covid-19 and prior to the initial lifting of restrictions across 50 u.s. states. eligible participants were young adults aged 18 to 30 years currently living in the u.s. or receiving education from a u.s. institution. participants were recruited online via email list serves, social media, and word of mouth (i.e., list serves and facebook groups for school organizations or clubs, alumni groups, classes, churches). this took place initially through organizations from the new england area before additional list serves from other regions of the u.s. (midwest, south, and west) were targeted. respondents were asked to complete a 30minute online qualtrics survey regarding covid-19-related experiences, risk and resilience, and physical and mental health outcomes. to ensure data quality, human verification and attention checks were implemented throughout the survey; the data was further inspected visually for response irregularities indicative of bots. participants were compensated via raffle in which one out of every 10 participants received a $25 gift card. all procedures were approved by the institutional review board at boston university. binary scores were created after calculating the mean or sum of each measure. rather than relying on the sample characteristics to categorize our data (e.g., mean, median, tertile or quartile split), the determination of the cutoff score was based on standard cutoffs from previous research; when a standard was not available, scale response descriptors to determine the cutoffs. psychological resilience was measured using the 10-item connor-davidson resilience scale (cd-risc-10, connor and davidson, 2003) , which assesses one's ability to cope with adverse experiences. participants indicated how they felt in the past month on a 5-point scale, with 0 indicating -not true at all‖ and 4 indicating -true nearly all the time.‖ sum scores were recoded dichotomously into -high resilience‖ and -low resilience‖ with a cutoff score of 30 or greater. this cutoff score characterizes responses that tended to be -often true‖ and -true nearly all the time,‖ with those endorsing a score ≥30 considered to be at -very high risk with mental disorders‖ (andrews and slade, 2001; kessler and mroczek, 1992) . the distress tolerance scale is a 15-item measure that assesses participants' abilities to withstand and cope with emotional distress (simons and gaher, 2005) . respondents rated personal attitudes towards feelings of emotional distress on a 5-point scale, ranging from 1 (-strongly agree‖) to 5 (-strongly disagree‖), with higher ratings indicating greater distress tolerance. a global mean score of distress tolerance was calculated. we considered the scale descriptors and followed the cutoffs used for the cd-risc, which was also a 5-point scale. as such, scores were dichotomously recoded so that global mean scores less than 4 indicated -low distress tolerance‖ and scores of 4-to-5 indicated -high distress tolerance.‖ perceived social support was measured using the multidimensional scale of perceived social support (mspss, zimet et al., 1988) , in which participants rated perceived emotional support using a 7-point likert scale ranging from 1 (-very strongly disagree‖) to 7 (-very strongly agree‖). this measure includes three subscales assessing perceived support quality from family, friends, and partners. because mean scores greater than 5 reflected responses indicating -mildly agree,‖ -strongly agree,‖ and -very strongly agree,‖ each subscale mean scores were recoded so that scores 5 or greater referred to -high perceived social support,‖ and scores below 5 were referred to as -low perceived social support.‖ instrumental support was assessed through a 4-item subscale of the two-way social support scale (shakespeare-finch and obst, 2011). participants indicated the extent of their received instrumental support based on a 6-point likert scale ranging from 0 (-not at all‖) to 5 (-always‖). items were summed to create a total score with a possible range of 0-to-20. given cutoffs used for the other 5-point scale in our survey and the scale descriptors, a cutoff score with a sum of 16 or greater indicated -high instrumental support,‖ whereas scores lower than 16 indicated -low instrumental support.‖ loneliness was measured using an adapted 3-item version of the ucla loneliness scale short form (hughes et al., 2004) . participants rated lack of companionship, feelings of being left out, and isolation from others on a scale of 1 to 3, with 1 as -hardly ever,‖ 2 as -some of the time,‖ and 3 as -often.‖ a sum score for loneliness was calculated with a total possible range of 3-to-6 and recoded dichotomously; a cutoff score of 6 or greater indicated -high loneliness‖ as used in prior studies (lowthian et al., 2016; tymoszuk et al., 2019) . severity of covid-19 pandemic-related worry was assessed using a newly developed measure consisting of 6 items, which included the following concerns: -having enough groceries during city lockdowns/social distancing protocols‖, -obtaining a covid-19 test if i become sick‖, -getting treated for covid-19 if i contract it‖, -keeping in touch with loved ones during social distancing protocols‖, -maintaining employment during the subsequent economic downturn‖, and -having enough money to pay for rent and buy basic necessities.‖ participants were asked to indicate their level of worry for each item on a scale of 1 to 5, with 1 being -not worried at all,‖ and 5 being -very worried.‖ sum scores were calculated with a total possible range of 6-to-30 and recoded into a dichotomous variable with a cutoff score of 24 or greater as -highly worried.‖ cronbach's alpha for measure items was .70, indicating good reliability. depression was assessed with the 8-item version of the patient health questionnaire (phq-8, kroenke et al., 2009) which assessed frequency of depressive symptoms in the past two weeks on a scale of 0 (-not at all‖) to 3 (-nearly every day‖). sum scores of the phq-8 had a total possible range of 0-to-24 and were recoded dichotomously based on a cutoff score of 10 or higher (wu et al., 2019) . anxiety was assessed with the generalized anxiety disorder scale (gad-7, spitzer et al., 2006) a widely used measure assessing the frequency of anxiety symptoms in the past two weeks on a scale of 0 to 3, with 0 being -not at all‖ and 3 being -nearly every day.‖ sum scores ranged from 0-to-21. following the convention of other studies (plummer et al., 2016) , responses were recoded dichotomously based on a cutoff score of 10 or higher to determine elevated anxiety. the ptsd checklist-civilian version (pcl-c), a validated 17-item measure, was administered to assess ptsd symptoms (weathers et al., 1993) . participants indicated how much they were bothered by problems and experiences in response to stressful life events in the past month, with 1 as -not at all‖ and 5 as -extremely.‖ sum scores of the 17 items were calculated and created into a dichotomous variable with a cutoff score of 45 or greater, based on the psychometric properties for the measure and as suggested by the national center for ptsd (blanchard et al., 1996) . the variables were normally distributed, with predictors indicating acceptable levels of collinearity (vif < 5). to identify potential risk and protective factors of mental health symptoms, three logistic regression models were performed to examine depression, anxiety, and ptsd symptoms as primary outcomes. resilience, distress tolerance, perceived social support, instrumental social support, loneliness, and covid-19-specific worries were entered as predictors in unadjusted models. age, gender, income, and race were entered in each of the three adjusted models. all variables were binary with exception to age and income, which were continuous. two-tailed p-values were used. to guard against type i error, bonferroniadjustments were made to consider the 8 predictors and 4 covariates used in each model (.05/12=.004). our results and interpretations are therefore based on a significance set at a p<.004 (note that the significance in the tables remain unadjusted to provide more rather than less information to the reader). all analyses were performed using spss 25.0. table 1 shows demographic characteristics of our participants and descriptive data on all predictors and outcomes. the sample was racially and ethnically diverse, with 59.6% white, 21.2% asian, 5.3% black, 6.0% hispanic/latino, 0.1% ai/na, 6.2% mixed race, and 1.4% indicating another race. the majority of respondents were women (81.3%), u.s. born (86.3%), employed (66.7%), students (61.3%), and those who earned less than $50,000 per year (82.1%). among those identifying as students, 89.7% were enrolled as full-time and 7.3% were international students. overall, participants scored as having high loneliness (61.5%), low resilience (72.0%), and low distress tolerance (74.1%). at the same time, the majority of respondents reported having high levels of social support (family, partners, peer, and instrumental). finally, 43.3% of our sample had high levels of depression (phq-8 scores ≥ 10), 45.4% had high anxiety scores (gad-7 scores ≥ 10) and 31.8% had high levels of ptsd symptoms (pcl-c scores ≥ 45). table 2 displays the associations between predictors and mental health outcomes in each of the three models adjusted for the age, gender, race, and income. the results described here pertain only to significance set at p < .004 with bonferroni corrections. predictors that were significantly associated with depression, anxiety, and ptsd included loneliness (or range = 1.98 -2.72), covid-19-specific worries (or range = 2.87 -5.05), and distress tolerance (or range = 0.22 -0.42). specifically, those who endorsed high levels of loneliness and worries about covid-19 and low levels of distress tolerance were more likely to score above the clinical cutoffs for depression, anxiety, and ptsd. those with high levels of resilience were less likely to score above the cutoff for depression and anxiety. those with high levels of family support were less likely to score above the clinical cutoff for depression and ptsd (or = 0.46 and 0.44, respectively). instrumental support was negatively associated with depression. no associations were obtained between support from partners and friends. in analyses of associations between covariates and outcomes, age and income were not associated with depression, anxiety, or ptsd. with regard to gender, men who identified as transgender were more likely to report high levels of ptsd (or = 4.20, ci = 1.62 -10.89, p=.003); no differences were observed between men and women. asian americans compared to whites were less likely to report high levels of depression (or = 0.50, ci = 0.33 -0.76, p=.001) and ptsd (or = 0.40, ci = 0.25 -0.64, p<.001). asians americans and hispanic/latinos were less likely to report high levels of anxiety (or = 0.35, ci = 0.24 -0.53, p<.001, or = 0.35, ci = 0.18 -0.68, p=.00, respectively2). our findings highlight major psychological challenges faced by young adults during the initial weeks of the covid-19 pandemic. at least one-third of young adults reported having clinically elevated levels of depression (43.3%), anxiety (45.4%), and ptsd symptoms (31.8%). the rates of depression, anxiety, and ptsd in our study are considerably higher compared to prior studies that have used the same cut points (phq-8 ≥ 10; gad-7 ≥ 10; and pcl-c ≥ 45). year (26.3%; zhang et al., 2011) . the high rates from our sample may reflect ongoing distress, as we measured the symptoms in the weeks following the government directives for closures. young adults may have been particularly distressed in managing school or work responsibilities during this time while having no sense of certainty regarding the pandemic's end. as well, the high rate of mental health concerns among study participants may be partially attributable to the specific characteristics of our sample; given that the study was launched on the east coast, our young adult respondents may have been located at pandemic -hot spots,‖ with proximity to a greater number of covid-19 cases potentially being an added stressor for our sample. strikingly, the majority of respondents reported feeling lonely during the first two months of the pandemic, as well as having low resilience and low ability to tolerate distress. however, the majority reported having social support from family, partners, and peers, as well as instrumental support during this time. we note that the absolute rates of low perceived social support remains seem problematic. for instance, approximately 37% of respondents reported low family support. these findings highlight major psychological challenges currently faced by young adults during the initial weeks of the covid-19 pandemic. our study also identified factors associated with clinical levels of depression, anxiety, and ptsd symptoms. high loneliness and low distress tolerance levels were consistently associated with high levels of depression, anxiety, and ptsd. high levels of resilience were associated with low anxiety. social support from family was associated with low levels of depression, and ptsd symptoms, whereas support from partners or friends were not associated with any mental health outcomes. high levels of instrumental support were associated with low levels of depression. our data is consistent with findings demonstrating loneliness as a risk factor for mental health (banerjee et al., 2020; hawkley and cacioppo, 2010; okruszek et al., 2020) ; this is particularly salient with government directives for social distancing and isolation. feeling cut off from social groups may lead one to feel vulnerable and pessimistic about one's circumstances, altogether producing negative mood states and anxiety (muyan et al., 2016) , that are further heightened during a pandemic. the high levels of reported loneliness in our sample and its association with depression, anxiety, and ptsd symptoms underscore the severity of experiences of young adults during the pandemic. distress tolerance, or one's ability to manage and tolerate emotional distress, was strongly associated low levels of depressive and anxiety, and ptsd symptoms; individual resilience was associated with low levels of depression and anxiety symptoms, but not ptsd. individual resilience, which encompasses personal competence and trust in one's instincts (connor and davidson, 2003) , has been associated with low levels of depression, anxiety, and ptsd symptomatology after disasters (blackmon et al., 2017) . one's perceived ability to tolerate negative or aversive emotional and/or physical states may be more protective than the personal qualities that comprise psychological resilience, especially for those experiencing symptoms of ptsd during a pandemic. the pandemic is worldwide stressor without a foreseeable endpoint, and the effects of the pandemic cannot be controlled by a single individual. furthermore, the pandemic simultaneously impacts various domains (e.g., financial, relational, and health) with this stress potentially exacerbating the sensations associated with ptsd symptoms. as such, psychological resilience that is typically associated with overcoming setbacks may not be sufficient for protecting against ptsd symptoms within the first several weeks of a widespread pandemic. interventions that target distress tolerance, such as mindfulness-based interventions, may be more effective than cognitive interventions targeting core beliefs about the self especially for those with ptsd symptoms (nila et al., 2016) . longitudinal approaches would help to examine this possibility further. emotional support from family but not from friends and significant others was associated with low levels of depression and ptsd. friends and significant others may have or are perceived to have less capacity to validate other's emotional experiences during a pandemic, considering that they may be young adults who are experiencing similar struggles. emotional support provided by family may be more stable and coupled with the provision of material resources that young adults may still receive from parents. our findings are consistent with prior work showing that family support but not friend and partner support mediates the effects of stress on health (lee et al., 2018) . family support may be more meaningful in providing reassurance to young adults, considering the possible concrete needs during the pandemic. instrumental support, or tangible assistance, may be an important factor for the mental health of young adults during the immediate weeks of the covid-19 pandemic onset given that many were faced with acute disruptions, such as unemployment, financial stress, and relocation following university campus closures. however, instrumental support was not significantly associated with any of the outcomes after adjusting the p-value to .004. additional research is needed to clarify the respective roles on both emotional and instrument support given variations in their potential effects on depression, anxiety, and ptsd. our newly developed covid-19 worries measure uniquely predicted mental health symptoms, underscoring how the specific features of this pandemic give rise to acute stress. the stress resulting from lifestyle changes due to features of covid-19 itself may lead to greater mental health concerns distinct from the endorsement of other risks. our analyses showed that the six items in our measure were reliable and the total subscale score was significantly associated with the symptoms assessed in this study; however, additional work is required to determine the validity of this measure. in general, asian americans were less likely to report high levels of mental health symptoms compared to whites, with hispanic/latino respondents also being less likely to report high anxiety. asian and latino immigrants compared to those who are born in the u.s. are less likely to endorse psychological distress (dey and lucas, 2006; takeuchi et al., 2007) . it is possible that other experiences such as ethnic identity, social networking, and family cohesion serve as a protective factor for mental health, especially for non-u.s. born participants (leong et al., 2013) . the under-recognition of distress symptoms may also be possible among ethnic minorities (liu et al., 2020) . although our sample size of gender minorities was small, men who identified as transgender were more likely to report a high level of ptsd symptoms, consistent with prior research (reisner et al., 2016; shipherd et al., 2011) . greater attention to gender differences in mental health symptoms as well as a deeper study regarding the specific experiences faced by racial/ethnic and gender minorities during pandemic is warranted. the cross-sectional design limits our ability to infer causality involved in leading to mental health problems. we used a convenience sample, and caution must be taken in the generalizability of our findings to the broader population of young adults in the u.s. given the uneven sampling of subgroups. the reliance of self-report itself has limitations, such that it may be prone to misinterpretation. future analyses with the anticipated waves of data collection will enable us to examine the association of our predictors to outcome measures of mental health and to adjust for additional confounds. as well, we will have an opportunity to examine potential moderation effects to understand whether outcomes vary by circumstances or individual characteristics, such as socioeconomic capital, social support type, distress tolerance, and resilience. to our knowledge, our study is the first prospective cohort study to assess mental health outcomes and risk and resilience factors in u.s. young adults during the first several weeks of the covid-19 pandemic. in our study, one in three u.s. young adults reported clinical cut-off symptoms of depression, anxiety, and ptsd as well as high levels of loneliness. we present new evidence that signifies the roles of loneliness, distress tolerance, family support, and covid-19 worries on mental health outcomes during the first month of the covid-19 pandemic. mental health interventions should incorporate these constructs to help mediate the impact of covid-19 on adverse mental health status among u.s. young adults. interpreting scores on the kessler psychological distress scale (k10) clinical significance of pain at hospital discharge following traumatic orthopaedic injury: general health, depression, and ptsd outcomes at 1 year social isolation as a predictor for mortality: implications for covid-19 prognosis adapting to life after hurricane katrina and the deepwater horizon oil spill: an examination of psychological resilience and depression on the mississippi gulf coast psychometric properties of the ptsd checklist (pcl) the prevalence and distribution of major depression in a national community sample: the national comorbidity survey previous exposure to trauma and ptsd effects of subsequent trauma: results from the detroit area survey of trauma a second look at prior trauma and the posttraumatic stress disorder effects of subsequent trauma: a prospective epidemiological study the effects of initial trauma exposure on the symptomatic response to a subsequent trauma psychiatric symptoms and diagnoses among u.s. college students: a comparison by race and ethnicity distress tolerance and social support in adolescence: predicting risk for internalizing and externalizing symptoms following a natural disaster development of a new resilience scale: the connor-davidson resilience scale (cd-risc) universities' response to supporting mental health of college students during the covid-19 pandemic [www document the prevalence of potentially traumatic events in childhood and adolescence physical and mental health characteristics of us-and foreign-born adults: united states the issue of loneliness in the period of -emerging adulthood prevalence and correlates of depression, anxiety, and suicidality among university students prevalence of probable mental disorders and help-seeking behaviors among veteran and non-veteran community college students loneliness matters: a theoretical and empirical review of consequences and mechanisms a short scale for measuring loneliness in large surveys: results from two population-based studies an update of the development of mental health screening scales for the us national health interview study trends in mental illness and suicidality after hurricane katrina the phq-8 as a measure of current depression in the general population trauma, depression, and resilience of earthquake/tsunami/nuclear disaster survivors of the relational context of social support in young adults: links with stress and well-being disentangling immigrant status in mental health: psychological protective and risk factors among latino and asian american immigrants parent perceptions of mental illness in chinese american youth the prevalence and predictors of mental health diagnoses and suicide among u.s. college students: implications for addressing disparities in service use hospitals and patients working in unity (how r u?): protocol for a prospective feasibility study of telephone peer support to improve older patients' quality of life after emergency department discharge disordered gambling and comorbidity of psychiatric disorders among college students: an examination of problem drinking, anxiety and depression national trends in the prevalence and treatment of depression in adolescents and young adults loneliness and negative affective conditions in adults: is there any room for hope in predicting anxiety and depressive symptoms? mindfulness-based stress reduction (mbsr) enhances distress tolerance and resilience through changes in mindfulness safe but lonely? loneliness, mental health symptoms and covid-19 screening for anxiety disorders with the gad-7 and gad-2: a systematic review and diagnostic metaanalysis discriminatory experiences associated with posttraumatic stress disorder symptoms among transgender adults post-traumatic stress disorder across the adult lifespan: findings from a nationally representative survey the development of the 2-way social support scale: a measure of giving and receiving emotional and instrumental support potentially traumatic events in a transgender sample: frequency and associated symptoms the distress tolerance scale: development and validation of a self-report measure a brief measure for assessing generalized anxiety disorder: the gad-7 immigration-related factors and mental disorders among asian americans cross-sectional and longitudinal associations between receptive arts engagement and loneliness among older adults prevalence of traumatic events and post-traumatic psychological symptoms in a nonclinical sample of college students annual convention of the international society for traumatic stress studies one year later: mental health problems among survivors in hard-hit areas of the wenchuan earthquake the multidimensional scale of perceived social support support for this manuscript was provided through the national science foundation key: cord-324981-teywszlm authors: eccles, ron; meier, christiane; jawad, martez; weinmüllner, regina; grassauer, andreas; prieschl-grassauer, eva title: efficacy and safety of an antiviral iota-carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold date: 2010-08-10 journal: respir res doi: 10.1186/1465-9921-11-108 sha: doc_id: 324981 cord_uid: teywszlm background: the common cold, the most prevalent contagious viral disease in humans still lacks a safe and effective antiviral treatment. iota-carrageenan is broadly active against respiratory viruses in-vitro and has an excellent safety profile. this study investigated the efficacy and safety of an iota-carrageenan nasal spray in patients with common cold symptoms. methods: in a randomized, double-blind, placebo-controlled exploratory trial, 35 human subjects suffering from early symptoms of common cold received iota-carrageenan (0.12%) in a saline solution three times daily for 4 days, compared to placebo. results: administration of iota-carrageenan nasal spray reduced the symptoms of common cold (p = 0.046) and the viral load in nasal lavages (p = 0.009) in patients with early symptoms of common cold. pro-inflammatory mediators fgf-2, fractalkine, gro, g-csf, il-8, il-1α, ip-10, il-10, and ifn-α2 were reduced in the iota-carrageenan group. conclusions: iota-carrageenan nasal spray appears to be a promising treatment for safe and effective treatment of early symptoms of common cold. larger trials are indicated to confirm the results. common cold is the most prevalent contagious viral disease in humans. it is caused by a variety of viral pathogens with human rhinoviruses (hrv) being the most abundant ones. affecting the upper respiratory system, symptoms like blocked nose, cough and sneezing are most common [1, 2] . the socioeconomic losses associated with viral respiratory tract infections, however, are huge [3, 4] with enormous direct and indirect costs for our health care system [5] . colds also pose a threat for the very young or old, ailing and/or high risk groups like immunocompromised patients, copd patients, asthmatics or lung transplant recipients [1, 6] . a wide range of remedies is sold on prescription and over the counter, but evidence-based medicine systematic reviews conclude that there is still no reliable prevention or cure available and potential serious side effects of popular products also have to be considered. given the multiple causes of common cold, the cochrane collaboration suggested to focus future research efforts on non virus-specific compounds [7] . effective formulations containing antiviral agents are needed for the safe and efficacious treatment of common cold symptoms and the containment of viral propagation. potential side effects should also be minimal due to the usually nonhazardous nature of the indication. carrageenan is a sulphated galactose polymer, derived from rhodophyceae seaweeds. it is commonly used in food preparations and topical products for its gelling and emulsifying properties. the three main copolymers are designated as iota (ι), kappa () and lambda (λ), depending on the number and location of sulphate moieties on the hexose scaffold structure [8] . carrageenan compounds are on the us food and drug administration "generally recognized as safe" (gras) list of products for consumption and topical applications [9] . in the pharmaceutical industry, carrageenans are used in topical formulations at daily dose levels up to 2% (~30 mg/person). in a recent publication, we presented our in-vitro findings on the antiviral properties of iota-carrageenan against hrvs (11) , which add proof to previous findings on antiviral properties against other viruses [10] [11] [12] [13] . the presented exploratory study was designed to determine the magnitude of any effect of iota-carrageenan nasal spray on the severity of common cold symptoms relative to placebo treatment. the secondary objective was to analyse effects on biomarker levels and presence of common cold viruses in nasal lavage samples. healthy volunteers > 18 years, who were briefed in advance and signed the consent declaration prior to any study-related procedures, were recruited for the study. anonymity was guaranteed as study data and information on subjects was kept safe to prevent communication to third parties. subjects were free to withdraw from the study at any time without prejudice to further treatment. the following symptoms were assessed with inclusion into the study and on each study day: local symptoms were sore throat, blocked nose, runny nose, cough, sneezing and systemic symptoms were defined as headache, muscle ache, and chilliness. symptoms were assessed on a 4 point scale: 0 = none (symptom not present in previous 24 h), 1 = mild (sensible, but not disturbing or irritating), 2 = moderate (symptoms sometimes disturbing/irritating), 3 = severe (symptoms disturbing/irritating most of the time). this scoring system was developed by jackson in 1958 and is widely used in common cold clinical trials [14] . in order to recruit subjects with early onset of common cold, on study entry, subjects had symptom scores of 1 or greater for sore throat, runny or blocked nose and a total symptom score of 9 or less for the sum of severity scores comprising headache, muscle ache, chilliness, sore throat, runny nose, blocked nose, cough, and sneezing. study participants agreed to refrain from taking any other medications intended to prevent, intervene with or treat coughs/colds/flu-like symptoms, starting with study entry and continuing through day 7. entrants were excluded from the study for the following predefined reasons: unwilling to sign the consent form, a known hypersensitivity or allergy to any component of the study medication, a clinically significant cardiovascular, endocrine, neurological, respiratory, or gastrointestinal disease or history, or any other current disease that was considered by the investigator as an exclusion criteria, e.g. current allergic rhinitis, chronic obstructive pulmonary disease (copd). although not explicitly mentioned in the study protocol asthma was such an exclusion criterion and no patients with asthma were recruited. furthermore, subjects were also excluded by the investigator if a severe nasal septum deviation or other condition was present that could have caused nasal obstruction, such as nasal polyps or nasal/sinus surgery in the past, and influenced symptom scores. additionally, participants with a history of alcohol/substance abuse or on prescription medication/concomitant therapy other than for contraception, e.g. systemic steroids, intranasal medicines, antibiotics, were also excluded by the investigator. further reasons for exclusion were incidence of common cold or flu like symptoms for more than 48 h, current smoking, relationship to any study personnel, and administration of any investigational drug or participation in any other clinical trial within 4 weeks of entry into our study. all co-existent diseases or conditions were to be treated in accordance with prevailing medical practice. the current study was designed as a single centre, randomised, double-blind, parallel group, placebo-controlled comparative survey in subjects with early symptoms of common cold to assess the efficacy of a 0.12% iota-carrageenan nasal spray in the early treatment of natural colds. chosen research design, control groups and variables assessed are standard for this field of research, as are the ordinal scales used. a study flow chart is shown in figure 1 . subject randomization was done following verification of inclusion/exclusion criteria. neither investigators nor subjects knew the assigned treatment. randomization was performed by providing a each test nasal spray with a unique code number. randomized subjects were assigned a nasal spray at visit 1 (treatment day 1). subjects completed a daily diary of common cold symptom scores over 7 days and underwent nasal lavage on day 1 before the first treatment and on days 3 or 4. nasal dosing of study medication was 3 ×/day for 4 days. the study was conducted between february and may 2008 at the common cold and nasal research centre, cardiff school of biosciences, cardiff university, uk. symptoms and application of treatment was documented in the patient diary. coding was performed by cro bioconsult gmbh (perchtoldsdorf, austria) and decoding after trial review and data base lock. this study was performed in compliance with the ich e6 note for guidance on good clinical practices (cpmp/ich/135/95)5, and the principles of the declaration of helsinki, local drug law and standard operating procedures of the investigator, sponsor and cro involved. the study protocol and attached documentation (consent form, subject information, crf etc.) were approved by the responsible south east wales local research ethics committee [15] . the signed study protocol was available to the journal editor during the reviewing process. this trial was registered in the european clinical trial registry under the eudract number 2007-007577-23. the primary efficacy measure was defined prospectively as the mean total symptom score (tss) for study days 2-4 with tss being the sum of 8 individual symptom scores as described above. maximum tss score was 24 for each recorded time point. for statistical analysis, tss of study days 2-4 were summarized per subject and individual means calculated. the secondary efficacy measure was defined prospectively as tss on separate study days 1/2/3/4/5, as the mean total systemic symptom score (tsss) (headache, muscle ache, chilliness) for study days 2-4, and tsss on separate study days 1/2/3/4/5. further secondary efficacy variables were local symptom score (lss) (sore throat, blocked nose, runny nose, cough, sneezing) mean of study days 2-4, and on separate study days 1/2/3/4/5, and individual symptom scores (iss) (headache, muscle ache, chilliness, sore throat, blocked nose, runny nose, cough, sneezing) on separate study days 1/2/3/4/5. exploratory efficacy variables included virus detection/ total viral load, cytokine expression detected in nasal lavage and subject acceptability of test nasal sprays using a visual analogue scale (vas, 1-10). furthermore, data on subjects' willingness to use the product in the future via an ordinal scale (strongly agree, agree, disagree, strongly disagree) were collected. iota-carrageenan nasal spray (verum; unlabelled coldamaris prophylactic®) 1,2 g/l, nacl 5 g/l, water for injection [wfi] ad 20 ml 20.4 g) and placebo (nacl 9 g/l, wfi ad 20 ml 20.4 g) were manufactured by mono chem-pharm produkte gmbh (vienna, austria). spray solutions were clear, colourless, odourless and free of particles. verum and placebo nasal sprays were identical in shape, size and colour to allow a double-blind design, and were randomized at the cro. before administration, the spray was to be shaken and primed until a fine mist was delivered. one spray application of 140 μl was delivered to each nostril 3 ×/day for 4 days. on day 1, the first application was taken at study entry (9 a.m. to 5 p.m.), the next two applications of the spray were equally spaced through remaining waking hours on day 1. nasal spray applications on days 2/3/4 were administered equally spaced during waking hours. to control compliance with the study protocol, returned spray bottles were weighted and weights compared to weights on dispensing, thereby evaluating the weight of medication taken over the study period. subject no. 10 (placebo) missed the first dose on day 1 and 4, the third dose on day 2, and therefore took only 75% of planned doses. all other subjects had 100% compliance according to the diary documentation. in total, 99.3% compliance was reached in this study. dependent on the time point of inclusion in the study, the expected range of difference in weights was between 2.80 g and 3.36 g. mean difference in the verum group was 3.12 g (± 0.84 g), and in eccles et al. respiratory research 2010, 11:108 http://respiratory-research.com/content/11/1/108 placebo group 3.84 g (± 1.85 g) concluding that more placebo than verum doses were administered. this result supports the good compliance reported by the subjects in the diary. onset of common cold symptoms (days before visit 1) is displayed in additional file 1: table s1 . nasal lavage was performed on day 1 (study inclusion) and on days 3 or 4. samples were collected by instillation of 5 ml of 0.9% sterile saline into each nostril, washes expelled into waxed paper cups, samples pooled (per subject) before processing at 4°c within 3 h. 8 parts lavage were mixed with 1 part 5% bovine albumin (sigma aldrich, vienna, austria) and 1 part 10× protease inhibitor cocktail (roche, germany), portioned to 5 samples, and stored at -80°c until further analysis. for the determination of respiratory virus load and virus identification in nasal lavage, real time pcr analysis was performed for influenza virus type a + b, respiratory syncytial virus type a + b, parainfluenza virus types 1/2/3/4, coronavirus types oc43 and 229e, rhinoviruses (major/minor group viruses), human metapneumovirus. assays were performed using qiaamp viral rna mini and qiagen quantifast probe pcr kits (qiagen gmbh, hilden, germany), realaccurate respiratory rt pcr kit (pathofinder, maastricht, the netherlands) and real time pcr 7900 ht sequence detection (applied biosystems, foster city, usa) according to the manufacturer's instructions. this setup enables detection of 12 rna viruses that account for approximately 90% of respiratory tract infections. in brief, 140 μl samples were thawed on ice, transferred to 560 μl buffer avl with carrier rna, spiked with 10 μl internal control, and eluated rna was stored at -20°c for a maximum of 4 hours until transfer to -80°c. rt-pcr reaction was performed in a final volume of 20 μl. lavage samples were assayed in duplicates for measurement of relative cytokine quantity. cytokine concentration was determined by milliplex map human cytokine/chemokine kit 96 well plate assay (millipore corp., st. charles, usa) according to the manufacturer's instruction. 0.9% nacl was used as matrix complying with lavage medium and the following cytokines measured: il-1 α, il-1 β, il -2, il-3, il-4, il-5, il-6, il-7, il-8, il-9, il-10, il-12 p40, il-12 p70, il-13, il-15, il-17 , egf, eotaxin, fractalkine, g-csf, gm-csf, ifn-γ, ip-10, mcp-1, mip-1 α, mip-1 β, tnf-α, fgf-2, gro (includes gro alpha, beta and gamma), ifn-α2, il-1ra, mcp-3, mdc, scd40l, vegf. fluorescence was determined in a luminex 100 reader and data analysed by luminex software (riverside ca, usa) using a 4-parameter logistic curve fitting method. the lower quantification limit was 3.2 pg/ml, values below were set to 'zero'. duplicates that resulted in only 1 detectable concentration were omitted from analysis. comparisons between the groups were done by means of mann-whitney u-tests for continuous variables and by means of chi square tests for ordinal or nominal distributed variables. tests between treatment groups were performed by mann-whitney u-tests. for tests within groups, the wilcoxon matched pairs signed rank test was used. the trial was designed as an exploratory study. the magnitude of any effect of the nasal spray on common cold symptoms was unknown. based on the experience of the study centre it was calculated that a study number of 30 healthy subjects should provide sufficient data to determine if there was any effect on nasal symptoms and to allow power calculations for any further studies. efficacy of the iota-carrageenan nasal spray 35 subjects were screened, enrolled and randomized. one subject (iota-carrageenan) was lost in the follow up after the initial screening visit and no additional data were obtained. 34 subjects completed the study drug administration and were included in the safety analysis. demographic data and a study flow chart are shown in figure 1 . two subjects were excluded from the analysis of symptoms due to protocol violations that were defined as an exclusion criterion in the study protocol. subject 11 reported vomiting, nausea and abdominal pain presumably caused by an infection of the gastrointestinal tract and furthermore used ibuprofen as concomitant medication. subject 23 reported migraine that was treated with ibuprofen and a swollen eye due presumably to an allergic reaction that was treated with an oral anti-histamine during the observation period. the subject was therefore excluded from the efficacy analysis of symptoms. in total, 14 iota-carrageenan patients and 18 placebo patients were eligible for analysis of symptoms. the predefined primary efficacy parameter for the trial was the difference between iota-carrageenan and placebo in total symptom scores on days 2-4 (tss 2-4). iota-carrageenan nasal spray was superior to placebo (p < 0.046) with respect to the primary endpoint mean of tss over days 2-4 ( table 1) . the mean total symptom scores over 7 days are shown in figure 2 . the efficacy of the iota-carrageenan nasal spray treatment appears to be mainly observable on the local symptom scores (lss) sore throat, blocked nose, runny nose, cough, and sneezing, as there was little difference between treatments for the systemic symptom scores (sss) headache, muscle ache, chilliness ( figure 2 ). this is reflected in the results of lss and sss mean of sum on days 2-4 which were lower for iota-carrageenan patients with significance levels of 0.064 and 0.704, respectively (table 1) . while there is no statistical difference tss on day 1 (p < 0.231), the difference is significant on day 3 (p < 0.040) indicating a faster relief of symptoms in the iota-carrageenan group. average individual symptoms scores blocked nose, runny nose, cough, and sneezing were higher for placebo when compared to verum (figure 3 ). the individual symptoms blocked nose and runny nose show the highest scores indicating that these symptoms are most bothersome. for all individual lss a trend towards superiority of the iota-carrageenan nasal spray can be observed. at inclusion subjects reported a slightly higher score for the iota-carrageenan group for the symptoms blocked nose, cough and sore throat. these three symptoms showed an increase in the placebo group but not in the iota-carrageenan group at the next reporting time points. this result suggests that the iota-carrageenan nasal spray treatment has an inhibitory effect on the development of common cold symptoms shortly after start of therapy. at the study end point (day 7), placebo patients reported a mean blocked nose score of 0.78. in contrast, iota-carrageenan patients reported a mean blocked nose score of 0.42, corresponding to a reduction of approximately 50% (figure 3 ). further post hoc analysis of this symptom revealed that 71.4% of iota-carrageenan patients did not report the symptom blocked nose at the end of the study. in the placebo group only 36.4% of subjects were free of this symptom. nasal lavages were analyzed by quantitative real time rt-pcr for the presence of viral genomes. samples of 6 iota-carrageenan and 5 placebo patients were virus positive. 5 patients tested positive for human rhinovirus, another 5 patients for coronavirus, and one patient for parainfluenza 3 virus. as shown in figure 4 , viral load in the placebo group increased almost 6-fold (579%), while it dramatically decreased by 92% in the iota-carrageenan group (p < 0.009). this result indicates that the treatment of patients with iota carrageenan nasal spray leads to a highly statistically significant reduction of viral load in the nasal cavity, while placebo treatment has no influence on viral replication at all. the basis for the statistical analysis and the ct-values are shown in additional file 2: table s2 . nasal lavages of both patients that were excluded due to protocol violations were tested negative for respiratory viruses (data not shown). the analysis of cytokines revealed that the median level of the following cytokines was below the detection limit of 3,2 pg/ml: egf, eotaxin, gm-csf, ifn-γ, il-12(p70), il-13, il-15, il-17, il-1β, il-2, il-4, il-5, il-6, il-9, mcp-3, mdc, mip-1α, mip-1β, scd40l, sil-2rα, tgfα, tnf-α, tnf-β, and vegf. the relatively low level of these parameters suggested no major biological relevance at the time point of sampling and consequently no further analysis of above cytokines was carried out. cytokine ip-10 (cxcl10) was found to be present in the highest concentration of all tested cytokines. while there was a decrease from 1790 pg/ml at the first visit to an average of 970 pg/ml on day 3/4 in the iota-carrageenan group there was an increase to 3016 pg/ml in the placebo group from day 1 to day 3/4 (table 2 ). however, due to a high standard deviation the difference of ip-10 levels between iota-carrageenan and placebo is not significant. at a much lower level a similar effect was observed for gro, g-csf, il-8, il-1α, il-10, ifn-2α and the difference was even significant for fgf-2 (p = 0,04) and fractalkine (p = 0,023). in contrast, two molecules that are known for their function as antagonists of inflammation, il-1rα and il-12(p40), were higher in the iota-carrageenan group. however, the result allows hypothesizing that the observed reduction in viral replication resulted in a lower level of pro-inflammatory cytokines and consequently in a lower symptom score. product acceptability by subjects for iota-carrageenan and placebo nasal spray, respectively, was significantly higher for iota-carrageenan in itt (p = 0.041), pp (p = 0.009) and also for virus positive patients (p = 0.005) ( table 3 ). in pp only 1 subject (7%) using iota-carrageenan but 6 subjects using placebo (33%) opposed future consistent medication. it is of note that the placebo formulation was identical to verum except iota-carrageenan, showing that all components of iota-carrageenan nasal spray are exceptionally well tolerated by the subjects, remarkably with even increasing support by viruspositive subjects. these results indicate that the observed benefit of iota-carrageenan-treated patients both on the levels of symptom scores and biomarkers correlates with a higher product acceptability. no serious adverse events (sae) were reported and there were no withdrawals due to adverse event (ae) development. aes were listed by patients including the reported term by the investigator, the meddra preferred term (pt) and the meddra system organ class (soc) [16] . 5 subjects (4 iota-carrageenan, 1 placebo) experienced at least one ae. iota-carrageenan patient 11 reported three aes -vomiting, nausea and abdominal pain -used ibuprofen as concomitant medication and was therefore excluded from the efficacy analysis of symptoms. the aes were not considered to be associated with the study medication. iota-carrageenan patient 23 reported migraine and puffy eye lids, used ibuprofen and anti-histamine as concomitant medication and was therefore excluded from the efficacy analysis of symptoms. one iota-carrageenan patient reported a loss of voice and another iota-carrageenan patient reported a dry mouth. intermittent epistaxis was reported by a placebo patient. a total of 8 aes were reported, 2 were rated as possibly related to treatment: dry mouth (iota-carrageenan, n = 1) in the itt and pp groups and puffy eye lids (iota-carrageenan, n = 1) (additional file 3: table s3 ). since all side effects were resolved, no special actions were necessary. the small number of ae reports supports in particular the good safety-profile of iota-carrageenan as an active agent and iota-carrageenan nasal spray components in general. the results of this study indicate that the iota carrageenan nasal spray is a safe and effective treatment when taken within 48 hours of development of common cold symptoms. designed as an exploratory trial, the size of the study was relatively small but reached statistical significance (p = 0.046) for the predefined primary endpoint (tss mean of sum on days 2-4). all patients reported relatively low levels of systemic symptoms indicating that no severe infection of the respiratory tract had occurred (figure 2 ). the efficacy of the iota-carrageenan nasal spray treatment appears to be mainly dependent on the local symptom scores (lss) sore throat, blocked nose, runny nose, cough, and sneezing (table 1, figure 3) . interestingly, 63.6% of placebo and only 28.6% of iota-carrageenan patients reported the symptom blocked nose at the end of the study period. although not explicitly tested, we conclude that the above fact is one of the main reasons why there was a significantly better acceptability in patients with the iota-carrageenan nasal spray (table 3) . both the iota-carrageenan and the placebo group reached a mean tss level of around 2 at the end of the 7 day observation period (figure 2 ). the study medication was applied only for the first 4 days. this could be a reason why a complete relief of symptoms did not occur in the study period of 7 days. we conclude that both a longer treatment and observation period should be considered in future trials for better determination of the therapeutic effect of the iota-carrageenan nasal spray. the study population consisted mainly of students with a mean age of 19.6 (sd 1.2) years, and the compliance was very high. since this age group reflects only a small proportion of the general population, this study might serve as a best case indicator for the design of bigger trials targeting the population in general. it is well known from studies with other antiviral substances that early intervention correlates with efficacy. the vast majority of patients (>88%) reported symptoms for 1 day or less on the day of inclusion into the study (additional file 1: table s1 ). we conclude that treatment of common cold with iota-carrageenan nasal sprays is effective when started early after onset of symptoms. iota-carrageenan nasal spray is formulated as a solution of iota-carrageenan and nacl in water intended for direct intranasal application. tests for effectiveness of blinding of the study medication were not carried out. although the study medication of both groups appeared completely identical this might be a weakness of the study. independent reviews of randomised controlled clinical trials on upper respiratory tract infection show limited evidence for a benefit of saline nasal irrigation. however, the use of this treatment is widely accepted and some trials obtained satisfactory results [17] [18] [19] . the nasal cavity is the site of choice for inhibition of common cold virus infection and replication. the iota-carrageenan effects are complemented by the known efficacy, safety and patient satisfaction of saline nasal irrigation in acute or chronic rhino sinusitis via the nacl/wfi spray component that served as placebo in this study. the symptomatic benefit for iota-carrageenan patients correlated well with the decrease of detectable virus genome copies in nasal lavages of patients ( figure 4) . the statistical analysis of the 11 virus positive patients revealed a p-value of 0.009 for the difference between the iota-carrageenan nasal spray and the placebo. since the number of virus positive-tested subjects was low, further confirmation of this result is needed. it cannot be ruled out that some patients were infected with respiratory viruses that were not tested or were below the detection limit. however, this result in patients further supports earlier in-vitro findings of the antiviral effect against human rhinoviruses [10] and against other viruses such a papillomaviruses or dengue virus [11, 13] . the results of this study might encourage clinical developments for these viruses as well. common cold symptoms are caused by the reaction of the immune system against viruses and virus infected cells as well as local and newly recruited immune cells. in nasal lavage samples the presence of immune mediators was tested. while the majority of the growth factors and cytokines were expressed below the detection limit, 11 mediators including il-8, ip10, and gro were easily detectable. it is interesting to note that the expression of the majority of the molecules (fgf-2, fractalkine, gro, g-csf, il-8, il-1α, ip-10, il-10, and ifn-α2) was reduced in the iota-carrageenan group upon treatment, while il-1 receptor antagonist and il-12p40 were increased. il-1 receptor antagonist is regarded as counter-acting molecule to il-1. the role of il-12p40 during a respiratory infection in humans is not fully understood. a recent study suggested suggest that endogenous il-12p40 is essential for inhibition of airway hyperresponsiveness and peribronchial fibrosis, but not eosinophilic inflammation, in a murine asthma model with prolonged antigen exposures [20] . the above results suggest that the treatment with iota-carrageenan reduces the viral replication. consequently fewer cells are infected, the immune reaction against the viruses is less pronounced and fewer symptoms occur. in addition, it is reported that the expression of pro-inflammatory mediators in the course of a common cold may worsen pre-existing co-morbidities such as asthma or copd [6, 21, 22] . therefore, a reduction of the immune response due to lower viral load appears as an attractive property of this novel treatment. the iota carrageenan nasal spray used in this study may reduce the severity of nasal symptoms by an antiviral effect rather than any pharmacological effect on nasal blood vessels and glands. this has some advantages as pharmacological interventions to control symptoms such as nasal decongestants and antisecretory agents are associated with side effects such as nasal bleeding and crusting [21] . young children with respiratory symptoms are major spreaders of rhinovirus in the family setting. rhinovirus infections are a common cause of hospitalization of children, most often because of wheezing [23, 24] . as the vast bulk of viral transmission occurs among children and families an intervention affecting the transmission would be of great socioeconomic value [25] . the lack of toxicity and pharmacological activity of the iota carrageenan nasal spray with its high safety profile means that this treatment may be suitable for use in children as well as adults. iota-carrageenan nasal spray appears to be a promising compound for safe and effective treatment of early symptoms of common cold. larger clinical trials are needed to study the therapeutic index in more detail. additional file 1: table s1 -analysis of days of onset of common cold symptoms. shown are the numbers of patients for verum, placebo and total divided into groups with days of onset of common cold symptoms at the point of inclusion into the study. p-value comes from chi square test. additional file 2: table s2 -viral load of identified viruses, lavage on study day 1 and 3 or 4. shown are ct-values of real time pcr: ct values of 35 -40 indicative for minimal amounts of target viral nucleic acid, cts 30 -35 for moderate amounts, cts < 30 mark strong positive reactions p-values: comparison verum versus placebo by mann-whitney u-test. unit: ct value. additional file 3: table s3 -summary table of authors' contributions rec was principal investigator of the study and was responsible for the study and protocol design. mja performed the study on site and served as medical director. rwe and cme performed the quantitative virus analysis and the cytokine analysis. agr, epg, mja, rec participated in the design, statistical analyses and coordination of the study, interpretation of data and writing the manuscript. all authors read and approved the final manuscript. the trial was funded by marinomed biotechnologie gmbh. rec and mja did not receive any direct payments from marinomed. the authors epg, agr, cme, and rwe are employed by marinomed. authors agr and epg are assessment of subject acceptability of iota-carrageenan vs. placebo nasal sprays in intention to treat (itt), per protocol (pp) and subgroup (virus positive) analysis using a vas scale (0-10). p-values come from mann-whitney u-test. unit: cm ± standard deviation. co-founders of marinomed. agr and epg are co-inventors on patent # wo2008067982 held by marinomed biotechnologie gmbh that relates to the content of the manuscript. marinomed biotechnologie gmbh is financing the processing charge of this manuscript. received: 12 april 2010 accepted: 10 august 2010 published: 10 august 2010 the human rhinovirus: human-pathological impact, mechanisms of antirhinoviral agents, and strategies for their discovery understanding the symptoms of the common cold and influenza the economic burden of non-influenza-related viral respiratory tract infection in the united states the common cold allergic rhinitis and the common cold -high cost to society cough and viruses in airways disease: mechanisms antivirals for the common cold biological properties of carrageenan us food and drug administration: generally recognized as safe (gras) iota-carrageenan is a potent inhibitor of rhinovirus infection interference in dengue virus adsorption and uncoating by carrageenans polysaccharides as antiviral agents: antiviral activity of carrageenan carrageenan is a potent inhibitor of papillomavirus infection transmission of the common cold to volunteers under controlled conditions. i. the common cold as a clinical entity the medical dictionary for regulatory activities the efficacy of hypertonic saline nasal irrigation for chronic sinonasal symptoms efficacy of daily hypertonic saline nasal irrigation among patients with sinusitis: a randomized controlled trial saline nasal irrigation for acute upper respiratory tract infections il-12p40 is essential for the down-regulation of airway hyperresponsiveness in a mouse model of bronchial asthma with prolonged antigen exposure respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology drug targets in rhinoviral infections rhinovirus transmission within families with children: incidence of symptomatic and asymptomatic infections rhinovirus infections in children: a retrospective and prospective hospital-based study rhinovirus chemotherapy submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution key: cord-298536-kksivbh8 authors: lahav, yael title: psychological distress related to covid-19 – the contribution of continuous traumatic stress date: 2020-08-10 journal: j affect disord doi: 10.1016/j.jad.2020.07.141 sha: doc_id: 298536 cord_uid: kksivbh8 objective: the novel coronavirus (covid-19) is a substantial stressor that could eventuate in psychological distress. evidence suggests that individuals previously exposed to traumatic events, and particularly to continuous traumatic stress (cts), might be more vulnerable to distress when facing additional stressors. this study aimed to investigate these suppositions in the context of the ongoing shelling of israel from the israel-gaza border, which continues even amidst the covid-19 crisis. method: an online survey was conducted among israel's general population. the sample included 976 participants. seven-hundred-and-ninety-three participants had been exposed to traumatic events, with 255 participants reporting cts. trauma exposure, covid-19-related stressors, and psychological distress related to covid-19 (anxiety, depression, and peritraumatic stress symptoms) were assessed. results: most participants reported experiencing at least one psychiatric symptom related to covid-19. being younger, female, not in a relationship, having a below-average income, being diagnosed with the disease, living alone during the outbreak, having a close other in a high-risk group, and negatively self-rating one's health status were associated with elevated distress. individuals who had been exposed to trauma, and to cts in particular, had elevated anxiety, depression, and peritraumatic stress symptoms compared to individuals without such a history or to survivors of non-ongoing traumatic events. cts moderated the relations between ptsd symptoms, anxiety symptoms, and peritraumatic stress symptoms, with significantly stronger relations found among individuals exposed to cts. limitations: this study relied on convenience sampling. conclusions: trauma survivors, and particularly traumatized individuals exposed to cts, seem at risk for psychological distress related to covid-19. in december 2019, the novel coronavirus (covid-19) appeared in wuhan, china. early stages of covid-19 include severe acute respiratory infection, with some patients developing acute respiratory distress syndrome, acute respiratory failure, and other severe complications . this disease is highly infectious (ryu et al., 2020) , and after it was identified in wuhan, it was identified in other parts of the world. on january 30, 2020, the world health organization (who) declared covid-19 a "public health emergency of international concern." in february 2020, the virus was identified in israel, and by april 19 th , the number of individuals diagnosed with the virus was 13,107, with 158 people deceased (world health organization). to slow down the spread of this highly contagious and potentially fatal virus, strict measures were taken in israel, including restricting outdoor activities, cancelling gatherings, closing schools and institutes of higher learning, shutting down all "nonessential" businesses, minimizing public transportation, etc. the outbreak itself and the measures taken to bring it under control have likely been highly stressful for many individuals. as such, it is reasonable to suggest that the covid-19 pandemic will have implications not only for physical health, but also for mental health and well-being (brooks et al., 2020; lai et al., 2020; mcewen et al., 2015; shigemura et al., 2020) . furthermore, as with the sars outbreak (hawryluck et al., 2004; wu et al., 2009) , it would not be surprising to find that the covid-19 pandemic has been experienced by many as a traumatic event, leading to trauma-related symptoms, namely peritraumatic stress reactions. although research exploring psychological distress related to covid-19 is only in its initial stages, recent studies have provided support for this view. a recent cross-sectional study of 1,257 healthcare workers in hospitals equipped with clinics/wards for patients with in china found that a considerable proportion of these workers reported experiencing symptoms of depression, anxiety, insomnia, and distress (lai et al., 2020) . a longitudinal study conducted among the general population in china during the initial outbreak of covid-19, and the epidemic's peak four weeks later, indicated clinically significant peritraumatic stress symptoms as well as moderate-to-severe stress, anxiety, and depression, which did not change significantly over time . a study among 6,049 chinese individuals ranging from 17-63 years of age uncovered three profiles of peritraumatic stress symptoms: mild (80.9%), moderate (13.0%), and high (6.1%; jiang, nan, lv, & yang, 2020) . lastly, a nationwide large-scale survey of psychological distress in the general population of china indicated that almost 35% of respondents experienced psychological distress during the covid-19 pandemic . the severity of an individual's psychological distress in response to covid-19 may be related to specific covid-19-related stressors. being diagnosed with covid-19, belonging to a risk group for covid-19 complications, and perceiving one's physical health in a negative fashion may all raise substantial concerns during the pandemic and might intensify one's emotional plight (e.g., shi et al., 2003) . having family members or close others who belong to a risk group for covid-19 might also increase worries and generate or exacerbate psychological distress. lastly, being quarantined or living alone during the pandemic might also have detrimental effects. reduced social interactions and loneliness are well-known risk factors for psychopathology (nolen-hoeksema and ahrens, 2002) and might increase individuals' vulnerability, particularly under conditions of exposure to stressors. indeed, a recent review which included 24 studies, found posttraumatic stress symptoms, confusion, and anger among quarantined children and adults (brooks et al., 2020) . that said, there are some individuals who might be even more vulnerable than others to the implications of the covid-19 crisis. according to the ''sensitization'' hypothesis, individuals who have previously been exposed to traumatic events might react more severely to additional stressors due to heightened sensitivity to stress or depleted coping capacities (resnick et al., 1995; yehuda et al., 1995) . research has supported this claim. a metaanalysis that was based on 68 studies indicated that previous exposure to a traumatic event was related to an elevated risk for ptsd following a later trauma (ozer et al., 2003) . this association seems to be applicable when the additional stressor is a physical illness; for example, previous exposure to a traumatic event was found to be associated with psychiatric symptomatology, depression, and ptsd symptoms in women with breast cancer (green et al., 2000) . this heightened vulnerability of individuals previously exposed to trauma might be rooted in posttraumatic distress subsequent to trauma exposure. during its follow-up periods, a longitudinal study revealed that traumatized individuals with ptsd were at a higher risk for ptsd than were individuals with no history of trauma exposure (breslau et al., 2008) . despite the evidence regarding the effects of prior trauma and posttraumatic distress on the distress of individuals who are facing an additional stressor, to the best of my knowledge no study to date has explored this subject with regard to a worldwide pandemic such as covid-19. furthermore, to date the research has been focused on the effects of additional stressors on survivors of past traumatic events (i.e., events that came to an end), and not on survivors of continuous traumatic stress. continuous traumatic stress (cts) or type iii trauma exposure (kira et al., 2013) reflects a situation in which individuals repeatedly face an ongoing and protracted threat, typically lasting several years (straker, 1987) . continuous traumatic stress is a common phenomenon worldwide (heidelberg institute for international conflict research, 2016), and can result from various traumatic situations, such as living under conditions of constant urban violence (roach, 2013) , or being exposed to continuous rocket shellings (greene et al., 2018) , the latter of which was the focus of the current study. living under conditions of ongoing exposure to traumatic events involves constant uncertainty, as well as constant alertness and preparedness (ruby, 2002) . recurrent exposure to traumatic stress impairs people's ability to maintain a stable routine and creates a sense of threat, vulnerability, anxiety, confusion, uncertainty, and helplessness (zimbardo, 2002) . research has indeed documented elevated distress among individuals exposed to cts situations, including ptsd symptomatology, anxiety, depression, and helplessness, as well as somatization (hobfoll et al., 2006; itzhaky et al., 2017) . the ramifications of ongoing and unceasing exposure to trauma might not be limited to cts-related psychological distress; rather, cts may very well affect one's ability to adjust to new challenges and stressors, such as the covid-19 threat. given that cts demands an ongoing effort to cope, individuals in cts situations might be worn down and depleted of coping capacities, and thus particularly vulnerable to covid-19-related stressors. furthermore, it is reasonable to assume that suffering from posttraumatic distress would be particularly difficult and painful when one continues to be exposed to the trauma, with such continuous exposure heightening one's vulnerability in the context of new challenges. thus, the negative effects of ptsd symptoms on psychological distress related to covid-19 might be particularly prominent among individuals exposed to cts, and more so than among individuals who were exposed to traumatic events that came to an end. sadly, the situation in southern israel today allows us to examine the aforementioned postulations. for the past almost two decades, as part of the israeli-palestinian conflict, individuals living in this region have been subjected to frequent rocket shelling from the gaza side of the border, with more than 17,000 rockets and mortars fired (israel ministry of foreign affairs, 2014). although there have been some relatively quiet periods, there have also been several intensive armed conflicts, each interspersed with varying amounts of shelling, right before and during the conflicts. these attacks have resulted in death, injury, damage, and disruption to the everyday life of israelis living in the "gaza envelope." these attacks have continued, even now, at a time when israelis are also contending with the covid-19 disaster. the present study aimed to explore whether individuals previously exposed to traumatic events, and particularly those previously and currently exposed to cts as part of their living in the "gaza envelope," suffer from increased vulnerability when facing covid-19. specifically, the current investigation strove to explore the contribution of ptsd symptoms as a result of past trauma exposure versus as a result of cts in explaining psychological distress (peritraumatic stress symptoms, anxiety symptoms, and depression symptoms) in the face of covid-19. being the first, presumably, to address this subject matter, the current study was exploratory in nature. three main objectives were set: 1. to describe the prevalence of covid-19-related stressors as well as the levels of psychological distress (peritraumatic stress symptoms, anxiety symptoms and depression symptoms) related to covid-19. 2. to explore the contribution of trauma exposure in explaining psychological distress related to covid-19, above and beyond demographic characteristics and covid-19related stressors. 3. to explore the moderating role of trauma type (cts versus past trauma exposure) in the associations between ptsd symptoms and psychological distress related to covid-19, above and beyond demographic characteristics and covid-19-related stressors. participants and procedure. an online survey was conducted among a convenience sample of israeli adults. the survey was accessible through qualtrics, a secure web-based survey data collection system. the survey took an average of 25 minutes to complete and was open from april 2, 2020 to april 19, 2020. it was anonymous, and no data were collected that linked participants to recruitment sources. the [masked for review] institutional review board (irb) approved all procedures and instruments. clicking on the link to the survey guided potential respondents to a page that provided information about the purpose of the study, the nature of the questions, and a consent form (i.e., the survey was voluntary; respondents could quit at any time; responses would be anonymous). the first page also offered researcher contact information. each participant was given the opportunity to take part in a lottery that included four $60 gift vouchers. a total of 1,263 people participated in the survey. of them, only 976 (77.3%) participants who provided data regarding the study variables were included. no differences were found between participants who were included in the study and those who were not in terms of relationship status, education, or income (p s >.05). yet there were significant differences between the groups in terms of age, t(1261)= -2.07, p = .04; gender, χ 2 (1, n=1263) = 4.94, p = .03; and religiosity, χ 2 (1, n=1263) = 4.08, p = .04. the average age among the current sample was higher (m = 44.37, sd = 14.28) than among the group of participants who were not included in the study (m = 42.37, sd = 14.78), and the proportion of women and secular individuals among the current sample was higher (81.6%, 69.4%, respectively) than among the group of participants who were not included in the study (75.6%, 62.9%, respectively). participants' ages ranged from 18 to 79 (m = 44.37, sd = 14.28), with the majority of the sample being below the age of 50 (61.6%). most of the participants were jewish (96.4%) women (81.6%); were secular (69.4%); had a high school degree or under (52.2%); were in a relationship (64.7%); and had an average or above-average income (50.3%). of the total sample, 793 participants (81.3%) were classified as having been exposed to traumatic events based on the trauma history screen (ths; carlson et al., 2011). the average age of this subgroup was 45.54 (sd =14.12). most of this sub-group were women (81.3%); were secular (69.3%); had a high school degree or under (53.5%); and had an above-average income (50.1%). regarding type of traumatic event, 255 participants (31.5%) reported continuous exposure to rocket attacks (thus, cts), and the rest of the 543 participants reported exposure to a traumatic event that had ended. the latter category (i.e., a traumatic event that had ended) included accidents (24.1%), a physical or sexual assault during childhood (26.9%), natural disasters (2.5%), a physical or sexual assault in adulthood (20.7%), being attacked with a gun, knife, or weapon (6.6%), the sudden death of a family member or close friend (69.1%), seeing someone die or get badly hurt or killed (20.8%), and seeing something horrible during military service (17.0%). the vast majority of participants reported two traumatic events or more (66.2%). background variables. participants completed a brief demographic questionnaire that assessed age, gender, education, relational status, religiosity, and income. specific stressors related to the covid-19 pandemic were measured via nine items designed by the research team. participants were asked 1) how they perceived their own physical health, 2) whether they were diagnosed with the disease, 3) whether they were quarantined, 4) whether they were living alone during the outbreak, 5) whether they belonged to a high-risk group for covid-19, 6) whether they had close others who belonged to a high-risk group, 7) whether they had close others who had been diagnosed with the disease, 8) whether they had close others who had been hospitalized due to the disease, and 9) whether they had experienced the loss of close others as a result of the disease. given that only four participants reported experiencing the last three stressors (having close others who were diagnosed with the disease, having close others who were hospitalized due to the disease, experiencing a loss of close others due to the disease), these specific stressors were not included in the present analyses. anxiety and depression symptoms related to covid-19. levels of anxiety and depression symptoms in response to covid-19 were assessed by the anxiety and depression subscales of the brief symptom inventory-18 (bsi-18; derogatis, 2001) . the bsi-18 is a self-report symptom checklist measure consisting of 18 items, each describing a psychiatric symptom. anxiety and depression subscales consist of six items each. participants were asked to indicate the extent to which they had been bothered by the symptom in the prior week, on a 5-point likert scale ranging from 0 (not at all) to 4 (extremely). mean scores on each subscale reflect the respondent's level of anxiety or depression symptoms, with higher scores reflecting greater symptoms. the raw scores are converted to t scores, with an accepted cutoff point of 63 for psychopathology on depression and anxiety subscales (derogatis, 2001) . the bsi-18 has been found to have adequate convergent and discriminant validity and good reliability (derogatis, 2001) . internal consistency reliabilities in this study were good for both the depression (α = 0.86) and anxiety subscale (α = 0.89). peritraumatic stress symptoms related to covid-19. peritraumatic stress symptoms in response to covid-19 were measured via a modified version of the ptsd checklist (pcl-5) (weathers et al., 2013 ). this 20-item self-report measure asks participants to indicate the extent to which they experienced each ptsd symptom, on a 5-point likert scale ranging from 0 (not at all) to 4 (extremely). items correspond to the newly approved ptsd symptom criteria in the diagnostic and statistical manual of mental disorders (5th ed., dsm-5; american psychiatric association, 2013). the original version was adapted so that the timeframe for experiencing each symptom was changed from "in the past month" to "since the outbreak of the covid-19 pandemic," and the index event was the covid-19 pandemic. a total score of peritraumatic stress symptoms was calculated by summing all 20 items. although not a definitive diagnostic measure, preliminary research suggests a cutoff score of 33 is a useful threshold to indicate symptomatology which may be at clinical levels (bovin et al., 2016) . the pcl-5 demonstrates high internal consistency and test-retest reliability (bovin et al., 2016) . internal consistency reliabilities in this study for the pcl-5 total score was excellent (α = 0.94). trauma exposure. exposure to traumatic events was measured via a modified version of the trauma history screen (ths; carlson et al., 2011) . the ths was developed as a brief, easyto-complete self-report measure of exposure to high-magnitude stressor events that could be traumatic. only 11 items (of the original 15 items) which reflect traumatic events according to the dsm-5 criteria were included. in addition, "continuous exposure to rocket attacks" was added to the list of events. for each event, respondents are asked to indicate whether the event occurred ("yes" or "no"). ptsd symptoms as a result of trauma exposure. ptsd symptoms were measured via the pcl-5 (weathers et al., 2013) . participants were asked to anchor responses to "stressful life experiences" on a scale ranging from 0 (not at all) to 4 (extremely). a total score is also calculated to assess the overall ptsd severity. internal consistency reliability in this study for the pcl-5 total score subscales was excellent (α = 0.95). the current analyses were conducted using spss 25 and process computational macro (hayes, 2012) . to assess the univariate associations between background characteristics and covid-19-related stressors, on the one hand, and psychological distress outcomes (i.e., anxiety symptoms, depression symptoms, and peritraumatic stress symptoms) on the other, linear regressions were conducted. to explore the unique contribution of trauma exposure in explaining psychological distress related to the covid-19 pandemic above and beyond background characteristics and covid-19-related stressors, three multiple regression analyses were conducted. anxiety symptoms, depression symptoms, and peritraumatic stress symptoms were treated as dependent variables. trauma exposure, covid-19-related stressors, and the background variables of age, gender, relationship status, and incomeall four of which variables had the largest contribution in explaining psychological distress outcomes compared to the other background variableswere treated as independent variables. to explore the moderating role of trauma type (cts versus previous non-ongoing trauma exposure) in the associations between ptsd symptoms and psychological distress related to the covid-19 pandemic, moderation analyses were conducted via process (model 1) computational macro (hayes, 2012) . these analyses were conducted only among participants who reported a trauma history and had data regarding ptsd symptoms (n = 543, 68.5%). scores of all the variables were standardized. significant interactions were probed using the process (model 1) computational macro (hayes, 2012) . to determine whether including the independent variable and covariates in the current analyses was adequate, we assessed for multicollinearity, and examined the variance inflation factors (vifs) for the study variables. findings indicated that all were within the acceptable range (all vifs were smaller than 2), indicating that multicollinearity was not a problem in our analyses. respondents reported several covid-19-related stressors. these consisted of being diagnosed with the disease (n = 5, 0.5%), being quarantined (n = 93, 9.5%), living alone during the outbreak (n =144, 14.8%), belonging to a high-risk group for covid-19 (n = 320, 33.6%), perceiving one's physical health in a negative fashion (n = 69, 7.0%), having a close other who was diagnosed with covid-19 (n = 67, 6.9%), and having a close other who belonged to a high-risk group (n = 817, 83.7%). the majority of the sample (n = 824, 84.4%) reported experiencing at least one anxiety symptom since the outbreak of the pandemic, and the average of the levels of anxiety symptoms was 0.92 (±.84). moreover, 101 (10.3%) participants met the anxiety criteria. similarly, the majority of the sample (n = 838, 85.9%) reported experiencing at least one depression symptom since the outbreak of the pandemic. the average of the levels of depression symptoms was 0.85 (±.77), and 99 (10.1%) participants met the depression criteria. among participants who suffered from clinically significant anxiety symptoms since the outbreak of the pandemic, 86.1% had a history of exposure to prior trauma; among participants who suffered from clinically significant depression symptoms since the pandemic's outbreak, 88.9% had a history of exposure to prior trauma. the vast majority of the sample (n = 749, 76.7%) reported experiencing at least one peritraumatic stress symptom specifically related to covid-19, and the average of the levels of peritraumatic stress symptoms was 15.39 (±.13.28). furthermore, 11.5% (n = 112) of the participants had a peritraumatic stress symptom total score of 33 and above, indicating that their symptoms were clinically significant. among participants who suffered from clinically significant peritraumatic stress symptoms in relation to covid-19, 90.2% had a history of exposure to prior trauma. table 1 presents the association between demographic characteristics and covid-19-related stressors, on the one hand, and psychological distress on the other. as can be seen in the table, age, gender, relationship status, and income were related to all outcomes. being younger was associated with higher anxiety, depression, and peritraumatic stress symptoms related to the pandemic. it should be noted that the current study's exploration of psychological distress among the different age groups (18-29, 30-39, 40-59, 60-79) corroborated the existence of this trend, indicating higher distress among younger people. being female, not being in a relationship, and having a below-average income were also associated with higher anxiety, depression, and peritraumatic stress symptoms related to covid-19. having a high school degree or below was related to elevated peritraumatic stress symptoms only, and religiosity was unrelated to any of the psychological distress outcomes. covid-19-related stressors were associated with psychological distress as well. negative perceived health was related to elevated anxiety, depression, and peritraumatic stress symptoms. being diagnosed with the disease was related to elevated anxiety and peritraumatic stress symptoms, and living alone during the outbreak was related to elevated depression and anxiety symptoms. being quarantined and belonging to a high-risk group for covid-19 were both related to elevated peritraumatic stress symptoms. lastly, having a close other who belonged to a high-risk group was associated with elevated anxiety and depression symptoms. three multiple linear regressions exploring the contribution of trauma exposure history in explaining psychological distress, above and beyond demographic characteristics (age, gender, relationship status, income) and covid-19 related stressors, were conducted. results of the analyses are presented in table 2 . as can be seen in the table, younger age, being female, and having a lower-than-average income were related to elevated anxiety, depression, and peritraumatic stress symptoms during the pandemic. not having a relationship was related to elevated depression symptoms. being diagnosed with covid-19 was related to increased anxiety symptoms, and living alone during the outbreak was associated with elevated depression symptoms. negative perceived health was associated with elevated anxiety, depression, and peritraumatic stress symptoms. more importantly, a history of exposure to a traumatic event had a significant effect in explaining anxiety, depression, and peritraumatic stress symptoms, above and beyond the other variables in the model, so that individuals who were classified as having been exposed to traumatic events had higher levels of anxiety, depression, and peritraumatic stress symptoms during the covid-19 pandemic than did individuals who had not previously been exposed to traumatic events. of the 793 participants who were classified as having been exposed to traumatic events, only 543 participants (68.5%) provided data regarding ptsd symptoms subsequent to these events. of them, 243 participants (44.8%) reported continuous exposure to rocket attacks, whereas the rest (n = 300, 55.2%) reported exposure to traumatic events that had ended. the average of the levels of ptsd symptoms subsequent to prior trauma was 12.43 (±.14.01), and 9.9% (n = 54) of the participants had a ptsd symptom score of 33 and above, indicating that their symptoms were clinically significant. among participants who had clinically significant peritraumatic stress symptoms in relation to covid-19, 41.7% had clinically significant ptsd symptoms subsequent to prior trauma. the proportion of clinically significant peritraumatic stress symptoms in relation to covid-19 was higher among participants who had ptsd symptoms at a clinical level subsequent to prior trauma than among participants with ptsd symptoms below a clinical level (55.6% vs. 8.6%). a supplementary logistic analysis indicated that the risk for clinically significant peritraumatic stress symptoms in relation to covid-19 was more than 13 times higher among participants with clinically significant ptsd symptoms subsequent to prior trauma than among participants with ptsd symptoms below a clinical level (odds ratio = 13.30, 95% confidence interval: 7.13 -24.80). to explore the moderating role of trauma type in the relations between ptsd symptoms and psychological distress during the pandemic, moderation analyses were conducted among this group of participants (n = 543). results of the moderation analyses are presented in table 3 . as can be seen in the table, younger age was associated with higher levels of anxiety, depression, and peritraumatic stress symptoms. being female was associated with elevated anxiety symptoms, and not having a relationship was associated with elevated depression symptoms. negative perceived health was associated with elevated anxiety, depression, and peritraumatic stress symptoms, and living alone during the outbreak was associated with elevated depression symptoms. trauma type and ptsd symptoms had a significant effect in explaining anxiety, depression, and peritraumatic stress symptoms. individuals exposed to cts had more elevated psychological distress during the covid-19 pandemic than did individuals exposed to traumatic stress that had ended. additionally, higher levels of ptsd symptoms subsequent to trauma exposure were related to elevated psychological distress manifested in anxiety, depression, and peritraumatic stress symptoms during the covid-19 pandemic. furthermore, trauma type significantly moderated the relations between ptsd symptoms on the one hand, and anxiety and peritraumatic stress symptoms during the covid-19 pandemic on the other. probing these interactions revealed a similar trend which is depicted in figures 1 & 2: although ptsd symptoms subsequent to trauma exposure had a significant effect in explaining anxiety and peritraumatic stress symptoms during the pandemic among participants exposed to cts as well as participants exposed to traumatic events that had ended, this effect was significantly stronger among participants exposed to cts (β = .69, p<.001; .70, p<.001, respectively) than among participants exposed to traumatic events that had ended (β = .47, p<.001; .44, p<.001, respectively). this study described the impact of the covid-19 outbreak on the mental health of israel's general population. the study's results indicated that the majority of the sample reported experiencing at least one symptom of anxiety, depression, or peritraumatic stress. furthermore, around one tenth of the sample had peritraumatic stress symptoms above the cutoff of 33, and another 10% of the sample met the criteria for anxiety or depression. these findings demonstrate the potential negative implications of covid-19 for mental health and are in line with recent studies that were conducted in china revealing anxiety, depression, and peritraumatic stress symptoms among general population samples as a result of covid-19 (jiang et al., 2020; qiu et al., 2020; wang et al., 2020) . several demographic characteristics were associated with elevated distress. consistent with a previous study , the present results indicated that female participants had a higher degree of psychological distress related to covid-19 than did male participants. this finding coincides with previous studies that found women to be at an elevated risk for depression and anxiety (bekker and van mens-verhulst, 2007; lim et al., 2018) , findings which might be rooted in biological and socioeconomic factors (albert, 2015) . the lack of being in a relationship and having a below-average income were also associated with intensified distress. in terms of explaining these associations, the lack of being in a relationship might have limited social support and exacerbated loneliness, particularly under the current circumstances of social distancing, and having a below-average income might have increased financial worries and concerns stemming from the covid-19 crisis, and potentially exacerbating distress. the current results, indicating a relation between younger age and elevated distress, are also consistent with a previous study that found respondents aged 12-21.4 years to suffer from a higher psychological impact of covid-19 than did older respondents . this finding suggests that although people in the 65+ age group are actually the ones most at risk of suffering from covid-19 complications, they might not be particularly susceptible to potential psychopathology. young adults, on the other hand, showed elevated vulnerability, which may have been rooted in obtaining a large amount of information via social media (roberts et al., 2018) . exploring the univariate relations between covid-19-related stressors and the psychological distress connected with the pandemic revealed significant associations between all of the stressors and psychological distress outcomes. nevertheless, when demographic characteristics and trauma exposure were also included in the analyses, only four stressors had a significant effect in explaining the levels of psychological distress. specifically, being diagnosed with the disease, living alone during the outbreak, having a close other who belonged to a high-risk group, and negatively self-rating one's health statusall of which have been documented in previous studies (e.g., fiorillo & gorwood, 2020; wang et al., 2020 )were found to significantly explain the levels of psychological distress. whereas negatively self-rating one's health status was related to all psychological distress outcomes, the other three covid-19-related stressors were associated with specific types of symptomatology. namely, being diagnosed with the disease and having a close other who belonged to a high-risk group, which could intensify tension and worries, were related to anxiety symptoms. living alone during the outbreak, a condition that could deepen feelings of loneliness, was linked to elevated depression. the importance of this study, however, lies in its discovery of the effects of previous trauma exposure in the context of the covid-19 pandemic. the present findings indicated that individuals who had previously been exposed to traumatic events had elevated levels of anxiety, depression, and peritraumatic stress symptoms as related to covid-19, compared to individuals who had not previously been exposed to traumatic events, even after taking into account demographic characteristics and covid-19-related stressors. going a step further, the present study demonstrated that the impact of trauma exposure on the psychological distress connected with covid-19 depended upon the nature of the exposure. in comparison to exposure to traumatic events that had ended, exposure to cts was related to elevated levels of anxiety, depression, and peritraumatic stress symptoms. furthermore, exposure to cts moderated the relations between ptsd symptoms on the one hand, and anxiety and peritraumatic stress symptoms during the covid-19 pandemic, on the other. although ptsd symptoms had a significant effect in explaining anxiety and peritraumatic stress symptoms during the pandemic among trauma survivors in general, its effect was significantly stronger among participants who were exposed to cts than among participants who had been exposed to traumatic events that had ended. suffering from ptsd symptoms is highly debilitating. vivid intrusive recollections, emotional numbness, and hyperreactivity in response to trauma reminders severely interfere with the daily lives of affected individuals (american psychiatric association, 2013) and are likely to take a toll when such individuals are exposed to an additional stressor (breslau et al., 2008; kessler et al., 2018) . that said, coping with such difficulties while still being exposed to an ongoing trauma could be even more devastating. unceasing exposure to trauma leads to a substantial degradation of individuals' psychological, social, and economic resources (e.g., hobfoll et al., 2008) , and this degradation could in turn limit one's capacity to handle a new stressor. furthermore, the reality of ongoing threat/danger not only deprives one of the opportunity to experience recovery in a safe and protected environment (lahad and leykin, 2010; nuttman-shwartz and shoval-zuckerman, 2016 ), but also repeatedly confirms a sense of threat and helplessness. as such, the negative effects of the ongoing trauma and subsequent ptsd symptoms on coping with an additional stressor might be particularly potent. although the current study contributes to the understanding of psychological distress related to the covid-19 pandemic among individuals previously exposed to trauma and cts, it has several limitations. first, the cross-sectional design precludes any conclusions regarding causal relations between the study variables. second, this study relied on convenience sampling and, similar to other surveys conducted during the covid-19 pandemic (lai et al., 2020; wang et al., 2020), suffered from an overrepresentation of the female gender which might be reflected in higher response rates in surveys among women (underwood et al., 2000) . furthermore, only participants who provided data regarding the study variables were included in this study: a group that was characterized by greater proportions of female and secular individuals as well as by a higher average age compared to participants who were not included in the study. although religiosity was not associated with psychological distress outcomes, and gender and age were controlled for in the present analyses, this limitation should be acknowledged prior to generalizing from the results to the population at large. third, this study did not include measures of potential protective factors, such as social support. lastly, this study was based on self-reported data which may be subject to response biases and shared method variance. future studies among a variety of populations, and specifically among gender-balanced samples, should include data from clinical interviews. despite these limitations, this study represents a step towards understanding the relations between trauma exposure and psychological distress in the face of an additional stressor. the present findings suggest that trauma survivors might be at risk for elevated distress following covid-19, and that individuals who are exposed to ongoing traumatic stress and who suffer from ptsd symptoms might be the most vulnerable to psychiatric symptomatology related to covid-19. the present study has important clinical implications. its results point to the need to provide clinical interventions to trauma survivors during this pandemic, and particularly to individuals exposed to cts. survivors of previous traumatic events (that are not ongoing) might benefit from evidence-based treatments such as trauma-focused cognitive behavior therapy (tf-cbt; hobfoll et al., 2008) , which could be provided online and would tap specific challenges that survivors might experience when dealing with the pandemic. individuals exposed to cts, on the other hand, need specific clinical interventions that are tailored to the particular struggles that they face (nuttman-shwartz and shoval-zuckerman, 2016) . treatment for individuals exposed to cts should be directed towards managing anxiety and physical symptoms, and the acquisition of day-to-day coping skills, and not on a reprocessing of the trauma, as is generally done when treating survivors of traumatic events that are not ongoing (diamond et al., 2010) . one of the main goals of cts treatment is to teach patients to differentiate between adapting to an actual danger versus symptomatic reactions to trauma reminders. core elements of stress management therapy such as relaxation, breathing exercises, and mindfulness-based practices might be beneficial (e.g., nuttman-shwartz & shoval-zuckerman, 2016) and a biopsychosocial approach, which is based on cognitive behavioral methods (hamblen et al., 2012) , might also be effective for individuals exposed to cts. given that numerous populations around the world are exposed to cts, providing these clinical tools via online mental health services during the ongoing covid-19 pandemic is of substantial value. although some nations are beginning to see the end of the pandemic's first wave, it is generally believed that another and potentially worse second wave will return in the fall, a situation which calls urgently for preparation and precautions. the author does not have any conflict of interests to disclose. .13*** .47*** .11*** ptsd symptoms .52*** .10** .51*** trauma type x ptsd symptoms .10** .04 .11** why is depression more prevalent in women? diagnostic and statistical manual of mental health disorders: dsm-5 anxiety disorders: sex differences in prevalence, degree, and background, but gender-neutral treatment psychometric properties of the ptsd checklist for diagnostic and statistical manual of mental disorders-fifth edition (pcl-5) in veterans a second look at prior trauma and the posttraumatic stress disorder effects of subsequent trauma: a prospective epidemiological study the psychological impact of quarantine and how to reduce it: rapid review of the evidence epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study bsi 18, brief symptom inventory 18: administration, scoring and procedures manual ongoing traumatic stress response (otsr) in sderot, israel the consequences of the covid-19 pandemic on mental health and implications for clinical practice trauma history as a predictor of psychologic symptoms in women with breast cancer psychopathology, risk, and resilience under exposure to continuous traumatic stress: a systematic review of studies among adults living in southern israel ptsd treatment research: an overview and evaluation sars control and psychological effects of quarantine process: a versatile computational tool for observed variable moderation, mediation, and conditional process modeling [white paper exposure to terrorism, stress-related mental health symptoms, and defensive coping among jews and arabs in israel the association of exposure, risk, and resiliency factors with ptsd among jews and arabs exposed to repeated acts of terrorism in israel psychiatric reactions to continuous traumatic stress: a latent profile analysis of two israeli samples psychological impacts of the covid-19 epidemic on chinese people: exposure, post-traumatic stress symptom, and emotion regulation the associations of earlier trauma exposures and history of mental disorders with ptsd after subsequent traumas advances in continuous traumatic stress theory: traumatogenic dynamics and consequences of intergroup conflict: the palestinian adolescents case ongoing exposure versus intense periodic exposure to military conflict and terror attacks in israel factors associated with mental health outcomes among health care workers exposed to coronavirus disease prevalence of depression in the community from 30 countries between 1994 and mechanisms of stress in the brain age differences and similarities in the correlates of depressive symptoms continuous traumatic situations in the face of ongoing political violence: the relationship between cts and ptsd. trauma, violence, abus predictors of posttraumatic stress disorder and symptoms in adults: a meta-analysis a nationwide survey of psychological distress among chinese people in the covid-19 epidemic: implications and policy recommendations effect of previous trauma on acute plasma cortisol level following rape shallow affect, no remorse: the shadow of trauma in the inner city factors associated with health service utilisation for common mental disorders: a systematic review the definition of terrorism an interim review of the epidemiological characteristics of 2019 novel coronavirus rationality of 17 cities' public perception of sars and predictive model of psychological behavior public responses to the novel 2019 coronavirus (2019-ncov) in japan: mental health consequences and target populations the continuous traumatic stress syndrome: the single therapeutic interview to mail or to web: comparisons of survey response rates and respondent characteristics. paper presented at the 40th annual forum of the association for institutional research a longitudinal study on the mental health of general population during the covid-19 epidemic in china the ptsd checklist for dsm-5 (pcl-5). scale available from the nationalcenter for ptsd at www world health organization situation report -90 the psychological impact of the sars epidemic on hospital employees in china: exposure, risk perception, and altruistic acceptance of risk impact of cumulative lifetime trauma and recent stress on current posttraumatic stress disorder symptoms in holocaust survivors the political psychology of terrorist alarms -.22*** -7.16*** -.27*** -8.78*** -.17*** -5.35*** genderfemale .17*** 5.24*** .11** 3.44** .10** 3.17** male reference reference reference in relationship -.13*** -4.09*** -.25*** -8.11*** -.14*** -4. key: cord-311398-uheb2cvg authors: prior, lindsay; evans, meirion r.; prout, hayley title: talking about colds and flu: the lay diagnosis of two common illnesses among older british people date: 2010-11-24 journal: soc sci med doi: 10.1016/j.socscimed.2010.09.054 sha: doc_id: 311398 cord_uid: uheb2cvg this paper reports on a study of the ways in which 54 older people in south wales (uk) talk about the symptoms and causes of cold and influenza (flu). the study was designed to understand why older people might reject or accept the offer of seasonal flu vaccine, and in the course of the interviews respondents were also asked to express their views about the nature and causes of the two key illnesses. the latter are among the most common infections in human beings. in terms of the biomedical paradigm the common cold is caused by numerous respiratory viruses, whilst flu is caused by the influenza virus. medical diagnosis is usually made on clinical grounds without laboratory confirmation. symptoms of flu include sudden onset of fever and cough, and colds are characterized by sneezing, sore throat, and runny nose, but in practice the symptoms often overlap. in this study we examine the degree by which the views of lay people with respect to both diagnosis and epidemiology diverge with that which is evident in biomedical discourse. our results indicate that whilst most of the identified symptoms are common to lay and professional people, the former integrate symptoms into a markedly different observational frame from the latter. and as far as causation is concerned it is clear that lay people emphasize the role of ‘resistance’ and ‘immunity’ at least as much as ‘infection’ in accounting for the onset of colds and flu. the data are analyzed using novel methods that focus on the co-occurrence of concepts and are displayed as semantic networks. as well as reporting on its findings the authors draw out some implications of the study for social scientific and policy discussions concerning lay diagnosis, lay expertise and the concept of an expert patient. the lay diagnosis of colds and flu colds and flu, collectively referred to in biomedical terms as upper respiratory tract infections or urtis, are the most common infections in human beings. adults may have between two and five episodes of the cold in a year, and schoolchildren from five to seven episodes (eccles, 2005) . during the twentieth century biomedical understanding of urtis was primarily focused on the identification of the viral agents that are regarded by medical professionals as their main cause. influenza virus was first identified during the 1930s, and during the 1950s and 60s numerous viruses including rhinovirus, coronavirus and adenovirus were associated with the common cold (heikkinen & järvinen, 2003) . by the beginning of the current century over 200 serologically different virus types had been implicated in the aetiology of the cold (mcchlery, ramage, & bagg, 2009, p. 151) . in parallel with the identification of viral agents, the public health effort from the latter part of the twentieth century was concentrated on delivering effective vaccines to reduce the prevalence of seasonal and pandemic flu variants e the most recent global attempt relating to the winter of 2009e2010. however, despite the fact that urti's have been progressively taken into the laboratory and systematically 'jennerized' (c.f. latour, 1988) , the main site for their diagnosis is in the community or the world of everyday life. and in that world the understanding of respiratory infections is mediated through a web of concerns e about the origins and interconnection of symptoms, the maintenance of personal health and the distribution of illness among relatives, friends, and neighbours. this paper focuses on such concerns and in particular how colds and flu are spoken about and diagnosed by lay people in ordinary, everyday, non-clinical settings. the data are drawn from a qualitative interview based study (n ¼ 54) of older people's understanding and acceptance of seasonal flu vaccine that was undertaken in south wales during the earlier part of the current decade. from the work of stimson and webb (1975) onward there has been an increasing recognition of the role played by lay people (as patients) in the diagnostic process (see, for example, beach, 2001; frankel, 2001; gill & maynard, 2006; gill, pomerantz, & denvir, 2010; heath, 1992; peräkylä, 2006) . however, the overwhelming majority of relevant studies look at doctorepatient activity in clinical settings e mostly using techniques of conversation analysis. interestingly, some of those who research into lay engagement with the diagnostic process argue that the word diagnosis should be reserved solely for categorizations of disease by doctors (e.g., gill et al., 2010, p. 17) . the research reported on here is somewhat different from the work just referred to in that it examines how lay people identify and categorize groups of symptoms in the 'lifeworld' (mishler, 1984, p. 104) , or the world 'grounded' in everyday life, rather than the world of the clinic or the consulting room. in the context of common respiratory symptoms, it is also worth noting that there has been a long tradition of looking at the ways in which lay people understand the symptomatology of urti's, and especially 'colds' (see, for example, ; baer, weller, garcia, 2008; baer, weller, pachter et al, 1999; helman, 1978; mccombie, 1987) . however, most of that work examines the range of symptoms lay people associate with cold e and to a lesser extent flu -and how they explain respiratory illness. such studies are not overly concerned with how lay people differentiate between or how they diagnose colds and flu e a topic that is the focus of this paper. the study of lay diagnoses of illness and infection is important for a number of reasons and not least because the manner in which ordinary people understand infection and its origins is directly relevant to the spread and control of disease in populations -the health of the public (mccombie, 1987) . it is also a topic directly relevant to discussions concerning the display of expertise by lay people in matters of health and illness more generally (fox, ward, & o'rourke, 2005; prior, 2003) . while in policy terms, the topic connects to a growing 'acknowledgment'e especially with regard to chronic conditions e of patient expertise in health care and the ways in which such expertise can be drawn upon in the delivery of services to the public at large (donaldson, 2003; lindsay & vrijhoef, 2009; rogers, bury, & kennedy, 2009; wilson, 1999) . in an age of threatened pandemics these discussions acquire an unusually clear resonance. the data in this paper are drawn from a qualitative study on the views of primary care staff and older people concerning the uptake of the seasonal flu vaccine in rural, urban, and semi-urban areas of south wales. the study was carried out during 2002-03 and the main objectives were to understand why a large percentage of individuals in high risk groups failed to seek or accept vaccination and what could be done to improve immunization rates among older people. respondents were selected from a previous agestratified random postal survey of people in the area aged over 65 who had reported on their immunization status. in light of those reports we chose to sample across a range of status groups. eighteen people who had refused immunization, 15 who had previously accepted immunization but had since 'relapsed', 5 people who claimed that they had never been offered immunization and 16 people who had accepted the vaccine (including 5 'first timers') were eventually included in the study. the work was funded by nhs wales office of r&d, and ethical approval granted by the local (bro taf) research ethics committee. findings relating to the original objectives were published in evans, prout and prior (2007) . data were gathered using a semi-structured interview schedule that contained a list of key topics for discussion. as well as focusing on the reasons why people might accept or reject the offer of a flu vaccine, the interview schedule contained questions asking: 'what do you think are the symptoms of colds and flu'? 'what do you think is the difference between cold and flu? 'how do you think people catch flu?' qualitative interviews of this kind have previously been categorized as a genre of conversation (kvale, 1996, p. 5) in which respondents tend to reply to questions in a free-flowing style. in our case, for example, that style led the research participants to talk about the causes of upper respiratory tract infections in general and not merely the causes of flu. the current paper is based on an analysis of that talk, and in that context the exercise might be seen as constituting a secondary analysis of an existing data set. for the purposes of this paper the 54 interview transcripts were initially analyzed using 'text-mining for clementine 12.0' (spss, 2007) . there are various advantages of using such automated text-mining techniques for data analysis. one offshoot is that the data set can be trawled for instances of co-occurrence between two concepts (such as flu jab and side-effects). the programme in use is capable of calculating a coefficient for all such co-occurring concepts and can display the results of such connections diagrammatically. following the exclusion of terms with fewer than 5 citations, the programme identified some 119 concepts (flu, flu jab, side-effects, colds, etc) in our data set. the coefficients of cooccurrence between these concepts naturally varied in strength. in some cases the strength of the links was unsurprising (e.g. the cooccurrence coefficient for the link between cold and flu was unity since the two terms occurred in all interviews); in other cases the link was considerably weaker (e.g. the link between 'virus' and flu was only 0.15). text-mining results provide a visible means of checking the veracity of interview analysis. for example, the number of instances a concept appears is given, as well as a visual representation as to how that term links to related concepts. using the text-mining results it is also possible to identify exactly which of the 54 respondents associated the various concepts together and how they combined them. these data form the basis for the information displayed in figs. 1 and 2. unfortunately, text-mining software uses the document (interview) as the basis for all its calculations and so it is not immediately clear whether the interviewer or the interviewee makes the connections between concepts. in our case we have restricted ourselves to looking at explicit links made only by the respondents, and for that reason we have extracted the textmining results and re-incorporated them into semantic networks using social network software (de nooy, mrvar, & batagelj, 2005) rather than the original text-mining software. our focus is of course more on the concept networks than on social networks, and the figures provide a graphic indication of the nature and strength of the co-occurrence relationships between the basic terms and concepts in the 54 interviews. colds and flu: a view from the clinic "cold. a contagious viral infection of the upper respiratory tract usually caused by a strain of rhinovirus. it is characterized by rhinitis, tearing, low-grade fever and malaise and is treated symptomatically". "influenza; a highly contagious infection of the respiratory tract caused by the orthomyxovirus and transmitted by airborne droplet infection. symptoms include sore throat, cough, fever, muscular pains and weakness . onset is usually sudden, with chills, fever, respiratory symptoms, headache, myalgia and extreme fatigue." (mosby's dictionary of medicine, nursing, and health professions, 2009 ). the view from the laboratory would suggest that colds and flu are viral infections, and indeed over 200 different virus types have been associated with the common cold. around 30e50% of all colds are said to be caused by rhinoviruses, followed by coronaviruses (10e15% of all colds), and influenza viruses (5e15%) (heikkinen & järvinen, 2003; mcchlery et al., 2009 ). it is not surprising perhaps that in biomedical literature cold and flu are regarded as syndromes rather than as clear cut ontological categories, and the preferred contemporary biomedical designation is 'urti' or upper respiratory tract infection. as is also implied above, colds and flu are diagnosed clinically, though laboratory findings are regarded as necessary for the confirmation of any diagnosis. studies that compare the two forms of diagnosis highlight disjunction in a high proportion of cases (call, vollenweider, hornung et al, 2005) . the symptom pattern for colds and flu is far from agreed upon. sudden onset of fever and cough are regarded as good predictors of influenza being present, but in general there is a variable list of symptoms associated with the two syndromes in the medical literature. eccles (2005) for example, lists sore throat, sneezing, rhinorrhoea, nasal congestion, sinus pain, cough, headache, chilliness (for cold) and fever (for flu), anorexia, psychological effects and muscle aches and pains. during the recent (2010) pandemic alert the uk department of health information (http://www.direct.gov.uk/ swineflu) stated that, "the symptoms of swine flu are a fever or a high temperature (38 c) and two of the following symptoms: unusual tiredness, headache, runny nose, sore throat, shortness of breath or cough, loss of appetite, aching muscles, diarrhoea or vomiting. the same symptoms were listed by the cdc in the usa (http:// www.cdc.gov/flu/about/disease/symptoms.htm) with an added remark that diarrhoea or vomiting were more likely in children than in adults. eccles (2005) makes no mention of either diarrhoea or vomiting, and nor do call, vollenweider, hornung et al, (2005) . diagnosis of flu, in particular, is not therefore a straightforward or clear-cut business. clinicians, if necessary, can combine reported symptoms, information derived from clinical examination, together with laboratory and radiograph evidence, and data about current circulating strains from flu disease surveillance systems so as to arrive at a firm diagnosis. lay people generally have access to only the first of these. as stated in our introduction, lay talk about colds and flu is set within a mesh of concerns e about causes, symptoms and consequences. such talk comprises the base elements of what has at times been referred to as the 'explanatory model' of an illness (kleinman, eisenberg, & good, 1978) . in this section we will focus almost entirely on the identification of symptoms and views concerning the causes of colds and flu. we do so by relating such views to a wider rhetoric of complaint in which the understanding of colds and flu is embedded. the diagnosis of colds and flu in the lay population concentrates, as one would expect, on the symptom pattern. in that respect the procedure differs little from that of clinicians. for diagnostic purposes, of course, clinicians have ultimate recourse to a laboratory identification of a causative agent e though that is rarely used in routine consultations. lay people have no recourse to such data and one might guess that even if they did they would interpret findings in a distinctly colloquial manner. indeed, from our data set it is clear that lay people understand symptoms in a markedly different frame from that of medical professionals. in particular they report not only on symptoms relating to the body (especially the head), but also on behavioural correlates e and to a lesser extent on some psychological factors. in addition, lay people mention symptoms that are not ordinarily associated with flu in the medical literature, and they also connect the body itself to colds and flu in ways that can run counter to a prevailing western medical cosmology that seeks to connect pathology to specific anatomical sites. fig. 1 shows in diagrammatic form the key symptoms that lay people associate with colds and flu respectively. the thickness of the lines between the concept nodes express the value of a coefficient of co-occurrence between a reference to any given symptom (in 54 interviews), and any other symptom mentioned. the diagram also displays links between the symptoms and the two key entities of 'cold' and 'flu'. the calculation of the coefficient is based on that used in text-mining software (spss: 2007, p. 183) , except that here the links are confined to those that are explicitly made by the respondent between the various concepts in the course of the interview (rather than the words merely appearing anywhere in the document). the size of a node is proportional to the total number of references to each concept in the 54 transcripts. looking at fig. 1 , we can see that there are a range of entities deployed for the purpose of diagnosis. these include parts of the body affected (nose, throat, eyes); physiological processes (coughing, eating, sneezing, vomiting, and fever); behavioral processes (being bedridden); and to a lesser extent psychological processes (feeling down). note that most (but not all) of the symptoms are common to both conditions. lay people naturally weave these entities into their accounts in idiosyncratic ways, but this diagram contains all of the elements that our respondents required to distinguish between a cold and the flu e in short, all that is required to make a differential diagnosis. essentially, the diagnosis of a cold focuses on symptoms in the head and colds are associated almost entirely with the head (headache, however, is viewed primarily as a symptom of flu e as is evident from the detail in fig. 1 ). so when respondents were asked to distinguish between colds and flu they would say such things as: 'well i think colds is (sic) just in the head and runny nose and stuffy nose.' (respondent (r): 44), or refer simply to "a head cold" (r:16). unsurprisingly, and as is also evident in fig. 1 , the nose (and sneezing) is particularly prominent in the symptom pattern for cold, though associated sites such as the sinus, the throat and the eyes also figure in the diagnostic frame. this is in marked contrast to flu which is invariably viewed as a whole body illness e characterized by whole 'bodyache' (fig.1) . interestingly, a number of respondents also referred (usually in a dismissive manner) to a third category of illness 'the sniffles' e which seemed to relate to very mild forms of rhinorrhea and associated nasal symptoms. the following data extracts illustrate some of the key ways in which lay people differentiate colds from flu. (r:24) "well, flu, you get all your aches and pains. you feel lethargic, that type of thing, but with a cold, it's usually a head cold and plenty of coughs, sneezes and such like that you don't always get with the flu. i feel the flu is more in the whole of the body." (r:30) "always the question is, i mean my daughters about 44 but i said, um, is your body aching all over? yes, or no? 'yes'. you've got flu then. if it's not, you've got a heavy cold and that's it." (r:23) "well, i think with flu you're aching all over aren't you, you go, you get hot and then you get cold and you're aching all over whereas if it's a cold you're sneezing. you have a sort of a heady cold. i think it's a big difference isn't there?" (r:7) "well. well the influenza usually affects your stomach. it usually affects aching all over the body. and, you usually have a higher temperature. you feel a lot worse with flu, obviously". as is suggested by r23 above, flu is strongly associated with fever. in addition, it is predominantly associated with myalgia, and exclusively related to being bedridden or to an inability to undertake routine and normal duties. it is sometimes associated with vomiting and co-related stomach pain (r:7). above all, to have flu is to be 'really ill' (r:46); flu is 'more of an illness than a cough or a cold', (r:17). and, 'when you've got the flu, you're really ill. when you've got a cold you can manage you know' (r:35). indeed, it is possible to 'shake off a cold' (r:48), but not the flu; flu 'knocks you for six' (r:10). "well, a cold you can really master" (r:25), but the flu, 'puts you right off your feet' (r:23). it is often the severity of the discomfort that enables a person to diagnose the one from the other. so, 'flu is woof, bang wallop, out, you're gone' (r:31). in short the flu necessitates withdrawal from normal and routine social intercourse. respondents also made clear that, on occasion, colds can develop into flu e which is why the behavioural features can be so crucial in diagnosing one from the other. and perhaps it is this unique capacity of flu to remove an individual from everyday affairs that warrants the invariable use of the definite article in discussions of the one (the flu) -as compared to the more probable use of the indefinite article (a cold) in discussions concerning the other. in any event, the possibility of a cold metamorphosing into flu serves to highlight the dynamic, 'wait-and-see' and emergent aspects of lay diagnosis with respects to both urti's and l(ower)rti's such as pneumonia. in sum, then, flu is not 'just in the head', but rather affects the entire human frame. as such, and as well as having corporeal symptoms e in the head, stomach, or muscles -flu affects one's routine activities and especially the capacity to function in daily affairs. flu in that sense is more 'serious'. we return to examine some of the implications of the analysis in the discussion section of the paper. for now we turn to an exploration of causation. fig. 2 is based on the talk that our respondents made in response to the question, "how do you think people catch flu?" as we have already stated, semi-structured interviews of the kind used for this study are often characterized as akin to 'a conversation with a purpose' (kahn & cannell, 1957, p. 97 ); as such they are designed to generate data rather than just to collect data. in our case and even though our focus was on the causes of flu, our respondents spoke extensively about the causes of both cold and flu and even of pneumonia (see extracts below). their responses led to the identification of a wide range of factors associated with the onset of the two key conditions; we can see virtually all of these referenced in fig. 2 . therein are mentioned items such as 'bugs' (and 'germs') as well as viruses; but the most commonly referred to causes invoked 'the air' and 'atmosphere'. the interview data also pointed toward means of transmission as 'cause' e so coughs and sneezes and mixing in crowds figure in the causal mix. most interesting perhaps is that lay people make a nascent distinction between facilitating factors (such as bugs and viruses) and inhibiting factors (such as being resistant, immune, or healthy), so that in the presence of the latter, the former are seen to have very little effect. in general, it is not easy to unravel the web of talk about causation that occurs in the interview data. causal agents, inhibiting agents and means of transmission are very often conflated by the respondents e as will be evident in the quotes that follow. in addition, a large proportion of our respondents pointed to the 'flu jab' as a cause of flu. we have not included inoculation as a causal agent in fig. 2 because it was rejection (or acceptance) of a flu jab that formed the focal point of the interviews -and therefore given undue attention. (r:32) "how do you catch it [the flu]? well, i take it its through ingesting and inhaling bugs from the atmosphere. not from sort of contact or touching things. sort of airborne bugs. is that right?" indeed 'the air' (and atmosphere) in particular were spoken of both as a cause of infection in its own right and as the key means of transmission between one person and another. thus; (r:3) "i suppose it's [the cause of flu] in the air. i think i get more diseases going to the surgery than if i stayed home. sometimes the waiting room is packed and you've got little kids coughing and spluttering and people sneezing, and air conditioning i think is a killer by and large i think air conditioning in lots of these offices. i know in the last years of when i was working, we had air conditioning in offices and i had more coughs and colds more during that period than i ever had". (r:46) "i think you catch flu from other people. you know in enclosed environments in air conditioning which in my opinion is the biggest cause of transferring diseases is air conditioning. worse thing that was ever invented that was. i think so, you know. it happens on aircraft exactly the same you know." while, the following respondent connects the air to flu's 'own little germs': (r:17) "i think it's [the flu] in the air with people who've got it. i don't really know. i know the old saying goes, coughs and sneezes spread diseases, but whether it's the flu or not or whether that's just colds or coughs. i don't think you catch it off someone else, i think you do it all by yourself. quite clever. i don't really know. i think it probably does come with the environment if you're working in an office and everybody's snuffly and .i think possibly flu can be more dangerous than people think. it's not just a cold plus. it has it's own little germs". as previously stated, being, cold, wet, or damp can also be viewed as a direct cause of flu. interviewer: "ok, good. how do you think you catch the flu?" r:39 "ah. the 65 dollar question. well, i would catch it if i was out in the rain and i got soaked through. then i would get the flu. i mean my neighbour up here was soaked through and he got pneumonia and he died. he was younger than me: well, 70. and he stayed in his wet clothes and that's fatal. got pneumonia and died, but like i said, if i get wet, especially if i get my head wet, then i can get a nasty head cold and it could develop into flu later." despite the presence of bugs and germs, viruses, the air and wetness or dampness, 'catching' the flu is not a matter of simple exposure to causative agents. for within each person there is a measure of immunity or resistance or healthiness that comes into play and is capable of counteracting the effects of external agents. for example being 'hardened' (r:14) to germs and harsh weather can prevent a person getting colds and flu. being 'healthy' (r:27) can itself negate the effects of any causative agents, and healthiness is often linked to aspects of 'good' nutrition and diet (r:35, r:16), and not smoking cigarettes. these mitigating and inhibiting factors can either mollify the effects of infection or prevent a person 'catching' the flu entirely. thus, (r:45) argued that it was almost impossible for him to catch flu or cold "cos i got all this resistance".interestingly respondents often used possessive pronouns in their discussion of immunity and resistance ('my immunity', and 'my resistance') e and tended to view them as personal assets (or capital) that might be compromised by mixing with crowds (see r:5 below). (r:45) "because i'm fairly healthy. as a matter of fact, i nearly said to you now, no, i don't want [the flu jab] now because i had shingles two years ago and i think i'm protected against the plague even. i have the full range of antibodies having recovered from shingles." (r:54) "because you and i can do exactly the same thing and be in exactly the same place, and you can have flu and i won't. your immune system you know plays a tremendous part in all this isn't it, so i think you know, if you're immune to it then you'll sail through it". equally, having a weak immune system (r:22) can sharpen the risk of contracting cold and flu and might therefore spur one on to take preventive measures such as accepting a flu jab. there are some, of course, who believe that it is the flu 'jab' that can cause the flu and other illnesses. the three extracts below illustrate the general idea, and we cite them not so much for what might be called their lay 'epidemiology' (davison, davey-smith & frankel; 1991) , but to illustrate the operation of what might be called a lay surveillance system -a system that is more often than not based on information derived from intimate knowledge of 'small worlds'. (r:4) "well, now it's coincidental you know that [my brother] died after the jab, but another friend of mine, about 8 years ago, the same happened to her. she had the jab and about six months later, she died, so i know they're both coincidental, but to me there's a pattern". (r:33) "i told him. i was awful poorly last week. i had that bloody flu injection. and next to me in the butchers. was a husband and wife, my age group, near enough. and she said oh, we're not having it any more either. yes, she said, we had a terrible time last year . there's a lot of people complaining". (r:5) "i'm nearly 87. i've had flu four times in my life. and i think i've developed a sort of immunity. and i don't want to spoil that immunity. and that is why i don't have an injection. int: right. so you think that because you've had flu four times, you probably won't have it again? r: well, it's a good record, isn't it and i'll be 87 in july. plus, i've got two other reasons why. i know somebody that's had gbs from it. int: gbs? (r:5) guillain-barré syndrome. you're paralyzed. he was paralyzed from there down. int: really! (r:5) yes, and i've got a friend, up grange road, here, who has flu every 21 days for 9 years because of a flu jab. yes. she has flu symptoms every 21 days. she's one, the doctors have told her. she's one in i don't know how many million. so that's another reason." what we can see in fig. 2 , then, is not so much an 'explanatory model' for either cold of flu, but the ingredients out of which a variety of explanations can be built. naturally, specific individuals weave these common elements into their own web of causation in distinctive ways. thus r:5 (above), for example, wove 'resistance'; 'immunity' and good health as well as the flu jab into his explanatory model; while r:4 placed emphasis on viruses, coughs and sneezes and 'resistance' in addition to the inoculation. indeed, people who refused inoculation proved highly likely to assert that the 'flu jab' caused the flu (which is partly why they avoided it). in the following section we highlight and discuss some of the implications of these observations. lay or 'folk' understandings of cold and flu have constituted the topic of investigation for a number of studies e especially crosscultural studies. however, the attention of such studies has normally been on the symptomatology of either cold or flu, rather than on the ways in which lay people differentially diagnose cold from flu (e.g. baer, weller, pachter et al, 1999; baer, weller, de alba garcia, & salcedo rocha, 2008) . in health service research literature also, there are numerous symptom surveys that concentrate on the reporting of symptoms for 'the cold' in particular (e.g. barrett, brown, mundt et al, 2009) . again, none of the latter looks explicitly at the process of lay diagnosis, or the ways in which lay people integrate observations of individual symptoms of cold into diagnostic procedures. in this paper, however, we have intentionally focused on describing the ways in which older lay people e as nonmedical professionals -assign clusters of symptoms to one of the two common disease categories (the views of younger people and of parents of young children may be different). it is relatively clear that while lay and professional knowledge of colds and flu intersect at various points, they diverge significantly when assessed as a whole. for even where there is apparent agreement on symptoms e and most of the symptoms mentioned by our sample also appear in the biomedical literature -it is evident that lay people assess such symptoms in a different frame from that used by clinicians. we know from cross-cultural studies that the symptoms for cold appear to be similar in many different linguistic and social cultures (baer, weller, pachter et al, 1999) and most, if not all, social groups seem to draw a distinction between cold and flu as separate illnesses. however, there are important differences to note. for example, members of the sample reported on here associated 'fever' with cold as well as with flu, and a number of people associated vomiting with flu (though not with cold). other populations e such as latin american populations -do not seemingly associate gastric symptoms with respiratory disease. more importantly, perhaps, it seems that the ways in which members of our sample integrated the symptom pattern into an understanding of cold and flu is quite different from that which appears in professional medical discourse. in particular, lay people place a heavy emphasis on behavioural correlates as distinguishing features of flu e being bedridden and therefore unable to function normally is exclusively associated with flu and constitutes a defining feature of flu. there is no consistent reference to causative agents here as a means of demarcating cold from flu. furthermore it is clear that flu is interpreted as a whole body illness characterized by an aching body (rather than just aching muscles) while colds are mainly confined to the head e head cold. it is not merely that in cases of flu people suffer with aching muscles (and of course they do), but that they, as homo totus, are ill. in medical anthropology the concept of a whole body illness is far from unknown. however, such illnesses are usually spoken of in the context of culture-bound syndromes and disorders with psychiatric symptoms. they are also reported on almost exclusively in studies of people living in countries outside of the advanced industrial world -see, for example, oths (1999) study of 'debilidad'. yet from the talk of informants in our study it seems plausible to suggest that, among this group of older white english speaking people at least, 'the flu' is essentially regarded as a whole body illness in which psychological symptoms (feeling low or down) play a very minor role (none of the respondents associated feeling low or feeling down with colds). in the discussion section of their 1999 paper, baer, weller, pachter et al, argued that in english speaking populations in the usa there was common reference to a 'folk flu' that differed in its symptomatology from the biomedical version; the key difference being an emphasis in folk flu on gastrointestinal symptoms, especially vomiting. the concept of 'folk flu' was a particular focus for mccombie (1987) , who placed a heavy emphasis on references to vomiting and diarrhea as symptoms of folk flu, and argued that such beliefs hampered the investigation of outbreaks of food-borne diseases. it is clear from our data that an association between flu and vomiting exists among some of our informants. in addition we have noted that it appears as a symptom of 'swine flu' in both uk and us health information sites. our respondents pointed to a wide range of causative agents e especially in their discussions concerning flu, but also in their talk about colds. extraneous causes of the flu can involve viruses, bugs and germs; the environment in general and 'stuffy' air in particular; being wet and wearing damp clothes; the flu jab; and coughs and sneezes of other people. however, any systematic understanding of the role of these factors has to take into account a series of countervailing factors such as a person's robustness, immunity, resilience and healthiness (attributes that, in turn, are often related to a regime involving 'good' nutrition and diet). colds and flu are 'caught', and the predominant notion of causation is one involving an infectious agent -usually referred to as a 'bug' or a 'germ', a 'virus' or merely 'it' -transmitted via coughs and sneezes through the air and 'atmosphere'. it's, "a germ that's floating around in the air" (r.17); it's 'airborne' (r.19); "you breath it in" (r.7), it's "a spray" (r.54); "germs in the atmosphere, that go through people" (r.35). there is no apparent recognition of transmission of infection via contact with infected surfaces (see, for example, the extract from r:32 in the previous section) e consequently hand washing does not figure at all in the armoury of preventive measures. more significantly, for a large proportion of people, 'bugs' and germs are believed to be capable of producing little more than the 'sniffles' in the presence of individual (bodily) 'resistance' or 'immunity'; a resistance that can be built up over a lifetime e rather like financial capital -through conscious self-care and a 'good' diet. there is, of course a parallel and alternative theory of causation that emphasizes factors such as getting wet, keeping warm and staying dry. in this frame, wearing damp clothes, getting wet feet, or simply getting chilled or cold, can in itself cause flu (and lead into pneumonia). thus, people catch flu by "getting wet, damp and neglecting themselves" (r:23); wearing "light clothes" (r:4); "staying damp too long" (r:15), while " a wind chill can kill as good as anything" (r: 51). these notions of catching cold and flu' from getting wet have been observed in uk populations previously (helman, 1978) . baer, weller, & de alba garcia (2008) , noted their existence across all their lay (and some of their spanish speaking professional) populations, and refer to it as the hot-cold classification system. helman (1978) examined it in the frame of a 'hotcold', 'wet-dry' matrix. interestingly, according to our informants, the potential for the hot-cold causation mechanism to bring about illness is often neutralized by a healthy constitution and is readily over-powered by the natural resilience of immune and resistant individuals. finally it is useful to note that lay people as well as professionals can call upon a nascent surveillance system. in the case of the former group it is a surveillance system reliant on anecdotal evidence and anchored in knowledge of small worlds e worlds composed of near neighbours, friends and close relatives. one implication of living in small worlds is that one (or two) reports of an adverse reaction to medication or vaccination can carry enormous weight in deciding, for example, whether to accept or reject the offer of immunization. the status of 'layperson' or 'expert' is dynamic and situated a one. to be an expert is to be positioned as an expert e via, say, an expert patient programme (eep) for chronic disorders, or by virtue of holding professional 'license'. according to rogers et al. (2009) , the expert patient is one who can, among many other things, recognise, monitor and respond to symptoms in terms of an effective programme of self-management, and they note how the eep as described in uk policy documents extends to encompass '70e80 per cent of patients'. in that context it is clear that our informants are expert e especially in the management of colds and flu. yet the ways in which the lay people in our study integrate their recognition and monitoring into an explanatory model suggests a different kind of comprehension from that contained in professional text-book discussions of such infections. in the case of flu, as we have seen, there is more emphasis on it as a whole body illness than there would be in professional discourse, and there is much more emphasis on 'the air' and the 'atmosphere' as a causative factor than one might find in professional epidemiological discussions of the flu. in this paper, we have explored such points of emphasis and pointed to such contrasts using relatively novel methods of data analysis and display. most interesting perhaps is the fact that lay people seem to assess information about disease and illness in the context of small worlds of family, friends and neighbours. we have pointed to that context by reference only to lay discussions concerning inoculation, wherein it certainly seems to be the case that, using popperian logic, a sighting of one sick but vaccinated 'swan' can be sufficient to reject the hypothesis that all vaccinated swans are healthy (c.f. popper, 1959, p. 27 ) e or that all vaccines are benign for all people. such reliance on small 'n' and anecdotal evidence about associations between specific causes and particular effects is apparent in relation to the public understanding of many medical debates (moore & stilgoe, 2009 ). in some circumstances it can prompt new lines of research and investigation about the causes of illness (brown, 1990) . under other circumstances it can hamper efforts to eradicate disease or establish 'herd' immunity (petts & niemeyer, 2004) . how lay knowledge is acquired, structured and deployed is seemingly central to public health efforts whichever direction we approach it from. one of our aims has been to demonstrate how a study of lay diagnosis and lay epidemiology can play a part in such a project. cross cultural perspectives on the common cold. data from five populations crosscultural perspectives on physician and lay models of the common cold popular epidemiology: community responses to toxic wasteinduced disease does this patient have influenza? lay epidemiology and the prevention paradox exploratory social network analysis with pajek expert patients usher in a new era of opportunity for the nhs understanding the symptoms of the common cold and influenza a qualitative study of lay beliefs about influenza immunisation in older people the 'expert patient': empowerment or medical dominance? the case of weight loss, pharmaceutical drugs and the internet clinical care and conversational contingencies. the role of patients' self-diagnosis in medical encounters explaining illness: patients' proposals and physicians' responses pre-emptive resistance: patients' participation in diagnostic sense making activities. sociology of health and illness the delivery and reception of diagnosis in the general practice consultation feed a cold, starve a fever' e folk models of infection in an english suburban community, and their relation to medical treatment the dynamics of interviewing. theory, technique and cases interviews. an introduction to qualitative research interviewing culture, illness & care, clinical lessons from anthropologic and cross-cultural research the pasteurization of france introduction. a sociological focus on 'expert patients respiratory tract infections and pneumonia folk flu and viral syndrome. an epidemiological perspective the discourse of medicine. dialectics of medical interviews experts and anecdotes. the role of 'anecdotal evidence' in public scientific controversies. science, technology and human values mosby's dictionary of medicine, nursing, and health professions. london. (online version accessed debilidad: a biocultural assessment of an embodied andean illness health risk communication and amplification: learning from the mmr vaccination controversy communicating and responding to diagnosis belief, knowledge, and expertise: the emergence of the lay expert in medical sociology rationality, rhetoric and religiosity in health care: the case of england's expert patient programme going to see the doctor e the consultation process in general practice text mining for clementine.12.0. user's guide. chicago: ill: spss acknowledging the expertise of patients and their organizations the empirical work on which this paper was based was funded by the wales office of research and development; grant r00/1/ 028. the analysis of the data was facilitated by the resources of the northern ireland centre of excellence in public health at qub. the authors wish to record their appreciation for the funding and the support. key: cord-022658-mq91h15t authors: nan title: executive summary date: 2008-12-30 journal: allergy doi: 10.1111/j.1398-9995.1998.tb04885.x sha: doc_id: 22658 cord_uid: mq91h15t allergic rhinitis is now recognized as a major cause of morbidity that significantly impairs function and quality of life. moreover, it is now widely held that the pathophysiologic mechanisms causing nasal allergy contribute, or predispose many individuals, to the development of other airway diseases, including asthma. allergic rhinitis may well be a factor in 24% of children with otitis media with effusion (ome), and perhaps 28% of cases of chronic sinusitis. as many as 78% of persons with asthma aged 15 to 30 years have elevated serum ige antibodies to five common aeroallergens. in many instances, nasal allergy signals the presence of more severe disease. considerable evidence now suggests that early and appropriate intervention can improve the quality of life and productivity of patients with allergic rhinitis, enhance the academic performance of children, and reduce the prevalence of airway complications. the goal of treatment has shifted from mere symptom alleviation to blocking the pathophysiologic mechanisms that cause chronic allergic inflammation and leave patients vulnerable to airway infections. the earlier in a patient's life that this can be accomplished, the better the anticipated consequences. a panel of experts was convened in amsterdam, the netherlands, on 2 september 1996, to explore these issues and their impact on allergy prevention and treatment in primary care. their undertaking was supported by an unrestricted educational grant from schering‐plough pharmaceuticals. allergic inflammation appears to be the first and primary occurrence in the chain of events leading to asthma and other airway disorders. chemical mediators released during hypersensitivity reactions give rise to the symptoms of allergic rhinitis, and induce the cell infiltration and activation that results in chronic inflammation. a key event in this process is the upregulation of specific intercellular adhesion molecules, including members of the immunoglobulin superfamily intercellular adhesion molecule-1 (icam-l), that permits inflammatory cells to migrate into nasal, sinus, and lung tissue. in certain conditions, inflammatory mediators stimulate the expression of icam-1, which is also a receptor for the subtype of human rhinoviruses that accounts for 90% of human rhinovirus infections. it is currently under investigation that allergen exposure and viral infection in the first 3 years of life may alter pulmonary and immune function irreversibly in genetically predisposed children. * moreover, these same mechanisms may contribute to other respiratory problems associated with eosinophilic inflammation, lymphoid hyperplasia, mucosal edema, and viral infection. therapies that downregulate icam-1 are being investigated as a means of preventing or minimizing allergic inflammation. treatments presently known to downregulate icam-1 include antihistamines (loratadine, terfenadine, cetirizine, and azelastine). allergic rhinitis is associated with impairments in how patients function physically, emotionally, socially, and at work or school. adults may complain of role and activity limitations, frustration, sleep disturbance, irritability, embarrassment over symptoms, cognitive impairment, decreased alertness, and performance deficits. in children, chronic nasal allergies are associated with learning deficits. unfortunately, sedating antihistamines can exacerbate these effects by hampering performance and cognition even when subjects have no sense of being impaired. at least one of the newer nonsedating agents, by contrast, can partially reverse allergic rhinitis' effect on cognition and performance. nasal allergy may usually be differentiated from other forms of rhinitis by an allergy diagnosis. this includes personal history of symptoms, the timing of their expression, triggers, and physical examination. skin prick tests and eventually in vitro diagnosis of specific ige are important. imaging studies are usually indicated only if the diagnosis is in doubt, if related airway disorders complicate the presentation (e.g., nasal polyps), or when occupational rhinitis is suspected. the the impact of allergic rhinitis temporal association of nasal or ocular symptoms with the workplace strongly suggests occupational rhinitis. treatment of chronic rhinitis and nasal allergies should be individualized, with therapeutic measures aimed at the underlying etiology, likely pathophysiology, and dominant symptoms. medication is best taken prophylactically for seasonal symptoms before the anticipated onset of symptoms in seasonal rhinitis or for episodic exposures to specific ailergensand regularly, rather than as needed. such usage of antihistamines and intranasal steroids has been found to alleviate exacerbations in patients with both nasal allergy and seasonally induced asthma. avoidance of inciting factors (e.g., allergens, irritants) can reduce the expression of nasal symptoms and minimize the need for medications. the avoidance measures that are easiest to implement are the ones most likely to be used and therefore to be successful. antihistamines. although traditional agents have some benefits (e.g., low cost), they can no longer be recommended due to their potential for causing cns impairment. nonsedating anthstamines are the preferred option. oral decongestants. although topical steroids are the first-line treatments for nasal blockage, a-adrenergic agonists such as pseudoephedrine, phenylpropanolamine, or phenylephrine also ameliorate nasal congestion. this symptom is a major factor in perennial rhinitis. careful dosing of agonists is required to avoid aggravating hypertension. moreover, these agents generally should be avoided in patients with cardiovascular disease, thyrotoxicosis, glaucoma, or diabetes. oral corticosteroids. a brief course is indicated only to relieve severe nasal blockage so that topical therapy can proceed. in such cases, patients should be referred to an allergist. intranasal corticosteroids are highly effective in reducing inflammation, rhinorrhea, itch, and nasal blockage. they are the first choice for treating nasal blockage and largely reduce, but may not eliminate, the need for other medications to treat ocular symptoms. they may be used safely in children, though youngsters often have difficuity with sprays. in addition to treating nasal allergies, these medications can be used to treat nonallergic rhinitis with eosinophilia syndrome (nares) and to shrink small nasal polyps or prevent their recurrence after surgery. the onset of action of topical corticosteroids is slow compared to antihistamines. topical nasal decongestants may be used to open nasal passages in preparation for the use of other agents, such as intranasal steroids. to prevent rebound congestion, they should be used for 2 to 3 days and no more than 7 to 10 days. mast-cell stabilizers include intranasal cromolyn and nedocromil sodium. cromolyn may be used for the prophylaxis of allergic symptoms, and is considered especially safe for elderly patients, children, and pregnant women. the need for frequent administration can raise compliance issues. nedocromd sodium, unlike cromolyn, can both prevent an allergic reaction and control a reaction in progress. topical antihistamines allay allergen-induced itching, sneezing, rhinorrhea, and ocular symptoms but are less useful for nasal blockage. intranasal anticholinergics such as ipratropium bromide are effective in controlling the excessive watery rhinorrhea associated with neurogenic stimuli (e.g., cold air, spicy foods) or the common cold. however, they have no effect on nasal blockage, sneezing or itching, or ocular symptoms. patients with rhinitis or asthma caused by allergens for which the clinical efficacy and safety of sit have been documented by placebo-controlled, doubleblind studies, and those requiring daily pharmacotherapy for longer periods (e.g., preventive treatment during a pollen season or perennially) are candidates for sit. sit is most effective if a single allergen is identified, rather than multiple allergens. injections should be prescribed by specialists and given by physicians only if a specific allergen has been identified. sit should never be initiated in pregnant women, though the continuation of maintenance therapy is safe. considerable care must be taken if allergic rhinitis coexists with moderate or severe asthma. local immunotherapy offers improved safety and equivalent effectiveness. when patients respond poorly to standard medical care, clinicians should a) ascertain whether compliance has been poor, b) adjust drug doses, c) consider combination therapy, d) reconsider the diagnosis, e) reassess the patient for a nasal structural defect or a complication of allergic rhinitis, or f) refer the patient to a specialist. referral can be helpful under the following circumstances: in most cases when significant airway comorbidity is present (asthma, chronic sinusitis, nasal polyps, or otitis media with effusion) when the diagnosis is in question or special diagnostic testing is required when occupational rhinitis is suspected, to distinguish between clear-cut allergic reactions and toxic or nonallergic reactions when poor symptom control necessitates a consultation for environmental control measures, pharmacotherapy, or specific immunotherapy when medication side-effects are intolerable when rhinitis is only part of a complex series of mucosal allergies. allergic rhinitis is a seasonal or perennial disorder characterized by mild to severe upper respiratory symptoms such as nasal congestion, rhinorrhea, sneezing, and itching. these symptoms arise from an underlying inflammatory process initiated by a reaction between the allergen and immunoglobulin e (ige), neurogenic stimuli, and other complex cellular processes. a panel of experts was convened in amsterdam, the netherlands, on 2 september 1996, to explore these issues and their impact on allergy prevention and treatment in primary care. their undertaking was supported by an unrestricted educational grant from schering-plough pharmaceuticals. conclusions and recommendations from that meeting are summarized subsequently and presented in expanded form later in this monograph. allergens are primarily responsible for provoking chronic inflammatory processes; viral infections underlie acute exacerbations of asthma, chronic sinusitis, and otitis media with effusion. there is a growing awareness of how allergic rhinitisand some of the medications used to treat itcan affect patients' quality of life, work or school performance, and emotional well-being. besides physical symptoms, patients may exhibit fatigue, psychomotor sluggishness, irritability, and mood and cognitive disturbances (1 -5). learning is impaired in children (6), while some adults may report reduced productivity and concentration (7). this combination of physical, emotional, and functional problems may diminish quality of life in both adults (7) and adolescents (8). moderate to severe perennial allergic rhinitis has been found to affect quality of life significantly compared to healthy subjects in eight of the nine dimensions of the medical outcomes study short-form health survey 36 (sf-36) (9). the prevalence of allergic respiratory disorders is high and is a burden on the health-care system: one study of patients in a london general practice found that nearly one in seven adults had allergic rhinitis (10). by the age of 6 years, 42% of 747 children followed from birth in the tucson children's respiratory study had physician-diagnosed allergic rhinitis (11). those who developed rhinitis before the age of 1 were more likely to have asthma by age 6 (11). as many as 78% of persons with asthma aged 15 to 30 years have been shown to exhibit high levels of ige antibodies to five common aeroallergens (12). of 200 patients with chronic sinusitis, 27.5% also had allergy in one study (13). about 24-50% of children with ome had allergic rhinitis (14) or nasal allergy (15). for comparison, about one-third of the general population has chronic sinusitis or ome. in general, the prognosis for patients with asthma or allergic rhinitis is mixed: only 10% of patients are cured, about 50% improve, 30% show no change, and 10% deteriorate over time (16). medicine has begun to revise its traditional therapeutic approach to allergic rhinitis. it is now acknowledged that impeding the natural course of airway allergies by interfering with the pathophysiologic mechanisms that cause mediator release and chronic inflammation may help prevent related airway disorders. this would reduce overall morbidity and improve patients' quality of life. it also should help make patients less vulnerable to the consequences of viral infection, as well as to environmental factors such as pollution. recent advances in allergy treatmentsmost notably the introduction of nonsedating selective histamine hiantagonists and intranasal corticosteroid sprayshold the promise of achieving these goals. of particular interest are the studies showing that tgeatment of allergic rhinitis reduces the incidence and severity of asthma (17) (18) (19) . the purpose of this monograph is to introduce new ways of thinking about and managing allergic rhinitis in the hope that physicians will look for related airway disorders and individualize therapeutic programs, considering tbe special needs of populations such as pregnant women, children, and the elderly. persons with allergic rhinitis have ige antibodies bound to high-affinity receptors on mast cells and basophils, and to low-affinity receptors on other cells, such as eosinophils, monocytes, and platelets. allergic inflammation is initiated when allergens deposited in the airway bind to ige molecules, causing cellular degranulation and releasing a number of inflammation mediators (20) . this process entails both an early-and a late-phase rqsponse (fig. 1) . the interaction of antigen with specific ige antibodies leads to the degranulation of mast cells and basophils and the prompt release of preformed and newly generated mediators, such as histamine, neutral proteases, leukotriene c,, prostaglandin d,, cytokines, and kinins (21). the interaction of these chemical messengers with blood vessels, mucous glands, and nerves produces the symptoms of allergic rhinitis, such as sneezing, rhinorrhea, and itching. histamine is one of the most important mediators of the early-phase allergic response in the nasal mucosa. its release stimulates sensory nerves, this reaction, manifested by some patients, entails a process of cell infiltration and activation occurring over 4-24 h. late-phase allergic reactions begin when autocoid mediators and cytokines released from mast cells during the early-phase response upregulate the expression of leukocyte endothelial adhesion molecules in the postcapillary venules of the nose. especially sensitive to histamine, postcapillary venules are also the site of blood cell extravasation. once adherent to the endothelium, these cells pass between adjacent cells to the perivascular space. various chemoattractants, essentially il-5 and the chemokines, draw primed leukocytes (eosinophils, basophils, neutrophils, and mononuclear cells) into the submucosal tissue. once there, by interacting with additional stimuli by matrix proteins, they release their own mediators. this perpetuates the inflammatory response and augments aspects of the immediate hypersensitivity reaction, such as mucosal congestion and mucus secretion. although pruritus the impact af allergic rhinitis and sneezing occur, the major symptoms in latephase reactions are hypersecretion and congestion. the chronic inflammation caused by repeated allergen exposure lowers the threshold for other provocative stimuli reactions (22) . as a result, allergic individuals react more strongly to a) low levels of the primary allergen, b) other allergens to which they are only mildly sensitive, or c) nonspecific "triggers", such as cold air, cigarette smoke, spicy foods, and strong chemical odors. a key event in chronic respiratory allergy is the upregulation of specific adhesion molecules that permit inflammatory cells (e.g., eosinophils) to migrate into nasal, sinus, and lung tissue. the first step is the experience of such molecules on endothelial cells and on activated circulating inflammatory cells. the accumulation of eosinophils in these tissues is injurious, and contributes to the pathogenesis of allergic rhinitis, sinusitis, and asthma (23 -26) . in certain conditions, histamine is known to stimulate the expression of adhesion molecules on nasal epithelial cells of normal subjects (27) . an important adhesion molecule required for effective cell recruitment in allergic disease is intercellular adhesion molecule 1 (icam-2) (28) . vascular inflammation induced in a primate madel of allergic sensitization and exposure (29) ; b) on bronchial epithelial and on vascular endothelial cells in symptom-free asthmatics (30) ; c) on epithelial cells of the nose and conjunctiva in patients with perennial and seasonal (31) allergic r~n i t i s (fig. 2) ; and d) on the nasal and conjunctival epithelium of patients with asymptomatic perennigl rhinitis when exposed to allergen, though not in cohabiting relatives or heqltby volunteers (32) . besides its role in allergic inflammation, icam-1 serves as a receptor for the major subtype of humqn rhinoviruses; this subtype accounts for 90% of all human rhinoviruses (33, 34) . rhinoviruses are a major cause of the common cold. evidence of minimal, persistent inflammation in asymptomatic allergic patients suggests that by inducing icam-1, subclinical allergen exposure may incregse the susceptibility of allergic patients to rhinovirus infection, and thereby explain the greater frequency of colds in asthmatic children (30) . in short, it now appears that both icam-1 and viral infection play a role in the patbophysiology of asthma (fin. 3 ) . the epidemiologic link between viral respiratpry infection and asthma is. strong. researchers have shown that such viral infections are associated with: 86% of wheezing episodes that last longer than 48 h in noqhospitalized children (35) 80% to 85% of asthqa exacerbations in 9 to 12-year-old children (36) . among the viruses associated with childhood asthma exacerbations are rhinoviruses, respiratory syncytial virus (rsv), adenovirus, and coronaviruses (36) . rhinovirus infection has been implicated in 50% of acute asthmatic episodes in schoolchildren, followed by coronaviruses in 13'%0 of cases (36) . levels of eosinophil, a major basic protein in children with asthma, have been shown to be higher during exacerbations associated with rhinovirus infection than during asymptomatic periods adults with allergic rhinitis exhibit bronchial hyperresponsiveness to histamine and antigen following rhinovirus infection. rhinovirus infection also predisposes the allergic patient to allergenprovoked late asthmatic reactions (38) . in asthmatics, but not in nonasthmatics, eosinophilia in the bronchial mucosa is still evident at 6-10 weeks after rhinovirus infection, probably due to ongoing secretions initiated by the virus in the allergenprimed mucosa (39) . (37) . rhinitis can be divided into three categories: allergici.e., acute or chronic conditions characterized by seasonal or perennial symptoms, or both infectiousi.e., nasal disorders caused by viral, bacterial, or fungal agents nonallergichoninfectiousi.e., a heterogeneous group of disorders comprising eosinophilic conditions, such as aspirin idiosyncracy; or noneosinophihc conditions, such as gustatory rhinitis, rhinitis of pregnancy, and vasomotor rhinitis. table 1 catalogues the characteristic features of the various forms of chronic rhinitis (10, [40] [41] [42] [43] [44] [45] [46] [47] [48] . despite the considerable overlap, it is usually possible to diagnose the disorder by skin prick test and the patient's symptoms, history (including relevant behavioral practices, such as smoking), and physical examination. the elements of a diagnosis include elicitation of a detailed patient history and physical examination of the nose, eyes, ears, and lungs. among the many factors that must be explored are patterns of symptom expression, environmental triggers, medication use, family history, and exposure to workplace allergens or irritants. it is important to determine the severity of symptoms and to uncover possible complications such as asthma, sinusitis, otitis media, or nasal polyps. questions related to psychosocial or quality-of-life problemssuch as fatigue or cognitive impairmentalso should not be overlooked. the differential diagnosis of rhinitis primarily depends on use of an allergy skin prick test. pharmacologic agents that may affect results should be withdrawn for a sufficient time before testing ( table 2) . because of its long duration of action (approximately 7-9 days), the antihistamine astemizole can suppress skin test reactivity for 8-12 weeks after its discontinuation (40) . by contrast, this effect lasts only 2-4 days with most other antihistamines. most patients who present with rhinitis exhibit clusters of symptoms that define them as either "sneezers and runners" or "blockers". those with seasonal allergic rhinitis are usually sneezers and runners. some patients with rhinitis have only a single symptom or many nonnasal complaints, such as headache, sore throat, postnasal drip, a "full" or a "stuffy" head, recurrent head colds, chronic "sinusitis", chronic cough, plugged ears, hyposmia, loss of the sense of taste, fatigue, or poor concentration. often, patients use the term "sinuses" or "sinusitis" to describe symptoms caused by nasal pathology. a thorough patient history yields information needed to classify nasal symptoms, determine their cause, and make appropriate therapeutic decisions. family studies indicate that environment generally influences the expression of allergic disease (ll), but genetics determines the severity and specificity of the symptoms (49) . genetics also is an important component of atopy as a general predisposition, involving multiple as yet unidentified genes. children not only inherit a tendency to atopy from their parents, but are likely to develop the same allergic disorders (50, 51) . consequently, the following information should be sought: symptom type, occurrence, and frequency symptom duration and severity aggravating factors current medications illicit drugs. the age at which symptoms began (episodic, seasonal, or perennial) allergen exposure in home or work environment although the physical examination of patients with chronic rhinitis centers on the nose, eyes, and throat, clinicians also should evaluate the ears, sinuses, and lungs to identlfy any related airway disorders, which often are present. general signs of an atopic predisposition, such as eczema, also are helpful. imaging studies are usually indicated only in specific circumstancesmost commonly, when the diagnosis is in doubt, when symptoms persis despite appropriate therapy, or when related airway disorders complicate the diagnosis. persistent symptoms or airway complications may be factors in perennial allergic rhinitis. plese.g., limiting outdoor activities during the height of the pollen season, shielding young children from passive tobacco smoke and gas heating or wood-burning stoves. they also may entail fairly complex undertakings aimed at specific allergens; e.g., cat dander. as people spend increasing amounts of time indoors, environmental control is focused largely on containing exposure to house dust, animal dander, mold, and cockroaches. as a rule, measures to avoid allergens are effective when they are likely to be usede.g., simple to follow and inexpensive to implement. patients should be informed that even partial compliance can help control symptoms and lessen the need for medicalion. they should be encouraged to persevere, as it may lake weeks or months of avolddnce before an improvement in sympfoms is noticeable. (see appendix for a patient information sheet about allergen-control measures.) the selection of an appropriate and effective medication for the treatment of chronic rhinitis entails consideration of several factors: although impaired olfaction is frequently overlooked in cases of nasal allergy, it is relatively easy to assess by olfactory threshold tests. patients who require more sophisticated testingsuch as assessment of mucociliary function or nasal airway patencyshould be referred to a specialist. underlying eriology. especially in patients for whom immunotherapy is being considered, this requires careful diagnosis of the allergen (s), primarily through skin prick testing. a likely parhophysiology. symptoms due to inflammatory processes (as in nasal allergy) require differed1 medications than those caused treatment options consist of allergen avoidance, pharmacologic therapy, or allergen-specific immunotherapy. efforts aimed at environmental control may involve relatively simple activities based on general princi-by-noninflammatory neurogenic mechanisms (as in gustatory, idiopathic, or atrophic rhiniiis). dominant symptoms. medications should address the patient's most prominent complaints. combination therapy may be warranted for patients with a mix of moderately severe lo severe symptoms. safety. it is important 10 determine whelher medication side-effects may impede a patient's perfarmance at work or scho61, diminish quality of life, or enhance risk of sustairiing personal the impact of allergic rhinitis table 2 withdrawal of pharmacologic agents that affect skin test reactions (38) individuals. regular antihistamine use over weeks or months has been found to reduce asthma symptoms significantly in allergic rhinitis patients with seasonal and chronic rhinitis (55) (56) (57) . injury or significant morbidity. the potential for drug interactions also must be considered when patients are taking multiple medications. patient age and other special considerations. the needs of special populationspediatric patients, the elderly, pregnant women, and competitive athletes must be evaluated. coexistence of related airway disorders. in patients with coexisting airway disease, the treatment of nasal allergy is important to prevent exacerbation of sinusitis or asthma. patient preferences and compliance historv. in some countries, patients prefer oral medications to sprays (52) . additionally, individuals differ greatly in their capacity to adhere to therapeutic regimens. consequently, an attempt should be made to determine each patient's understanding of abd willingness to comply with a specific treatment program. factors that may adversely affect compliance include poor symptom relief, the nature or severity of the side-effects, and the inconvenience or complexity of the therapeutic rkgimen (53,54). as a rule, it is best for patients to start therapy before the anticipated onset of symptoms, to suppress those immunologic and mediator mechanisms that cause inflammatory reactions and to minimize the priming effect. prophylactic therapy is usually possible in seasonal allergic rhinitis, when the onset of symptoms is relatively easy to predict, or for episodic exposures to specific allergens (e.g., before visiting the home of someone with pets). as a rule, patients with seasonal or perennial rhinitis should take their medication regularly, rather thhn as needed, because consistent use best controls mucosal inflammation. in turn, this helps lessen the risk of related airway complications in susceptible in its 1994 consensus statement, the international rhinitis management working group advocated a stepwise approach to therapy that took into account specific diagnoses and patient characteristics (40) . this approach is summarized in table 3 . stepwise management certainly represents a reasonable starting point for therapeutic decisions in cases of chronic rhinitis. nonetheless, the complexity and interrelationship of these disorders suggest that, while taking account of the guidelines, a case-by-case approach provides added value. what follows is a review of the benefits and limitations of various medications used to treat chronic rhinitis. among the agents considered are topical and oral antihistamines, topical and oral corticosteroids, topical and oral decongestants, crornolyn sodium, nedocromil, sodium intranasal anticholinergic agents, and saline sprays. the discussion concludes with a review of combination drug therapy and the ihdications for immunotherapy. there are at least three classes of histamine receptors, designated hi, h,, and h,. histamine can exert local or widespread effects on smooth muscles and glands. bronchoconstriction and contrktion of the intestine are mediated by h,-receptors, while gastric secretion results from h,-receptor activation (58) . h,-receptors appear to exist predominantly in the central nervous system (cns) and at presynaptic nerve endings (58) . histamine causes capillary dilation; hi-receptor stimulation leads to a rapid, brief dilator response, while h,-receptors mediate a response that is slowkr to develop and more sustained (58) . it also plays a role in extravascular smooth-muscle contraction and (more rarely) relaxation, with h,receptor activation responsible for contraction and h,-receptor stimulation usually resulting in relaxation (58) . the class of agents known as hi-receptor antagonists comprises drugs that act rapidly to antagonize the histamine activity of hi-receptors, thereby relieving the maiq symptoms of allergic rhinitis (sneezing, watery rdnorrhea, and itching of the ndse, eyes, and palate). in addition, some of the hewer agents have been shown to possess antiallergy properties that may contribute to diagnosis and treatment. these properties include the ability to: inhibit histamine release from human basophils block histamine, and partly block prostaglandin d, release, in the nasal secretions of highly allergic subjects (61) directly inhibit eosinophil activation (62, 63) block histamine activation of airway epithelial cells by suppressing the expression of surface markers, such as icam-1, and the major histocompatibility complex class i1 antigen hla-dr, involved in antigen presentation (27) . the ability both to inhibit histamine release and downregulate icam-1 makes certain anthistamines (e.g., terfenadine [65, 66] , loratadine [27] , cetirizine [65] , azelastine [65] , oxatomide [65] , and levocabastine [65] particularly suitable for treating allergic inflammation, because icam-1 is a marker of allergen-induced inflammation as well as a receptor for human rhinoviruses (33, 65) . (59, 601 reduce vascular permeability (64) sedating vs nonsedating antihistamines. "sedating" agents are distinguished from "nonsedating" ones by the higher incidence of drowsiness associated with the former at the doses used to control allergic ,symptoms. in part, this difference is due to the speed with which antihistamines cross the bloodbrain barrieri.e., rapidly in the case of the sedating agents and slowly in the case of the nonsedating agents. the sedative potential of the newer agents is limited further by their specificity for binding to peripheral hi-receptors. sedating antihistamines, in contrast, affect central hi-receptors and receptors of other types (e.g., muscarinic cholinergic, a-adrenergic, and tryptaminergic) (67) . this may contribute to their sedative and other side-effects (67) . sedating agents' effect on central hi-receptors may be especially relevant, as hstaminergic transmission originating from the posterior hypothalamus sustains waking arousal (68) . in short, by having a reduced capacity to cross the blood-brain barrier and specifically blocking hireceptors, the nonsedating agents are less able to cause cns effects and associated adverse reactions. (see subsequent discussion of cns effects.) efficacy. table 4 presents selection criteria for 10 of the antihistamines most commonly used in europe. studies have shown that the newer nonsedating antihistamines produce moderate to the impact of allergic rhinitis excellent symptom response in up to 67% of patients with seasonal allergic rhinitis (691, making them as effective as, if not more effective than, the older (i.e., sedating) agents (70, 71) . as a group, the newer agents demonstrate comparable efficacy (72, 73) . a comparison of loratadine and astemizole in patients with seasonal rhinitis found equivalent efficacy in the two (72) . cetirizine has been shown to lessen nasal blockages (74) . although the use of antihistamines in asthma is still controversial, the new nonsedating agents seem to offer some benefit for allergic patients with concomitant asthma. data indicate that terfenadine (75, 76) and loratadine alone (77) , and combined with pseudoephedrine ( 5 5 ) , astemizole (78), certirizine (79) , and azelastine (80) exhibit modest bronchodilating effects (75), reduce bronchial sensitivity to histamine (55) , and guard against exercise-(78) and antigen-induced bronchospasm. such effects may require higher than currently recommended doses, however. loratadine (5.9, cetirizine (56), and terfenadine (57) have been shown to reduce asthma symptoms in rhinitic patients with seasonally induced asthma when taken over weeks or months, though this evidence is disputed. together, such findings suggest that timely and appropriate use of antiallergy therapy may help prevent lower airway symptoms in susceptible patients if used in an adjunctive manner. moreover, they dispel the fallacy that antihistamines are contraindicated in asthmatic patients. cns effects. sedating antihistamines can exacerbate the cognitive and functional problems caused by untreated allergic rhinitis (81) . among their most troubling cns effects are fatigue, sedation, and performance impairment (81) . patient reports of unusual daytime drowsiness have been noted in 25-50% of users of sedating antihistamines (82) -e.g., diphenhydramine, pyrilamine, brompheniramine, chlorpheniramine, triprolidine, hydroxyzine, promethazine, and cyproheptadine. by contrast, when given at the recommended doses, the "nonsedating" antihistaminesastemizole, ebastine, fexofenadine, loratadine, and terfenadinecause no more drowsiness than placebo. confusion exists as to the sedating properties of two new agents, acrivastine and cetirizine. both medications have been associated with significantly more reports of daytime drowsiness than placebo at recommended doses: acrivastine, 8 mg, 11% versus 6% (82); cetirizine, 10 mg, 9% to 25% versus 6% (83) . although the lower dose ( 5 mg) of cetirizine is no more sedating than placebo (83) , it has been shown that, if allowed, more than 80% of cetirizine users will titrate the dose upward, to achieve symptom relief (84). after repeated dosing, some patients may become tolerant of the sedating effects of antihistamines (85) . however, it is unwise to depend upon tolerance to abolish the antihistamineinduced sedation and performance impairment that commonly occurs for at least 1 week after the medication is started (86) . it is generally agreed that tolerance is a highly idiosyncratic phenomenon that is not universal, complete, or predictable. virtually all antihistamines are equally effective in relieving allergy symptoms (see "efficacy" section). consequently, before recommending a particular antihistamine, physicians must weigh the benefits of that agent against its drawbacks. the lower cost of the older "sedating" antihistamines, and their general availability without prescription, may argue in their favor, but their use can no longer be recommended. the nonsedating agents offer the potential long-term benefits of safety and improved performance at work or in school compared to sedating antihistamines, and greater therapeutic compliance owing to their longer half-life and the need for less frequent dosing (81, 82) . ' consequences of cns effects. unfortunately, one's subjective sense of sleepiness or impairment is an unreliable gauge of whether it is safe to operate heavy machinery while taking sedating antihistamines. this is because impairment can occur without the patient's awareness (87, 88) . these factors have important safety implications in areas such as building consltuct ion, manufacturing, pub1 ic transpottation, and automobile driving. simulated and real-life driving studies verify that these agents carl impair performance significantly (87, 89, 90) . in one study, lane weaving by drivers given triprolidine 10 mg (emtamed release), was comparable to that ib pers6hs with a blood alcohol level of 0.05%; moreover. at 3-4 h after drug use, the drivers stopped feporting any sense of being impaired (87) (fig. 4) . another study found that the effects of a single 10-mg dose of cetirizine resembled those of alcohol (72 g/kg lean body mass), and that the impairment appeared to be greater when alcohol and cetirizine were taken together (91) (fig. 5) . by contrast, no psychomotor deficits have been observed in drivers given loratadine (87, 91) , or in individuals tested while taking astemizole (92); nor does the use of alcohol with these agents produce an additive effect. studies have also shown that terfenadine did not impait psychomotor performance or reaction time (65) , and that ebastine at 10, 20, or 30 mg given for 5 days did not impair driving performance compared to triprolidine 10 mg (93). besides causing psychomotor problems, sedating antihistamines also adversely affect cognition and functional performance (6, 88, 94, 101), compromising sustained attention and cerebral processing speed in adults (97) and children (95) . the effects of nonsedating agents on somnolence, cognition, and performance, by contrast, are comparable to those of placebo (70, 95, 96, 102) . specific findings to date include the following: performance on a digit symbol substitution test impaired by diphenhydramine (50 mg t.i.d.), but not by loratadine (10 mg q.d. and 40 mg visuavmotor coordinationimpaired by promethazine, chlorpheniramine, and clemastine, but not by terfenadine (101,115) clerical skills -8112 skills impaired by diphenhydramine; none by loratadine (96) learning in children with seasonal rhinitisimpaired by diphenhydramine (50 mg) compared to nonallergic, unmedicated children, with the impairment in allergic children offset partly by loratadine (10 mg) (6). nonallergic, unmedicated children performed significantly better on tests of learning ability than atopic children given placebo, diphenhydramine, or loratadine; performance among atopic children was q.d.) (99) the impact of allergic rhinitis best among subjects receiving loratadine and worst among those receiving diphenhydramine. this suggests that the learning problems associated with allergy are augmented by sedating antihistamines and offset somewhat by nonsedating agents. cardiovascular effects. two nonsedating agentsterfenadine and astemizolehave been found to cause malignant ventricular arrhythmias, such as torsades de pointes (103, 104), when patient factors or drug interactions result in greatly elevated serum drug levels (105, 106). although rare, these phenomena can delay cardiac repolarization and prolong the qt interval through blockage of a k rectifier channel, resulting in possible sudden death. at least 11 case reports involving 20 patients have been published in which patients taking astemizole experienced torsades de pointes, qt prolongation, and sometimes other cardiac effects (67) . eight such reports affecting 22 patients have appeared for terfenadine (67) . acrivastine, cetirizine, fexofenadine and loratadine appear to be the least likely of the newer antihistamines to be arrhythmogenic (67) . the risk of cardiac arrhythmias can be minimized by reviewing the medical and pharmacologic risk factors for torsades de pointes before prescribing terfenadine or astemizole for any individual. drug interactions associated with the potential for cardiotoxicity are a major concern of clinicians, as patients frequently fail to report all of the medications they are tdking. concomitant administration of certain antifungal agents (especially ketoconazole and itraconazole) or macrolide antibiotics (patticularly erythromycin), along with terfenadine or astemizole, inhibit metabolism of these two antihistamines through competition for hepatic p450 enzymes. this results in increased plasma cohcentrations of these antihistamines. coadministratiori of terfenadine or adtemiztde in users of such medications is thus sttictly contraindicated. hepatic dysfunction and preexisting cardlovascular disease also ate risk factors for cardiovascblar complication$ with these ztrltihfstamines. because the causes of qt prolongation are additive (106), patients with more risk factors have a potentially greater chance of developing ventricular arrhythmias while taking either terfenadine or astemizole. the use of these drugs at recommended doses without the aforemefitioned concomitant medications by patiedts lacking known rtsk factors carries a low risk of ah adverse catdiac event. still, such low-risk patients taking terfenadine or &temizble should be warned not to inmease antihistamine doses without 6!dnsulting their physician. cytochrome p450 enzymes are responsible for the metabolism of many drugs. all of the currently available nonsedating antihistamines are metabolized by the cytochrome p450 hepatic enzyme system. cytochrome p450 3a4 is involved in the metabolism of terfenadine, and erthromycin attenuates the metabolic effect of cyp3a4. loratadine is metabolized primarily by cyp3a4 and secondarily by cyp2d6. other considerations. side-effects involving the digestive tract (e.g., loss of appetite, nausea, vomiting, epigastric distress, and constipation or diarrhea) are among the most common for all antihistamines. many of the older agents are associated with significant anticholinergic or antimuscarinic sideeffects, such as dryness of the mouth and respiratory passages, urinary retention or frequency, palpitation, blurred vision, hypotension, headache, and tingling or weakness of the hands (58) . use of astemizole can cause weight gain. in a comparative trial with loratadine, weight gain was significantly greater with astemizole (pco.012) (72) . this sideeffect may argue against astemizole's use in selected individuals. nasal blockage is a major factor in perennial rhinitis, and a possible incitement to related airway disorders such as ome and chrohic sinusitis. topical steroids are the agents of choice for nasal blockdge (see subsequent section, "intranasal steroids"); however, leukotriene antagonists or oral decongestants also control this symptom. examples of the last class of agents include pseudoephedrine, phenylpt-opanolamine, and phenylephrine. these a-adrenergic agonists constrict blood vessels supplying the nasal mucosa, thereby decreasing congestion; they do not control the itchihg, sneezing, or rhinorrhea associated with upper-respiratory allergies. when such syifiptoni6 coexist with significant blockage, optimal rhariagement requires the use of intranasal steroids. another option is a combination decongestant/antihistamine medication (see next section). a-adrenoreceptor agonists are stimulatory agents that constrict vascular beds throughout the body, not just in the nose. this raises the potential for significant systemic side -effectse.g., hypertensibn, palpitations, tachycardia, and extrasystole, as well as restlessness, insomnia, and headache. as side-effects are dose-related, clirliciahs must choose the ptescribed dosage carefully to prevent aggravating or "unmasking" hypertension. patiefits shobld the impact of allergic rhinitis be cautioned against increasing dosages on their own. as a rule, oral decongestants should be avoided in patients who have cardiovascular disease, thyrotoxicosis, glaucoma, or diabetes. medications that combine an antihistamine with a long-acting oral decongestant offer another option for managing nasal blockage. the value of this practice has been proven in trials using formulations containing pseudoephedrine and either loratadine (107), acrivastine (108), or chlorpheniramine (109) . such combinations may be especially beneficial for patients at risk of chronic, allergen-induced eustachian tube obstruction, a condition that may favor the development of ome (109) . combined antihistamine/ decongestants can provide greater overall symptom relief than possible with either agent alone (107, 108), though the tradeoff may be a higher incidence of adverse events (110) . nevertheless, combination agents decrease the number of drugs patients must take, a fact which may facilitate therapeutic compliance in selected individuals. oral corticosteroids and systemic injected depot preparations carry a high risk of systemic sideeffects. consequently, the only justification for their use in chronic rhinitis is to improve nasal patency in patients with severe or urgent blockage, so that topical therapy can proceed. even then, systemic steroids should be given only by a specialist, and only to patients who lack contraindications to their use. these agents generally should not be used in children or pregnant women. a course of systemic steroids may be needed to gain control of nasal polyps, after which the patient can be managed with topical steroids (44) . in addition, oral corticosteroids can rapidly relieve anosmia associated with polyps and, by opening the nasal passages, facilitate the access of locally acting nasal corticosteroids. alternate-day dosing may improve the riskbenefit ratio of oral corticosteroids, but studies proving this point have yet to be undertaken. various topical agents are now available for relieving the symptoms and, in some cases, addressing the underlying pathology, of chronic rhinitis. the benefits, appropriate usage, and drawbacks of specific agents are discussed in this section. general limitations of topical treatments are reviewed in table 5 . the value of any topical agent in the treatment of allergic or nonallergic rhinitis syndrome may be limited by several factors. physical anomalies. severe septal deviation or enlarged turbinates may impede direct delivery of topical agents to the nasal mucosa. poor therapeutic compliance. compliance studies have shown that patients generally prefer taking pills to using medicinal sprays 150) slow therapeuric onset. in the case of intranasal steroids and crornolyn sodium. a slower onset of action may leave some patients frustrated and noncompliant. par!ent handicaps in particular. children and elderly persons may find it difficult to aim sprays or manipulate inhalers. intranasal steroids can relieve most of the symptoms of seasonal and perennial allergic rhinitis (112) (113) (114) (115) (116) (117) . they are more effective than cromolyn sodium (17). intranasal steroids are probably the most effective drug for all symptoms but they are particularly effective on nasal blockage topical steroids are the agents of choice for relieving nasal blockage. they permit direct delivery to the nasal mucosa, thus minimizing systemic sideeffects. the following specific actions are noteworthy: inhibition of both the early and late hypersensitivity response to allergens (111) reduction of the number of eosinophils in the nasal mucosa (112, 113) substantial inhibition of the nasal secretory response (1 14) reduction of mast cells and t cells desensitization of nasal irritant receptors (114). (1 17 -1 19) . appropriate use. intranasal steroids may be used to: relieve seasonal or perennial allergic rhinitis, when the main complaint is moderate to severe nasal blockage treat nares (only effective therapy at present) shrink small nasal polyps, or manage patients with polyps once control is gained through a course of oral steroids (44) prevent polyp recurrence after surgery reduce the risk of chronic sinusitis, ome, or bronchial asthma in allergic patients with a history of these complications. drawbacks. side-effects of intranasal steroids are generally minor and local, e.g., irritation, burning, and reactive sneezing, which usually disappear after several days; and nasal dryness followed by blood-stained crusts (124). in rare cases, treatment has to be stopped due to epistaxis. a few reports of septal perforation following intranasal steroid use have been published (124,125). some adverse effects (e.g., mucosal drying) can be avoided by using sprays with an aqueous base. the risk of systemic side-effects is very small, with one published report of a posterior cataract after intranasal steroid use and one report of children's growth being inhibited while taking an adult dose of budesonide (124). it is prudent to use the lowest efficacious dose in children and pregnant women (124). once-daily usage probably is sufficient for all glucocorticoids if the nose is patent and dry when the spray is used (124). some patients or agents may require multiple daily dosing, however, or multiple sprays per nostril. patients should be informed that onset of action is delayed compared with that of antihistamines and decongestants, and requires a few days for patients with seasonal allergic rhinitis (124). many patients are reluctant to use steroids in any form, and parents may be especially hesitant to sanction their use in children. individuals should be reassured that intranasal steroids are much safer than oral corticosteroids and that the former should not be equated with the latter. this anti-inflammatory agent has been proved safe and effective for the treatment of allergic rhinitis (126,127), although in one comparative study (17) it proved less effective than intranasal corticosteroids. owing to its control of both early-and late-phase hypersensitivity responses, cromolyn can relieve nasal itching, sneezing, hypersecretion, and nasal blockage. its need for frequent administration (four to six times daily [126], with possible reduction to two to three times daily in periods of low antigen load [127]), may impede therapeutic compliance. appropriate use. cromolyn sodium is best used for the prevention of allergic symptoms. given its wide safety margin, it often is prescribed for elderly patients, children, and pregnant women with seasonal or perennial allergies. it has virtually no utility in nonallergic rhinitis syndromes. the ocular formulation of cromoglycate is very effective in controlling eye symptoms. like cromolyn, nedocromil sodium controls both the early-and late-phase allergic reaction. unlike cromolyn, nedocromil can both prevent an allergic reaction and control a reaction in progress (126). nedocromil has significantly improved symptoms of rhinorrhea, congestion, itching, and sneezing (126). it is about 10 times more potent than cromolyn sodium. recommended dosing is two to four times daily (126). appropriate use. like cromolyn, nedocromil sodium is very effective at blocking symptoms when used immediately prior to an anticipated allergen exposure (126). both nasal challenge studies (128, 129) and those involving seasonal exposures (130) indicate that topical antihistamines can inhibit allergen-induced nasal symptoms, including sneezing and rhinorrhea. side-effects are locale.g., stinging and itching in the nose and, occasionally, the throatwith the incidence ranging from 7% to 30% of patients (128-131). azelastine has been shown to lessen nasal blockage, although reported side-effects include burning in the nose and altered taste (132) . the lack of major improvement in nasal blockage (128, 129) in some other studies, however, suggests that congestion entails more than the direct effect of histamine on receptors on the capacitance vessels of the nasal mucosa. levocabastine is a potent antihistamine available as nasal spray and eye-drops. minute amounts applied topically are sufficient to result in an antiallergic effect. appropriate use. on the basis of their safety profile, topical antihistamines may be used to relieve ocular or nasal symptoms in patients with mild to moderate seasonal allergies. when patients have severe ocular symptoms, specific topical preparations for ocular application should be used. azelastine (133) and levocabastine (134, 135) , for example, have been found to be nonsedating. topical nasal decongestants constrict the smaller arterioles of the nasal passages, thus reducing blood flow and relieving mucosal edema. these agents can relieve nasal congestion rapidly and effectively, and generally are available without a prescription. this probably explains their popularity among patients with perennial forms of allergic or nonallergic rhinitis. unfortunately, the overuse of decongestant sprays can cause rebound nasal congestion and rhinitis medicamentosa. moreover, like oral sympathomimetics, topical sprays are associated with systemic side-effects such as cardiac arrhythmias and exacerbation of hypertension (136) . thus, the impact of allergic rhinitis patients who overuse decongesting nose-drops should be assessed for hidden allergic nasal disease. appropriate use. the primary use for topical decongestants in chronic rhinitis is to open severely blocked nasal passages, so that slower acting drugs (e.g., cromolyn or intranasal steroids) can reach the necessary nasal passages to provide ongoing symptom control. their potential for causing rebound congestion is such, however, that these agents should never he used for inore than 3 consccurive days. ipratropium bromide, an anticholinergic drug, acts on the glandular cholinergic receptors in the nose to control excessive watery rhinorrhea (137) . rhinorrhea generally improves within 30 min, and remains in check for s-12 h. "here is no improvement, however, in nasal blockage, sneezing, or itching. nasal dryness, the main local side-effect of topical anticholinergics, may be alleviated by adjusting the dose. although rarely required, high doses of these agents may cause systemic side-effects. appropriate use. intranasal anticholinergics may be used to relieve the excessive rhinorrhea associated with allergic or nonallergic rhinitis syndromes e.g., gustatory or idiopathic rhinitis ("skier's nose"). the latter, perennial form of rhinitis entqils little if any nasal blockage, and tends not to respond to other treatments. intranasal anticholinergics also may help relieve the rhinorrhea associated with common colds (138) . various symptoms of perennial rhinitise g , nasal stuffiness, sneezing, rhinorrhea, and nose-blowing may improve with the use of saline or propyleneand-polyethylene glycol sprays. in one trial, patients also showed decreased eosinophil counts with propylene-and-polyethylene glycol spray (139) . symptom amelioration also may be accompanied by an improvement in nasal airway resistance and nasal biopsy findings (139) . although wetting agents act slowly, their lack of side-effects makes them attractive therapeutic options for some patients. appropriate use. wetting agents are indicated for the relief of mucosal irritation or dryness, the prevention of mucosal atrophy, and the removal of encrusted or thickened mucus. they also may be used immediately before intranasal steroid dosing, to prevent or mitigate drug-induced local side-effects. when the use of any of these medications results in poor control of chronic rhinitis, physicians have several options: determine whether there has been therapeutic noncompliance. if so, try to ascertain the reason e.g., poor symptom control, inconvenient dosing schedule, high medication cost. once the cause is known, engage the patient in therapeutic decision-making, as this may enhance treatment satisfaction and compliance. two or more antiallergy medications may be prescribed if a single agent fails to relieve adequately a patient's symptoms. combination therapy generally is indicated in the following situations. w h e n syrnptonis are moderately severe, severe, or diverse patients with severe nasal symptoms often benefit from taking both an antihistamine/decongestant and a topical nasal steroid. when patients have severe ocular symptoms, specific topical preparations for ocular application should be used. in a study comparing solo and combined drug use in patients with seasonal rhinoconjunctivitis, juniper et al. found that a ) nasal symptoms responded better to beclomethasone alone than to astemizole monotherapy, b) ocular symptoms were relieved more effectively by asteniiznle alone than by beclomethasone monotherapy, and c) the combination provided the best relief of ocular symptoms (121). when symptoms are intense or long-lasting patients who suffer from perennial rhinitis with seasonal exacerbations may benefit from using intranasal steroids on a continual basis and employing "rescue" antihistamines as needed. persons with allergic rhinitis and asthma might require a nasal corticosteroid and a bronchodilator to control their upper and lower airway problems. reliance on specific immunotherapy (sit) varies from country to country. physicians in the south of europe are more inclined to offer sit, while a decreasing number of patients receive this therapy in scandinavia and the uk (141) . immunotherapy used to be viewed as indicated only for patients responding inadequately to, or developing side-effects from, drug therapy (141) . current recommendations are to consider sit for a broader range of patients (see table 6 ). sit, unlike pharmacotherapy, modifies the immune system and plays a preventive role in asthma development. it is used in conjunction with drug therapy but should reduce the need for symptomatic pharmacotherapy. the efficacy of sit for table 6 specific immunotherapy for allergic rhinitis 1142) grass pollen, ragweed pollen, and house-dust mites is very well established (141, 142) . results are best when the patient has a single allergic sensitivity rather than allergies to multiple substances. it must be stressed, however, that sit should be undertaken only by physicians working in facilities equipped to handle possible adverse reactions (urticaria, laryngeal edema, bronchospasm, and anaphylaxis). although its safety under these conditions is good, a careful riskhenefit analysis is required for each patient before injections commence. some experts believe that children may be especially responsive to sit (142) . although childhood allergies show a strong tendency toward spontaneous improvement, sit may hasten this effect in a greater percentage of case% disagreement exists, however, about the age at which sit may be started (141, 142) . noninjective immunotherapy is another option to consider. nasal, sublingual, and oral immunotherapy have been demonstrated to be safe and effective (143) . perhaps the most enmuraging thing about sit is that it holds out the possibility at present, more than conventional pharmawlogic therapyof "curing" seasonal allergies and even preventing the progression to asthma (141, 142). children a variety of genetic and environmental factors favor the development of respiratory allergies in children (table 7) . allergy should be considered in the differential diagnosis when children have asthma, ige levels exceeding 100 iu/ml at age 6, or a maternal history of allergy (11). these were found on logistic regression to be risk factors for development of allergic rhinitis by age 6 in the tucson children's respiratory study, which followed 747 healthy children from birth to age 6 (11). presence of dogs as household pets and serum ige exceeding 100 iu/ml were significant risk factors for development of atopic (vs nonatopic) allergic rhinitis (1 1). wheezing in infancy usually implies no increased risk of asthma or allergies, but for the minority (14%) of children in whom wheezing persists at age 6, this symptom may signal a predisposition to asthma (144) . a prospective study following 826 children from birth to age 6 years found that risk factors for persistent wheezing were elevated serum ige at 9 months old and a maternal history of asthma (144) . preventive therapy may be especially relevant for these children. special concern is also indicated for those with severe or persistent nasal polyps. such children should be referred to a specialist, as polyps in the very young may be associated with cystic fibrosis or primary ciliary dyskinesia. environmental control assumes particular importance in children with allergic rhinitis, as considerable evidence shows that chronic respiratory symptoms are associated with significant early exposure to allergens (11, 145). the tucson children's respiratory study of 747 6-year-olds found that 42% had allergic rhinitis, and half of them had been diagnosed with this condition in their first year of life (11). accordingly, it is important to instruct parents about environmental control measures and the need to.implement them early in the course of their child's disease. early avoidance not only improves symptoms, but also may affect the natural history of nasal allergy and related disorders such as ome. moreover, if implemented aggressively at home, it has the added benefit of possibly preventing similar allergies in any siblings that the patient may have. when drug therapy is needed, a conservative approach to selection is warranted. nonsedating oral antihistamines are a good choice for children, owing to their lack of cns side-effects and ease of use. moreover, once-or twice-daily administration elunnates the need for dosing during school hours. pediatric formulations of the nonsedating antihistamines generally are available throughout europe. cromolyn sodium, nedocromil, or intranasal steroid sprays, although safe and effective, may be difficult for small children to use. this can lead to compliance problems. moreover, cromolyn must be dosed at least four times a day, whereas nedocromil is used twice a day. intranasal steroids usually are given at half the adult dose, once daily in the morning. as a rule, systemic steroids and topical vasoconstrictors should be avoided in very young children. perennial rhinitis in the elderly is generally idiopathic in nature (42) , with the underlying cause being autonomic imbalance, alteration in muscarinic receptors, or the sequelae of previously treated nasal disorders. almost invariably, the only symptom of nasal hyperresponsiveness in older persons is profuse rhinorrhea. treatment with ipratropium bromide, an anticholinergic drug, has been shown to be effective in some cases (146) . for elderly persons with true allergic rhinitis, treatment plans must take into account age, concomitant illnesses, and the use of other pharmacologic agents. nonsedating topical or oral antihistamines are a reasonable choice for this population. older antihistamines are best avoided, not only because of their sedative properties, but also because of the potential for urinary retention, problems with visual accommodation, and cns impairment. because of their sympathomimetic effects, oral vasoconstrictors (e.g., phenylephrine, phenylpropanolamine, or pseudoephednne) are generally contraindicated or need to be used with considerable caution in patients with diseases that frequently occur in the elderly such as hypertension, the impact of allergic rhinitis coronary artery disease, diabetes, glaucoma, or prostate hypertrophy. finally, elderly patients may require lower doses of certain antihistamines owing to slowed hepatic metabolism. moreover, because they often take multiple prescription and nonprescription medications, the elderly also run a greater risk of drug interactions than most other patients. pregnancy-associated hormones affect the nasal mucosa, and may indirectly affect the nose through increasing circulating blood volume (146) . as a result, some women with allergic rhinitis experience an exacerbation of symptoms, especially congestion, during pregnancy. this phenomenon generally starts toward the end of the first trimester and resolves rapidly after parturition. other women experience the apparent onset of allergic rhinitis during pregnancy (147) . although pharmacologic agents may help control nasal symptoms in pregnant women, chicians should prescribe them cautiously, bearing the following facts in mind: despite its probable safety in pregnant women, clinical experience with loratadine is still relatively limited. the safety of diphenhydramine remains uncertain (148) . all oral antihistamines are excreted in breast milk. in the usa, pseudoephedrine is approved for use in pregnancy at recommended dosages, and is widely prescribed in this population. owing to their overall safety, saline wetting agents and cromolyn sodium may be used to relieve congestion during pregnancy. in some european countries, topical antihistamines are recommended for the treatment of allergic rhinitis during pregnancy (149) . if cromolyn proves ineffective, intranasal steroids may be tried. their use at recommended doses has not been associated with teratogenicity or other adverse effects in pregnant women (38) . unfortunately, nasal congestion in pregnant women is often refractory to medical therapy. in such cases, patients may obtain some relief by using an external nasal dilator and saline douches. under no circumstances should immunotherapy be started during pregnancy, though continuation of maintenance doses is safe (38) . physical exercise causes vasoconstriction that lasts for about 1 h after exertion stops. however, endurance athletes (e.g., long-distance runners or cyclists) may experience long-lasting rebound congestion after a brief period of improved nasal patency. this rebound effect may impair athletic performance. when managing allergic rhinitis in competitive athletes, physicians must be careful to avoid prescribing medications with doping properties or therapy that may adversely affect performance. nonsedating antihistamines and topical steroids are generally the best choices for serious athletes. the international olympic committee and other international regulatory authorities prohibit sympathomimetic decongestants (e.g., phenylpropanolamine and pseudoephedrine). in large enough quantities, these agents can act as psychostimulants as strong as d-amphetamine. immunotherapy is recommended for athletes who wish to avoid being dependent on anti-allergy medications, though discomfort at the injection site may impede physical performance for several days at a time. the successful management of chronic rhinitis depends greatly on how well patients cooperate with the therapeutic program. educating patients about their disease and its management can promote that cooperation. it has been shown, for example, that allergic symptoms can be well controlled and a reasonable quality of life maintained when patients are given the appropriate medications, education, and written instructions before the pollen season commences (150) . specifically, patients benefit from knowing or understanding the following: h o w and why rhinitis develops. simple avoidance measures that can minimize exposure to allergens or rhinitis triggers. the appendix provides a handout about allergen control measures for patients in primary care. complications and related airway diseases that can develop f r o m poor allergy control. patients who understand the scope of their disease are apt to take it seriously and thus comply better with therapy. this, in turn, may help minimize their risk of developing related airway diseases. how specific medications work, and how to use nasal sprays correctly. patients must understand that antihistamines and intranasal steroids are most effective when taken on a regular basis and not as needed. for those who require two or more medications, an explanation of how each drug works provides a rationale for their use and may aid compliance. the necessity for prophylactic medication. patients should be informed that early use of medication can prevent the onset of severe symptoms. individuals with seasonal symptoms should start treatment at the outset of the spring or autumn seasons or in late summer. those with perennial allergies need to take medication in advance of specific exposuresfor example, before visiting a relative who keeps indoor pets. the side-effects associated with prescribed medications. patients should be told about common side-eff ects of particular pharmacologic agents, and what to do in the event of their occurrence. possible drug interactions. patients should understand the importance of informing their physician of all the medications they are taking, both prescription and nonprescription. because of the risk of torsades de pointes, this is especially vital for users of terfenadine or astemizole. for the same reason, patients taking either of the latter two agents should also be instructed not to increase the dosage without consulting their physician. the appropriate use of topical decongestants. the risks and consequences of overuse should be discussed. simply written instructions help to reinforce key messages. still, clinicians should ascertain whether patients truly understand what they have been told. consider having patients repeat instructions rather than merely asking whether everything is clear. reviewing key points with patients during subsequent office visits is advisable, especially when therapeutic goals are not being met. building a trusting alliance with patients is important in gaining their cooperation with therapy. in part, trust is established by attending to patients' concerns and preferences. specifically, patients should be asked the following types of questions: how does rhinitis affect you daily? what medications or measures have you tried to reduce your symptoms? what do you expect from anti-allergy therapy? do you anticipate any problems from treatment? do you have any preferences in medications? asking patients about their opinions and experiences in these matters fosters empathy and trust, and so encourages compliance. other pathways to improved compliance include the following: prescribing drugs with a longer half-life, so that less frequent dosing is possible. choosing combination agents when more than one medication is needed to control symptoms. selecting pharmacologic agents with few sideeffects. educating patients about their disease and its management (see prior section about patient education). for example, allergic patients who appreciate that poor compliance may increase the risk of asthma may be more motivated to follow pharmacologic and avoidance protocols. selecting medications that target what the patient considers to be his or her most troubling symptoms. impressing upon patients that compliance improves disease control and quality of life. allergists and immunologists find that compliance can be good, even when patients are not symptomatic, because failure to take medications or practice avoidance guarantees the return of symptoms. in conclusion, iherapeutic intervention in allergic rhinitis aims to relieve symptoms, improve longterm outcome and quality of life, and encourage patient satisfaction with medical management. patients who are compliant with therapy generally obtain better symptom relief and feel more satisfied with their care. allergy and depression: a neurochemical threshold model of the relation between the finesses effects of allergy season on mood and cognitive function allergic diseases from infancy to adulthood the allergic irritability syndrome: four case reports and a position statement from the neuroallergy committee of the american college of allergy assessment of quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire for clinical trials assessment of quality of life in patients with perennial allergic rhinitis with the french version of the sf-36 health status questionnaire epidemiology of acute asthma: ige antibodies to common inhalant allergens as a risk factor for emergency room visits middle meatus antrostomy: patency rates and risk factors the role of ige-mediated hypersensitivity in the development of otitis media with effusion the role of nasal allergy in otitis media with effusion: a clinical study increase in hospital admissions for childhood asthma: trends in referral, severity, and readmissions from 1970 to 1985 in a health region of the united nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness once daily intranasal fluticasone propionate (200 mg) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis the role of inflammatory mediators in allergic rhinitis quantitative intranasal pollen challenges. 111. the priming effect in allergic rhinitis weller pe the immunobiology of eosinophils the effects of activated eosinophils and neutrophils on guinea pig epithelium in vitro eosinophil-and neutrophil-mediated injury of human lung fibroblast cells inhibitory activity of loratadine and descarboethoxyloratadine on expression of icam-1 and hla-dr by nasal epithelial cells the expression of leukocyte-endothelial adhesion cells is increased in perennial allergic rhinitis intercellular adhesion molecule-1 (icam-1) in the pathogenesis of asthma mucosal inflammation in asthma evidence of intercellular adhesion molecule-1 expression on nasal epithelial cells in acute rhinoconjunctivitis caused by pollen exposure minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy the major human rhinovirus receptor i s icam-1 a cell adhesion molecule, icam-1, is the major surface receptor for rhinoviruses a longitudinal study of the role of viral infections in exacerbations of asthma in school children in the community community study of role of viral infections in exacerbations of asthma in 9-11 year old children increased levels of eosinophil, a major basic protein in nasal secretions in rhinovirus infection rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects international consensus report on the diagnosis and management of rhinitis nonallergic rhinitis with eosinophilia syndrome a precursor of the triad: nasal polyposis, intrinsic asthma, and intolerance to aspirin the diagnosis and treatment of recurrent and chronic sinusitis in children gustatory rhinitis: a syndrome of food-induced rhinorrhea nonallergic chronic rhinitis syndromes seasonal variation in dust mite and grass-pollen allergens in dust from the houses of patients with asthma rhinitis of pregnancy intranasal cocaine abuse in an allergist's office nasal, pharyngeal, and laryngeal manifestations of hypothyroidism allergy in 7000 twin pairs parental asthma, parental eczema, and asthma and eczema in early childhood the familial incidence of allergic disease comparison of patients' compliance with prescribed oral and inhaled asthma medications determinants of patient compliance with allergen immunotherapy is your asthmatic patient really complying? treatment of allergic rhinitis with loratadine plus pseudoephedrine in patients with mild asthma: effects on lower airway symptoms and function prophylactic treatment of grass pollen-induced asthma with cetirizine terfenadine, a potent histamine hi-receptor antagonist in the treatment of grass pollen sensitive asthma goodman gilman's pharmacological basis of therapeutics inhibitory effect of the h, antagonist loratadine on histamine release from human basophils in vitro inhibition, by loratadine and descarboxyethoxyloratadine, of histamine release from human basophils, and of histamine release and intracellular calcium fluxes in rat basophilic leukemia cells (rbl-2h3) antiallergic activity of hi-receptor antagonists assessed by nasal challenge effect of loratadine on human eosinophil function in vitro effect of terfenadine on human eosinophil and neutrophil chemotactic response and generation of superoxide the effect of antihistamines on the immediate allergic response: a comparative review topical azelastine reduces eosinophil activation and intercellular adhesion molecule expression on nasal epithelial cells: an antiallergic activity terfenadine exerts antiallergic activity reducing icam-1 expression on nasal epithelial cells in patients with pollen allergy position paper. the clinical safety of hi-receptor antagonists. an eaaci position paper histaminergic transmission in the mammalian brain a multicentric study of loratadine, terfenadine, and placebo in patients with seasonal allergic rhinitis non-sedating antihistamines a comparison of loratadine, a new nonsedating antihistamine, with clemastine and placebo in patients with fall seasonal allergic rhinitis once daily loratadine versus astemizole once daily the role of antihistamines in the treatment of chronic urticaria perennial allergic rhinitis: clinical efficacy of a new antihistamine treatment of bronchial asthma with terfenadine: a randomised controlled trial effect of terfenadine in asthmatic patients effect of a non-sedative antihistamine (loratadine) in moderate asthma: a double-blind controlled clinical crossover trial the effect of astemizole on exercise-induced asthma comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-tomoderate asthma corticosteroidsparing effect of azelastine in the management of bronchial asthma comparative safety of hi-antihstamines physicians' desk reference double-blind comparison of cetirizine and placebo in the treatment of seasonal rhinitis dose-ranging comparative evaluation of cetirizine in patients with seasonal allergic rhinitis sleepiness and performance during three-day administration of cetirizine or diphenhydramine hi-receptor antagonists. comparative tolerability and safety antihistamines and driving performance: the netherlands cetirizine effects on objective measures of daytime sleepiness and performance does cetirizine belong to the new generation of antihistamines? an investigation into its acute and subchronic effects on highway driving, psychometric test performance and daytime sleepiness effects of terfenadine on actual driving performance hanlon je effects of loratadine and cetirizine on actual driving and psychometric test performance, and eeg during driving psychomotor effects of astemizole and chlorpheniramine, alone and in combination with alcohol acute and subchronic effects of the hi-histamine receptor antagonist ebastine in 10, 20, and 30 mg dose, and triprolidine 10 mg on car driving performance double-blind, placebo-controlled trial of terfenadine in seasonal allergic rhinitis and conjunctivitis benefit/ risk ratio of the antihistamines (h,-receptor antagonists) the effects of loratadine, diphenhydramine and placebo on worker productivity: results of a double blind trial [abstract 5601 differential cognitive effects of terfenadine and chlorpheniramine antihistamines, drowsiness, and psychomotor impairment: central nervous system effect of cetirizine antihistamines and visual function: studies on dynamic acuity and the pupillary response to light a double-blind study of the effects of loratadine versus placebo on the performance of pilots comparison of the effect of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin on terfenadine steady-state pharmacokinetics and electrocardiographic parameters torsades de pointes associated with drugs and toxins: recognition and management loratadine and pseudoephedrine sulfate: a double-bhd, placebo-controlled comparison of a combination tablet (sch 434) and its individual components in seasonal allergic rhinitis a cross-over comparison of acrivastine, pseudoephedrine and their combination in seasonal allergic rhinitis fireman l? effect of an antihistamineldecongestant on nasal and eustachian tube function following intranasal pollen challenge effects of terfenadine and pseudoephedrine, alone and in combination in a nasal provocation test and in perennial rhinitis intranasal allergen challenge during corticosteroid treatment the impact of allergic rhinitis efficacy of oncea-day intranasal administration of triamcinolone aceto once daily triamcinolone acetonide nasal spray is effective for the treatment of perennial allergic rhinitis topical corticosteroids and nasal reactivity fluticasone propionate nasal spray for allergic rhinitis intranasal fluocortin butyl in patients with perennial rhinitis: a 12-month efficacy and safety study including nasal biopsy a comparative study of beclomethasone dipropionate aqueous nasal spray with terfenadine tablets in seasonal allergic rhinitis pegelow k-0. efficacy of an oral antihistamine, astemizole, as compared to a nasal steroid spray in hay fever a comparative study of dexchlorpheniramine maleate sustained release tablets and budesonide nasal spray in seasonal allergic rhinitis comparison of beclomethasone dipropionate aqueous nasal spray, astemizole, and the combination in the prophylactic treatment of ragweed pollen-induced rhinoconjunctivitis oral antihistamine or nasal steroid in hay fever: a double-blind double-dummy comparative study of once daily astemizole vs twice daily nasal beclomethasone dipropionate local effect of intranasal beclomethasone dipropionate aerosol in hay fever glucocorticosteroids and rhinitis nasal septa1 perforation associated with topical corticosteroid therapy the effect of cromolyn on nasal disease blychert l-0. effects of topical treatment with h, and h, antagonists on clinical symptoms and nasal vascular reactions in patients with allergic rhinitis comparison of levocabastine, a new selective hi-receptor antagonist, and disodium cromoglycate, in a nasal provocation test with allergen topical levocabastine, a selective hi-antagonist, in seasonal allergic rhinoconjunctivitis azelastin in der allergologischeu praxis doubleblind assessment of azelastine in the treatment of perennial allergic rhinitis a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential absence of central effects with levocabastine eye drops effects of topical administration of levocabastine on psychomotor and cognitive function topical nasal sprays: treatment of allergic rhinitis anticholinergic treatment of watery rhinorrhea the common cold: current therapy and national history beneficial effects of propylene and polyethylene glycol and saline in the treatment of perennial rhinitis a novel therapy concept for the treatment of allergic rhinitis eaaci position papers report of bsaci working party alternative routes of immunotherapy: a review asthma and wheezing in the first six years of life the effect of genetic and environmental factors on the prevalence of allergic disorders at the age of two years ipratropium (atrovent) in the treatment of vasomotor rhinitis of elderly patients the course and management of asthma and allergic diseases during pregnancy drugs in pregnancy and lactation pharmacotherapy of allergic rhinitis aqueous beclomethasone dipropionate nasal spray in treatment of seasonal (ragweed) rhinitis key: cord-293472-d3iwlpsr authors: afilalo, marc; stern, errol; oughton, matthew title: evaluation and management of seasonal influenza in the emergency department date: 2012-04-06 journal: emerg med clin north am doi: 10.1016/j.emc.2011.10.011 sha: doc_id: 293472 cord_uid: d3iwlpsr seasonal influenza causes significant morbidity and mortality, primarily due to increased complication rates among the elderly population and patients with chronic diseases. timely diagnosis of influenza and early recognition of an influenza outbreak or epidemic are key components in preventing influenza-related complications, hospitalizations, and deaths. emergency departments are the most frequent points of entry for most influenza cases and are well positioned to identify and manage influenza community outbreaks and epidemics. emergency departments need specific infection control measures to curb the spread of influenza in the emergency department and hospital during the influenza season. 226,000 hospitalizations, an estimated 3.1 million hospitalization days, with costs of more than $5 billion annually. 3, 8 costs related to influenza epidemics surpass $12 billion and cause millions of lost work hours each year. 9 timely diagnosis of influenza and early recognition of an influenza outbreak or epidemic are key components in preventing influenza-related complications, hospitalizations, and deaths. as the primary gateway to the health care system, emergency departments (eds) are the most frequent points of entry for patients with influenza who seek medical attention. as a result, emergency physicians are well positioned to play a pivotal role in promptly identifying and adequately managing influenza community outbreaks and epidemics. this article provides an updated overview of influenza to enhance the clinical judgment of emergency physicians and facilitate accurate decision making and diagnosis of seasonal influenza, thereby minimizing influenza's potential morbidity and mortality. the epidemiology of influenza differs globally. influenza outbreaks can occur during a specific season, referred to as seasonal influenza, or influenza activity can be present throughout the year. in northern and southern hemisphere temperate zones, influenza is highly seasonal and attacks predominantly occur during the winter months. for northern hemisphere countries like the united states and canada, seasonal influenza usually starts in november, peaks from december to march, and abates in may, 10 whereas for southern hemisphere countries like australia, the flu starts in may, peaks in june to september, and ends in november. substantial fluctuations in influenza viral transmission patterns may occur with peaks occurring much earlier or later than anticipated. 11 in contrast, tropical regions lacking a distinct winter season exhibit different patterns of activity, in which influenza viruses may be isolated year round 12 with biannual influenza outbreaks. 13 typical outbreaks usually begin suddenly, spread in the community peaking during a period of 2 to 3 weeks, and continue for an average duration of 3 months. 14 in terms of clinical signs important for the emergency physician, the first indication of onset of a flu outbreak in a community is a surge in pediatric febrile respiratory illnesses, followed by increases in adult influenza-like illnesses (ili). 15 as the predominant front line of health care systems, eds including emergency physicians are well positioned to detect local outbreaks of the flu in their early stages and notify appropriate public health authorities to take proper measures to contain the outbreak. similarly, emergency physicians can play a pivotal role in containing emerging flu pandemics by keeping abreast of global influenza epidemics. influenza viruses belong to the orthomyxoviridae class of viruses and structurally consist of an inner core and outer membrane. the core contains a nucleoprotein antigen that determines the classification of the influenza virus into its 3 basic types: a, b, or c. 16 the outer membrane contains a coat of proteins including glycoproteins. influenza a viruses are categorized based on 2 immunologically important glycoproteins: hemagglutinin (h) with 16 different subtypes (h1-h16) and neuraminidase (n) with 9 different subtypes (n1-n9). 17 for instance, the influenza a (h1n1) virus responsible for the 2009 flu pandemic expresses hemagglutinin 1 (h1) and neuraminidase 1 (n1) subtypes, whereas influenza a (h2n2) virus, which caused the influenza pandemic of 1957 to 1958, expresses hemagglutinin 2 (h2) and neuraminidase 2 (n2) subtypes. influenza b and c viruses are not subcategorized. influenza a, b, and c viruses have similar structural and biologic characteristics but differ antigenically with varying prevalence and virulence. influenza a is the most prevalent of the 3, frequently causes seasonal outbreaks and epidemics in humans, and infection with this subtype leads to more severe morbidity than influenza b and c. in addition, influenza a is the only subtype that causes pandemics. influenza a h1n1 and h3n2 are currently the predominant virus subtypes causing influenza infection in humans. since 1977, these 2 flu viruses have been circulating, causing seasonal influenza worldwide, whereas influenza a h2n2 subtype has not circulated in humans since 1968. 10 influenza b viruses circulate less widely than influenza a, causing fewer seasonal outbreaks and epidemics, whereas influenza c viruses cause only sporadic cases or minor outbreaks but not epidemics. in both cases, humans develop antibodies to these influenza viruses during childhood that provide some protection later against severe disease. 18 however, in children less than 6 years of age who have not yet acquired antibodies to influenza c, this virus can cause serious respiratory infections. 19 antigenic drift and antigenic shift influenza a viruses, more than influenza b and c viruses, have a natural tendency to periodically undergo hemagglutinin and neuraminidase antigenic changes. small point mutations in the rna gene segments that code for these 2 glycoproteins lead to minor hemagglutinin and neuraminidase antigenic changes called antigenic drifts that result in localized outbreaks. large mutations with viral gene reassortment that result in major hemagglutinin and neuraminidase antigenic changes referred to as antigenic shifts are associated with more widespread epidemics and pandemics. influenza a, because of their greater propensity for antigenic variation, is the only influenza virus type able to undergo antigenic shifts, whereas all 3 virus types (influenza a, b, and c) have the ability to undergo antigenic drifts. influenza viral infection starts with transfer of virus-laden respiratory secretions from an infected person to an immunologically susceptible host. the virus initially attaches to the epithelial cells of the upper respiratory tract and, if not neutralized by the host's immune system, the virus can continue to invade more and more cells as the virus descends the respiratory tract. after adsorption and binding of viral hemagglutinin to host cell sialic acid-conjugated glycoproteins, the virus enters the host cell. this adsorption and binding is deemed necessary for virus cell entry, 20 and is epidemiologically significant because the configuration of sialic acid-conjugated glycoproteins differs from one species to another, which may exert a crucial role in limiting transfer of influenza viruses across species. 21 once the virus has entered the host cell, it immediately disrupts normal cell function and starts replicating and releasing its viral progeny. neuraminidase is essential for viral release and propagation. 22 viral replication leads to host cell degradation and death via several mechanisms that shut off protein synthesis and release potent cytokines. 23, 24 cytokines, such as type i interferons, interleukins, tumor necrosis factor, as well as other inflammatory mediators, are thought to cause coughing and other systemic symptoms of flu. virus replication starts within 4 to 6 hours of host cell infection, and continues until about 24 hours before symptom onset. 25 the duration between incubation period, symptom onset, and virus shedding can range from 18 to 72 hours depending, in part, on inoculum dose. 26 the quantities of shed virus measured in specimens exhibit a distinct pattern and temporally correlate with symptom onset and severity of illness. virus shedding is observed starting within 24 hours before the onset of symptoms, peaks in 1 to 2 days after the onset of symptoms develop, remains high for another 1 to 2 days correlating with when the illness is most severe, and then rapidly declines, coming to an end approximately 7 to 10 days after infection. however, in certain circumstances, virus shedding can continue for weeks. two key factors that influence the duration of viral shedding are age and severity of illness. [27] [28] [29] young children, because of their relative lack of immunity, can shed virus for 10 days or more. 29, 30 patients with chronic diseases and more severe, complicated influenza shed the virus for an average of 2 days longer than uncomplicated influenza. 27, 31, 32 in elderly 31 and immunocompromised patients, 33-37 viral shedding and potential infectivity can persist for weeks, even months. multiple pathologic changes and pulmonary function abnormalities are observed during active uncomplicated acute influenza infection. bronchoscopy often shows inflammation and edema of the bronchial mucosa, most notably in the lower respiratory tract, that lead to decreased forced flow rates and increased pulmonary resistance, which may persist for weeks after clinical recovery. in patients with asthma and chronic obstructive pulmonary disease, influenza can cause acute decreases in forced expiratory vital capacity (fvc) and forced expiratory volume in 1 second (fev1). 38, 39 virus infection can advance into the lung parenchyma either via inhalation or contiguous spread from the upper respiratory tract causing primary viral pneumonia. tracheitis, bronchitis, and bronchiolitis are seen, characterized by submucosal hyperemia, edema, focal hemorrhage with bloody fluid, and loss of normal ciliated epithelium. 40 disruption of the normal epithelial barrier to infection, and abnormalities in ciliary clearance mechanisms, along with increased adherence of bacteria to virusinfected epithelial cells, predispose to bacterial superinfection. the most common pathogens responsible for bacterial infection are staphylococcus aureus, streptococcus pneumoniae, and haemophilus influenzae. the signs and symptoms of seasonal influenza are variable in severity, and dependent on the age of the patients. in adults, influenza is usually characterized by respiratory symptoms with other constitutional symptoms such as fever, myalgia, malaise, and headache. an abrupt onset is common, such that patients are often able to report the time of onset. respiratory symptoms and cough may initially be mild, but can progress causing dyspnea and pleuritic chest pain. degree of fever is variable; fever in the elderly is usually not as severe as in young patients. during the flu season, patients with influenza-like symptoms and proven influenza infection were more likely to have cough (93% vs 80%), fever (68% vs 40%), cough and fever together (64% vs 33%), and/or nasal congestion (91% vs 81%) compared to those without influenza. 41 for decreasing the likelihood of influenza, the absence of fever (likelihood ratio [lr], 0.40; 95% confidence interval [ci], 0.25-0.66), cough (lr, 0.42; 95% ci, 0.31-0.57), or nasal congestion (lr, 0.49; 95% ci, 0.42-0.59) were the only findings that had summary lrs less than 0.5. 42 patients may also present with isolated gastrointestinal or central nervous system (cns) involvement. children with influenza often do not present with the classic symptoms. they often cannot describe their symptoms, and tend to have more gastrointestinal symptoms. symptoms can mimic bacterial sepsis with high fevers, and children with influenza may present with febrile seizures. 43 in uncomplicated influenza, there are a few physical findings. there may be evidence of hyperemia of the pharynx, even with severe sore throat complaints. mild cervical lymphadenopathy and otitis media may be present, especially in younger patients. a dry cough is usually noted on chest examination with clear lungs or rhonchi, unless complicated by pneumonia. if there are no complications, fever and body aches can last 3 to 5 days, and the cough and lack of energy may last for 2 or more weeks. 44 pneumonia is the major complication of influenza and occurs especially in high-risk patients: children aged less than 5 years (especially those aged <2 years) adults aged 65 years or more persons with chronic diseases persons with immunosuppression women who are pregnant or postpartum (within 2 weeks after delivery) persons aged 18 years or younger who are receiving long-term aspirin therapy first nations/alaska natives persons who are morbidly obese (ie, body mass index [bmi] greater than or equal to 40) residents of nursing homes and other chronic-care facilities. 45 pneumonia can either be of viral or secondary bacterial cause. primary viral pneumonias are uncommon but tend to have increased symptom severity. however, during influenza outbreaks, influenza virus types a and b are responsible for more than half of all community-acquired viral pneumonia cases. secondary bacterial pneumonia is a significant complication of influenza, accounting for 25% of all influenza deaths. 46 children hospitalized with influenza-associated pneumonia have a higher risk for intensive care admission, respiratory failure, and death compared to those hospitalized with influenza without pneumonia. classically, influenza patients complicated with pneumonia have an exacerbation of fever and respiratory symptoms after an initial improvement. the most common bacterium is s pneumonia, accounting for approximately 50% of cases. staphylococcus aureus and haemophilus influenza are also important common organisms. during the 2006 to 2007 influenza season, 51 cases of community-acquired s aureus pneumonia were reported to the cdc. almost 50% of these cases had antecedent or concomitant viral illness, and just under 80% of the s aureus cultures were mrsa. the median age was 16 years, 44% had no known pertinent medical history, and approximately half of patients, for whom final disposition was known, died a median of 4 days after symptom onset. despite the selection bias in the cases reported, community-associated s aureus (ca-mrsa) influenza in the emergency department pneumonia accounts for severe pneumonia with high mortality in young otherwise healthy patients with influenza. therefore, empiric therapy for severe communityacquired pneumonia should include treatment against s aureus, including mrsa. 47 neurologic complications include encephalitis, transverse myelitis, and guillain-barré syndrome. reye syndrome has been reported in patients using aspirin after influenza infections. myositis is rare, but has been reported more commonly in children than adults. it presents in early convalescence with acute onset of pain and tenderness in the lower leg muscles severe enough to limit walking. serum creatine kinase (ck) levels transiently increase, with complete recovery generally occurring in 3 to 4 days; renal failure is rare. 48 cardiovascular involvement occurs by directly affecting the myocardium or exacerbating existing cardiovascular conditions. the frequency of myocardial involvement in influenza infection is variable, with rates of up to 10% having been reported in the literature, although this depends on the methods used to detect myocardial involvement. although many patients are asymptomatic, a significant proportion of these have electrocardiogram changes. fulminant myocarditis resulting in cardiogenic shock and death may occur. when a patient's condition deteriorates with hemodynamic compromise, cardiac involvement should be considered. the mainstay of treatment of influenza myocarditis is supportive. cardiovascular deaths also increase during influenza epidemics by increased deaths from coronary artery disease. these deaths have been shown to be reduced by influenza vaccination, which should be offered to all patients with cardiovascular disease. 49 other rare complications encountered include toxic shock syndrome in conjunction with secondary s aureus infection and parotitis. 50 influenza can be difficult to diagnose based on clinical symptoms alone because the initial symptoms of influenza can be similar to those caused by other infectious agents including mycoplasma pneumoniae, adenovirus, respiratory syncytial virus, rhinovirus, parainfluenza viruses, and legionella. it is important for the ed to develop clinical pathways to identify ili so that contagious patients can be segregated and treated effectively. the cdc defines ili as patients with temperature greater than 37.8 c (100 f) plus either cough or sore throat in the absence of a known cause other than influenza. as described, patients with influenza may have atypical presentations. fever is not always present, especially in premature infants, young infants, elderly patients, or immunosuppressed patients, and patients may present with only myalgias, headache, fatigue, or other complications. 51 the ed needs to consider the variability of clinical presentations and the prevalence of influenza in the community regarding investigation and treatment, and infection control isolation protocol. patients with suspected influenza should have standard laboratory investigations such as a complete blood count and electrolytes; the results are usually nonspecific, but leukopenia is typical and thrombocytopenia may be present. patients with physical signs that suggest meningitis should undergo a lumbar puncture. in patients with hypoxemia, the elderly, or high-risk patients with pulmonary symptoms, a chest radiograph should be performed to exclude pneumonia. dyspnea and chest pain are typically used as indicators for obtaining a chest radiograph. shortness of breath may be a useful indicator of pneumonia-complicating influenza. 52 radiological findings include bilateral interstitial infiltrates, and focal infiltrates may indicate superimposed bacterial pneumonia. diagnostic testing does not have to be performed on every patient who presents to the ed with ili, especially when there is a circulating influenza outbreak or epidemic. confirmation of influenza virus infection is not required for clinical decisions to prescribe antiviral medication. the decision to administer influenza treatment or chemoprophylaxis should be based on clinical illness and epidemiologic factors, and the start of therapy should not be delayed pending results, especially during an influenza outbreak. 51 influenza diagnostic testing is not clinically indicated when test results will not alter a patient's clinical care or influence clinical practice for other patients (fig. 1) . a positive influenza test may be used to confirm influenza virus in the community, which may affect clinical practice related to home care guidance, hospital infection control practices, future testing practices, and so forth. neither the rapid influenza test nor clinical prediction rules were superior to clinical judgment alone in the diagnosis of influenza. in one study of 258 patients with 21% confirmed influenza, the overall clinical judgment had a sensitivity of 29% (95% ci, 18%-43%) and specificity 92% (95% ci, 87%-95%), which improved to a sensitivity of 67% (95% ci, 39%-86%) and specificity of 96% (95% ci, 81%-99%) when patients presented within 48 hours. rapid influenza tests only had a sensitivity of 33% (95% ci, 22%-47%) and specificity of 98% (95% ci, 96%-99%), and a clinical prediction rule showed a sensitivity of 40% (95% ci, 27%-54%) and specificity of 92% (95% ci, 87%-95%). 53 thus, in times of high disease prevalence such as during influenza outbreaks or epidemics, most patients exhibiting ili symptoms can be diagnosed clinically as having influenza, without performing any diagnostic tests. clinicians should consult the cdc's global flu activity update (http://www.cdc.gov/flu/ international/activity.htm) for the latest updates on the international flu situation, and fluview (http://www.cdc.gov/flu/weekly/) for a summary of flu activity in the united states. diagnostic testing is ideally indicated in 2 circumstances: (1) for sporadic cases of ili, during periods of low disease prevalence, and (2) for severely ill patients. influenza should be confirmed in sporadic cases of ili to rule out another viral diagnosis, for example severe acute respiratory syndrome (sars) or coronavirus. diagnostic testing is recommended in severely ill patients because there is a greater urgency to make the correct diagnosis to provide appropriate medical management. in these 2 cases, rapid influenza diagnostic tests (ridts) and reverse transcriptase polymerase chain reaction (rt-pcr) are appropriate. the 2009 evidence-based clinical practice guidelines for the diagnosis, management, and chemoprophylaxis of seasonal influenza developed by the infectious diseases society of america recommend that the following patient populations undergo diagnostic testing for influenza if testing results will influence medical management (box 1). 54 influenza virus can be isolated from different types of specimens, including nasal, throat, or nasopharyngeal swabs, aspirates or washes, and sputum samples. nasopharyngeal specimens (swabs and aspirates) are more sensitive for detecting the virus than throat swabs or sputum specimens 54, 55 ; in one comparison of 3 rapid assays and immunofluorescence for influenza detection, sensitivity for all of these methods increased by approximately 40% when nasopharyngeal swabs instead of throat swabs were used. 56 acceptable specimens also vary depending on the specific diagnostic test ( table 1 ). the optimal time frame for collecting diagnostic specimens influenza in the emergency department confirmation of influenza virus infection by diagnostic testing is not required for clinical decisions to prescribe antiviral medications. decisions to administer antiviral medications for influenza treatment or chemoprophylaxis, if indicated, should be based upon clinical illness and epidemiologic factors, and start of therapy should not be delayed pending testing results (http://www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm). respiratory specimens should be collected from an ill patient as early as possible after onset of symptoms (ideally <48-72 hours after onset) to help maximize influenza testing sensitivity. 2 influenza like-illness (history of feverishness or documented fever with either cough or sore throat), fever with other respiratory symptoms, etc. note that some persons may have atypical presentations (eg, elderly, very young infants, immunosuppressed, and patients with certain chronic medical conditions). fever is not always present (eg, premature infants, young infants, elderly, immunosuppressed). other symptoms associated with influenza include myalgias, headache, and fatigue. complications include exacerbation of underlying chronic disease, (eg, congestive cardiac failure, asthma), pneumonia, bacterial co-infection, bronchiolitis, croup, encephalopathy, seizures, myositis, and others. 3 eg, decisions on use of antibiotics or antiviral medications, on conducting further diagnostic tests, on recommendations for home care, or on recommendations for ill persons living with persons with high-risk conditions. consult infectious disease society of america, american thoracic society, association of american physicians, and advisory committee on immunization practices for antibiotic guidance. 4 persons ‡65 years or <2 years; pregnant women; persons with chronic lung disease (including asthma), heart disease, renal, metabolic, hematologic and neurologic disease; immunosuppression; and morbid obesity. 5 largely depends on the amount of viral shedding at the time of testing. in immunocompetent children and adults, in whom viral shedding is brief, specimen samples yield the best results during the first 1 to 5 days of illness. 54, 57 low viral titers in the first 12 to 24 hours following onset of clinical illness have been suggested as a cause of falsenegative results in patients tested early 58 ; similarly, specimens obtained after 5 days of illness have an increased likelihood of false-negative results because of decreased virus shedding. immunocompetent infants and young children spread virus for longer (1 week), which ideally permits the collection of specimens after 5 days of illness. 54 irrespective of age, specimen collection in immunocompromised persons can also exceed 5 days of illness because virus shedding in this patient population can last for weeks, even months. 54 in the ed, collection of serum specimens is not recommended for diagnostic purposes because results are not readily available and therefore cannot guide clinical decision making and management. 54 during influenza season (testing should be done in the following persons if the result will influence clinical management) outpatient immunocompetent persons of any age at high risk of developing influenza complications (eg, hospitalization or death) presenting with acute febrile respiratory symptoms 5 days or less after illness onset (when virus is usually being shed) outpatient immunocompromised persons of any age presenting with febrile respiratory symptoms, irrespective of time since illness onset (because immunocompromised persons can shed influenza viruses for weeks to months) hospitalized persons of any age (immunocompetent or immunocompromised) with fever and respiratory symptoms, including those with a diagnosis of community-acquired pneumonia, irrespective of time since illness onset elderly persons and infants presenting with suspected sepsis or fever of unknown origin, irrespective of time since illness onset children with fever and respiratory symptoms presenting for medical evaluation, irrespective of time since illness onset persons of any age who develop fever and respiratory symptoms after hospital admission, irrespective of time since illness onset immunocompetent persons with acute febrile respiratory symptoms who are not at high risk of developing complications secondary to influenza infection may be tested for purposes of obtaining local surveillance data throughout the year (testing should be done for the following persons) health care personnel, residents, or visitors in an institution experiencing an influenza outbreak who present with febrile respiratory symptoms within 5 days after illness onset persons who are epidemiologically linked to an influenza outbreak (eg, household and close contacts of persons with suspected influenza, returned travelers from countries where influenza viruses may be circulating, participants in international mass gatherings, and cruise ship passengers) who present within 5 days after illness onset table 3 ). b serologic testing is not recommended for routine patient diagnosis. c a fourfold or greater increase in antibody titer from the acute (collected within the first week of illness) to the convalescent phase (collected 2-4 weeks after the acute sample) indicates recent infection. data from refs. 55, 59, 64 several different laboratory testing methods for detecting influenza virus are available in the united states ( table 1) and canada ( table 2) . these methods include immunofluorescence microscopy (direct or indirect antibody staining), viral culture (conventional and rapid), rt-pcr, ridts, and serologic testing. among these testing methods, ridts with rapid processing yielding timely results that can influence clinical decision making and patient management are most pertinent for the needs of the ed. based on which type(s) of influenza virus (a and/or b) can be detected, diagnostic tests can be categorized into 3 types: (1) those that detect only influenza a; (2) those that detect either influenza a or b, but cannot discriminate between the two; and (3) tests that both detect and distinguish between influenza a or b viruses. only rt-pcr and viral culture can identify influenza strains. ridts are rapid antigen point-of-care tests capable of identifying influenza a and b viral types in respiratory specimens in approximately 10 to 15 minutes. 59 ridts are immunoassays that come in user-friendly, diagnostic kits with varying complexity that either: (1) only detect influenza a virus, (2) detect but cannot distinguish between influenza a and b viruses, or (3) both detect and distinguish between influenza a and b viruses. commercial ridts currently available in the united states and canada are listed in table 3 , and general ridt characteristics, including advantages and disadvantages, are described in box 2. ridts are valuable in the ed because they produce results in a timely and clinically relevant manner that facilitate on-site point-of-care diagnosis of influenza that, according to limited research, has led to a decrease in demand for further diagnostic tests (eg, chest radiography, blood cultures) and the use of antibiotics, thus resulting in decreased patient costs. 61 recommendations for the use of ridts were developed and promulgated by the world health organization (who) (box 3). the cdc has recently issued guidelines for clinicians on the use of ridts for the 2010 to 2011 influenza season. 59 a major drawback of ridts is their limited reliability in accurately detecting influenza virus, which depends on a wide variety of factors, including ridt sensitivity, specificity, positive and negative predictive values, type of specimen collected, and time of collection with respect to onset of symptoms. although ridts exhibit high specificities ranging between 90% and 95%, ridts have substantially lower sensitivities, ranging from about 70% to 90% in children, decreasing even further to approximately 40% to 60% or lower in adults, compared with viral culture and rt-pcr. 54, 62, 63 thus, if ridts are the only diagnostic assay used in a center, positive results can be trusted but a negative result cannot reliably exclude disease. table 4 displays specifically selected commercially available ridts and corresponding test sensitivities, specificities, and positive and negative predictive values, which also vary according to the study. time of specimen collection also influences the accuracy of ridt results: the closer within the period of viral shedding and illness the specimen sample is obtained, the more accurate the result. 60, 64 in an effort to minimize false interpretation of ridts, the cdc has published the following guidance statements that emergency physicians and other health care professionals must keep in mind when performing and interpreting ridts 59,65 : 1. the reliability of a positive ridt result increases in patients with clinical signs and symptoms consistent with influenza. 2. collection of specimens within 48 to 72 hours of illness onset increases the likelihood of producing a positive ridt result. 4. use ridts with high sensitivity and specificity (see table 4 ): a. ridt sensitivities are generally low to moderate, ranging between 10% and 70% (most are approximately 50%-70%) compared with the gold standard viral culture or rt-pcr. an ridt with low sensitivity yields false-negative results. b. ridt specificities are generally high, approximately 90% to 95%, compared with the gold standard viral culture or rt-pcr. an ridt with high specificity yields few false-positives. rt-pcr is replacing viral culture as a reference standard because it is currently the most sensitive, specific, and versatile diagnostic test available for diagnosing influenza. 66 based on nucleic acid amplification, rt-pcr can detect the influenza virus but also differentiate between virus types, subtypes, and even determine viral strain, all in approximately 4 to 6 hours. as a result, rt-pcr has become the recommended test of choice for accurately diagnosing influenza in a timely fashion. 54 during the recent pandemic, the cdc released a method through the who for rt-pcr detection of influenza a that allowed clinical and reference laboratories to standardize methodology and thus produce data that could be compared between laboratories. 67 however, the major advantage of rt-pcr lies in its ability to more readily detect influenza viruses in people with chronic lung diseases and immunosuppressed persons, who may exhibit lower levels of the virus. 68 in these susceptible patients, rt-pcr can efficiently and accurately confirm the diagnosis of influenza to support therapeutic and infection control decisions. immunofluorescence yields timely results within 2 to 4 hours, and this can be used as a screening test. however, immunofluorescence has several disadvantages, including lower sensitivity (47%-93%) 69, 70 and specificity compared with viral culture, and is labor intensive, requiring specially trained laboratory personnel who may not be available 24/7, even in large hospitals. in addition, test performance depends on an adequate specimen sample that must include respiratory epithelium cells. 54 influenza virus can be cultured either by isolation of virus in cell culture (conventional tube culture), which provides results in 3 to 10 days, or by shell vial culture, which offers the advantage of a faster turnaround time of 48 to 72 hours. 54 because of the lengthy turnaround times of either method, viral culture is not a useful diagnostic test in the ed for aiding initial clinical decision making and management. however, viral culture allows for subsequent analyses, including sensitivity testing and subtyping performed by reference laboratories. during the influenza season, viral culture is indicated primarily for confirming negative ridt and immunofluorescence results, as well as for influenza virus surveillance because it provides key information regarding influenza virus strains and subtypes. 54 during the off-season, viral culture is indicated in patients who present to the ed within 5 days of symptom onset with suspected ili, especially if the person is epidemiologically linked to an influenza outbreak. 54 serologic testing is not useful or recommended in the ed because results are not readily available and therefore cannot facilitate clinical judgment, diagnosis, or management of influenza. 57 serologic tests that include hemagglutinin inhibition, neutralization, complement-fixation, and enzyme-linked immunosorbent assay (elisa) are mainly used to establish a diagnosis retrospectively and for research purposes. 57 because most individuals have previously been infected with influenza viruses, to reliably determine antibody titers, a single serum sample collected in the ed is inadequate, but paired specimen samples (acute and convalescent sera) are needed. whenever interpreting any influenza diagnostic test, the emergency physician or other health care professional must keep in mind the limitations of these tests, especially for ridts. in addition, the clinician should be aware of the disease prevalence in the community at any given time, because the level of influenza activity is known to affect the accuracy and reliability of test results. with respect to patient management, a positive influenza test result does not necessarily rule out any overlying coinfection by additional pathogens, and in the case of initial negative influenza test results from less sensitive diagnostic methods like ridts, the clinician should contemplate additional diagnostic testing (such as rt-pcr or culture) and decide whether antiviral treatment should be initiated empirically. currently, 4 antiviral medications from 2 drug classes have been approved and are available for the treatment and prevention of influenza in the united states, canada, and most other countries. these medications include amantadine and rimantadine, which belong to the drug class adamantanes, and oseltamivir (tamiflu; roche) and zanamivir (relenza; glaxosmithkline), which belong to the class neuraminidase (na) inhibitors. adamantanes are active only against influenza a virus, whereas na inhibitors are active against both influenza a and b viruses. other antiviral pharmacologic properties are compared in table 5 . in the last several years, adamantines have become less clinically useful because of their widespread resistance to influenza a (h3n2) and 2009 (h1n1) virus strains. 71 as a result, amantadine and rimantadine are currently not recommended for the treatment or chemoprophylaxis of influenza a virus. 45 the goals of influenza pharmacotherapy are to decrease symptoms, prevent associated complications, and reduce functional disability, hospitalizations, and mortality. treatment decisions on administering antiviral therapy should take into account factors such as time since symptom onset, underlying conditions, and severity of disease. abbreviations: crcl, creatinine clearance; fda, us food and drug administration; gi, gastrointestinal. a fda has authorized treatment of s-oiv with oseltamivir in children greater than or equal to 3 months of age. b fda has authorized prophylaxis for s-oiv with oseltamivir in children greater than or equal to 1 year of age. according to the cdc 45 and other published guidelines, 54 antiviral treatment is recommended for patients infected by the influenza virus who meet the following criteria: 1. patients with laboratory-confirmed or highly suspected influenza virus infection considered high risk for developing influenza complications (box 4). treatment is recommended irrespective of illness severity or vaccination status; 2. patients with laboratory-confirmed or highly suspected influenza virus infection requiring hospitalization, irrespective of underlying illness or vaccination status; 3. patients with laboratory-confirmed or highly suspected influenza virus infection who have severe, complicated, or progressive illness; antiviral treatment should be considered for adults and children with influenza virus infection who meet the following criteria: 1. outpatients at high risk of complications (see box 4) with illness that is not improving and who have a positive influenza test result from a specimen obtained more than 48 hours after onset of symptoms; 2. outpatients with laboratory-confirmed or highly suspected influenza virus infection who are not at increased risk of complications, whose onset of symptoms is less than 48 hours before ed presentation, and who would like to shorten the duration of illness and further reduce their risk of complications; 3. outpatients with laboratory-confirmed or highly suspected influenza virus infection who are in close contact with persons at high risk of complications secondary to influenza infection; 4. patients whose onset of symptoms occurred more than 48 hours before ed presentation with persisting moderate to severe illness may also benefit from treatment. because viral titers rapidly decrease by day 3 to 4 of illness in untreated, previously healthy persons, efficacy of antiviral therapy is directly related to time of treatment initiation. 72 studies have found that early treatment, especially initiated within the first 6 hours of symptom onset, provides the greatest benefit in reducing symptoms. 72 antiviral treatment initiated within 48 hours of onset of influenza illness can lead to shorter duration of symptoms and decreased illness severity. studies administering na inhibitor antiviral medications in previously healthy patients with uncomplicated influenza resulted in a shorter duration of illness by 1 to 2 days. 28, 29, [73] [74] [75] [76] [77] [78] [79] in addition, research has shown that early initiation of treatment with antivirals can also decrease the rate of serious influenza-related complications (eg, pneumonia, respiratory failure, and death) in high risk patients. 80 in contrast, slight or no benefit has been observed in healthy people when antiviral treatment is started more than 48 hours after the onset of uncomplicated influenza. 45 as a result, influenza antiviral treatment, when clinically indicated, should be initiated in a timely fashion, preferably within 48 hours of symptom onset, and not after laboratory confirmation of influenza. in certain patient populations, antiviral treatment may still be beneficial even if given more than 48 hours after symptom onset. these patients include pregnant women, patients with severe or progressive illness requiring hospitalization, and patients at high risk for suffering influenza complications. a study by siston and colleagues 81 found that, in pregnant women, treatment with antiviral medications decreased respiratory complications and death even when initiated 3 to 4 days after symptom onset compared with 5 days or more. based on observational studies, oseltamivir decreases severe clinical outcomes in hospitalized patients with influenza. in a multivariate influenza in the emergency department analysis, treatment with oseltamivir led to a significantly decreased risk of death within 15 days of hospitalization (odds ratio [or], 0.2; 95% ci, 0.1-0.8). 82 benefits were detected even in patients whose treatment was initiated more than 48 hours after the onset of symptoms. a study by lee and colleagues 83 found that among 99 hospitalized patients (median age, 70 years) with laboratory-confirmed influenza who received oseltamivir, benefits were observed even when oseltamivir was started up to 96 hours after illness onset. influenza virus vulnerability to antiviral drugs is continuously evolving. as a result, emergency physicians need to be familiar with the most recently updated information available on antiviral resistance and recommendations on antiviral use. as of january 2011, the cdc recommends the following antiviral drugs for treatment and chemoprophylaxis of seasonal influenza ( table 6 ). 45 the most effective way to prevent and control seasonal influenza is through immunization of both health care workers and patients. 84 procedures should be institutionalized, which ensures that patients and visitors with respiratory infection symptoms follow triage procedures in the ed that effectively isolate them as rapidly as possible. in hospital entrances and the ed triage, there should be clear signage with instructions regarding respiratory hygiene and cough etiquette. face masks should be available to cover the nose and mouth when coughing or sneezing, and waste receptacles are needed to dispose of contaminated tissues. there should also be instructions on how and when to perform hand hygiene. passive signage asks patients to self-identify; the triage health care team should actively ask patients about possible symptoms while maintaining a distance of at least 1 m from them. waiting times should be minimized and closely monitored, with staffing adjustments made accordingly. during periods of increased influenza activity, facilities should consider setting up pretriage stations that facilitate rapid screening of patients for symptoms of influenza to separate those patients from others. registration can identify the charts of patients with potential influenza to expedite care. waiting rooms should be segregated into 2 areas; patients with and without respiratory symptoms. when possible, physical barriers should separate the patients. in the ed, patients should be evaluated in single treatment areas. 85 the health care worker should use personal protection equipment (ppe), including a surgical mask, and a face-shield or mask with visor attachment, if there is a high chance of splash or spray of respiratory secretions. gloves and a long-sleeved gown should be worn when entering the room of a patient with suspected or confirmed influenza. 85 the health care worker should remove all ppe just before leaving the patient's room and discard it in the hands-free waste and linen receptacle within the room. hand hygiene should be performed after removing gloves and gown, before removing mask and protection, and again after leaving the room. 86 if a patient with droplet precautions in the ed needs to be moved for investigation, the patient should wear a face mask and continue to follow cough etiquette and hand hygiene. there should be appropriate communication to other personnel about patients with suspected or confirmed influenza before transferring them to other departments (eg, radiology) and admitting units in the facility. some procedures performed on patients with suspected or confirmed influenza infection may be more likely to generate higher concentrations of infectious respiratory aerosols. these procedures include intubation and related procedures (eg, manual ventilation, open endotracheal suctioning, cardiopulmonary resuscitation, sputum induction, nebulized therapy, and noninvasive positive pressure ventilation such as continuous positive airway pressure [cpap] or biphasic positive airway pressure [bipap]). although there are limited data available on influenza transmission related to such aerosols, many authorities recommend the additional precautions to be used when such procedures are performed. 87 the number of health care workers present should be limited to only those essential for patient care and support. those present should have received influenza vaccine. there should be a low threshold for intubation rather than using prolonged aerosol-generating procedures such as bipap and cpap. the health care worker should wear respiratory protection including a fitted n95 respirator during aerosol-generating procedures. n95 respirators should be used in the context of a comprehensive respiratory protection program that includes fit testing and training as required under the respiratory protection standard (29 cfr 1910 .134) of the occupational safety and health administration (ohsa). 88 the procedures should be conducted in an airborne infection isolation room (aiir), when feasible. aiirs reduce the concentration of infectious aerosols and prevent spread into adjacent areas using controlled air exchanges and directional airflow. aiir are negative-pressure rooms relative to the surrounding areas, with a minimum of 6 air exchanges per hour. the air should be exhausted directly to the outside or filtered through a high-efficiency particulate air (hepa) filter before recirculation. there should be environmental surface cleaning following the procedure. visitors should not be present during aerosol-generating procedures. visits to patients with suspected or confirmed influenza should be controlled such that visitors should be instructed to limit their movement within the facility. facilities should provide instruction before visitors enter a patient's room on hand hygiene, limiting surfaces touch, and use of ppe. 89 visitors should be advised to contact their health care provider for information on influenza vaccination, if this has not been received; if they are high-risk patients (as described earlier), 45 chemoprophylaxis may be offered if they are in close contact with the patient. health care workers in the ed presumably receive education and training programs on preventing transmission of all infectious agents, including influenza. these programs should be updated periodically and competency should be documented. health care workers who develop fever and respiratory symptoms should be instructed not to report to work, or, if working, they should put on a face mask and promptly notify their supervisor and/or infection control personnel. health care workers should be excluded from work for at least 24 hours after they no longer have fever. those with ongoing respiratory symptoms should be evaluated to determine appropriateness of contact with patients. health care workers caring for immunocompromised patients should be considered for temporary assignment or exclusion from work for 7 days from symptom onset or until the resolution of symptoms, whichever is longer. 85 administration of antiviral treatment and chemoprophylaxis of health care workers should be considered when appropriate. early treatment with antiviral agents and vaccination are especially important for health care workers at higher risk for influenza complications, including pregnant women and women up to 2 weeks after giving birth; persons 65 years and older; and persons with chronic diseases such as asthma, heart disease, diabetes, diseases that suppress the immune system, and morbid obesity. 45 work reassignment should be considered for those at higher risk to avoid potentially high-risk exposure such as performing or assisting aerosol-generating procedures in patients with suspected or confirmed influenza. the ed should have adequate isolation facilities and clear protocols of rapid admission to the wards to prevent boarding. lastly, discharge instructions should be developed and given to every patient with influenza discharged home from the ed. the emergency department team feels that you have the seasonal flu or influenza and your symptoms are mild enough to send you home for observation and recovery of your illness. influenza is contagious, and you should use proper precautions so that you do not pass your infection on to others. when you leave the emergency department, please wear a mask and keep it on until you arrive home if you cannot keep a distance of 2 m from others. you may also wear it at home, as necessary. do not use public transportation (bus, subway) to go home. go straight home; do not make any stops on the way (eg, drug store, grocery store). if you were given a prescription, make arrangements for a family member or friend to pick it up. you should isolate yourself in your home until 7 days after the onset of illness or at least 24 hours after symptoms have resolved, whichever is longer. do not go to work, school, or public places. do not share personal items, such as towels, drinking cups, cutlery, thermometers, and toothbrushes. always use hygiene and prevention measures to avoid contamination: wash your hands frequently. cough or sneeze into the crook of your elbow rather than into your hands. use tissues and dispose in waste basket. keep your surroundings clean. while at home, it is important that you monitor your own health to be sure that your illness does not worsen. you should consult your doctor or return to the emergency department if you develop one of these symptoms: shortness of breath, difficulty breathing, chest pain, recurrent vomiting, or high fever 38.5 c (101.3 f). pay attention to the onset of any illness stay home if mild flulike symptoms occur go to a doctor with a fever more than 38 c (100.4 f) and belong to a group at risk of developing influenza complications (children less than 2 years of age, pregnant women, person 65 years old and older, and persons with chronic diseases such as asthma, heart disease, diabetes, and diseases that suppress the immune system) go to a doctor with a fever more than 38 c (100.4 f) and one of these symptoms: chest pain child who is too quiet and less active than normal, or refuses to play, or is agitated the symptoms of an influenza pandemic can be similar to those of seasonal flu (ie, fever, headache, myalgia, coryza, gastrointestinal symptoms, sore throat, or cough). in the last century, 4 influenza pandemics were caused by novel influenza viruses. the most significant was in 1918, when the so-called spanish flu killed 40 to 50 million people worldwide. 90 in 2009, there was the emergence of a novel h1n1 virus, a genetic combination of human and swine influenza viruses. because many persons have little or no immunity to a new pandemic virus, the disease can spread quickly. with the h1n1 pandemic, the rate of infection was highest among young individuals; infections were less common in persons older than 65 years, perhaps secondary to preexisting immunity against antigenically similar viruses. [91] [92] [93] there are several differences between seasonal and pandemic influenza 94 : the who is responsible for monitoring the spread of influenza worldwide, declaring a pandemic, and coordinating the global response. however, the local health care systems need to develop surveillance to detect and monitor for a pandemic strain. it is important for the emergency physician to be cognizant that patients presenting with severe ili, with epidemiologic links to southeast asia, in particular china, with no diagnosis within the first 72 hours of hospitalization may represent the patient with an emerging respiratory infection. 95 patients with severe respiratory infections are those with fever and new onset of cough or shortness of breath with radiographic evidence of acute respiratory distress syndrome or other life-threatening complications such as encephalitis. the emergency physician should enquire about the patient's travel history or any close contact with persons who have traveled (especially from southeast asia) or contact with any health care provider. 95 such patients require isolation and consultation with the infection control team. during a pandemic, a comprehensive screening process is needed at triage to limit the exposure to other patients and health care workers. further elaboration of pandemics is beyond the scope of this article. the impact of influenza epidemics on mortality: introducing a severity index pandemic versus epidemic influenza mortality: a pattern of changing age distribution mortality associated with influenza and respiratory syncytial virus in the united states the annual impact of seasonal influenza in the us: measuring disease burden and costs influenza-associated morbidity and mortality in young and middle-aged women canadian consensus conference on influenza the efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community centers for disease control and prevention. recommendations of the advisory committee on immunization practices (acip) natural history of influenza type a in the united states, 1957-1972 influenza in singapore: assessing the burden of illness in the community epidemiology of influenza interpandemic influenza in the houston area, 1974-76 available at: http:// www.uptodate.com/contents/epidemiology-ofinfluenza?source5search_result& search5epidemiology1of1influenza&selectedtitle51%7e150 isolation of influenza virus ribonucleoprotein from infected cells. demonstration of the presence of negative-stranded rna in viral rnp age distribution of the antibody to type c influenza virus clinical features of influenza c virus infection in children the relationship of the influenza virus inhibitory activity of glycoproteins to their molecular size and sialic acid content sialic acid species as a determinant of the host range of influenza a viruses the influenza virus neuraminidase expression of cytokines on human bronchial epithelial cells induced by influenza virus a the cotton rat provides a useful small animal model for the study of influenza virus pathogenesis correlated studies of a recombinant influenza-virus vaccine. iii. protection against experimental influenza in man a study of illness in a group of cleveland families. xvi. the epidemiology of influenza 1948-1953 safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial oral oseltamivir treatment of influenza in children viral shedding in children with influenza virus infections treated with neuraminidase inhibitors duration of influenza a virus shedding in hospitalized patients and implications for infection control viral loads and duration of viral shedding in adult patients hospitalized with influenza prolonged shedding of amantadineresistant influenzae a viruses by immunodeficient patients: detection by polymerase chain reaction-restriction analysis common emergence of amantadineand rimantadine-resistant influenza a viruses in symptomatic immunocompromised adults prolonged excretion of amantadine-resistant influenza a virus quasi species after cessation of antiviral therapy in an immunocompromised patient influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy prolonged shedding of multidrugresistant influenza a virus in an immunocompromised patient the effects of influenza virus infection on fev1 in asthmatic children. the time-course study effect of viral infections on pulmonary function in patients with chronic obstructive pulmonary diseases studies on influenza in the pandemic of 1957-1958. ii. pulmonary complications of influenza clinical signs and symptoms predicting influenza infection does this patient have influenza? influenza a infection is an important cause of febrile seizures influenza symptoms and laboratory diagnostic procedures antiviral agents for the treatment and chemoprophylaxis of influenza -recommendations of the advisory committee on immunization practices (acip) the global impact of influenza on morbidity and mortality staphylococcus aureus communityacquired pneumonia during the 2006 to 2007 influenza season cardiovascular manifestations associated with influenza virus infection health protection agency. pandemic flu: clinical management of patients with an influenza-like illness during an influenza pandemic. provisional guidelines from the british infection society, british thoracic society, and health protection agency in collaboration with the department of health influenza diagnostic testing algorithm. centers for disease control and prevention influenza in the intensive care unit performance characteristics of clinical diagnosis, a clinical decision rule, and a rapid influenza test in the detection of influenza infection in a community sample of adults seasonal influenza in adults and children -diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the infectious diseases society of america role of laboratory diagnosis of influenza comparison of the now influenza a & b, now flu a, now flu b, and directigen flu a & b assays, and immunofluorescence with viral culture for the detection of influenza a and b viruses centers for disease control and prevention. influenza symptoms and laboratory diagnostic procedures diagnostic tests for influenza infection guidance for clinicians on the use of rapid influenza diagnostic tests for the 2010-2011 influenza season world health organization impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial performance of six influenza rapid tests in detecting human influenza in clinical specimens clinical manifestations of seasonal influenza in adults. uptodate role of the laboratory in diagnosis of influenza during seasonal epidemics and potential pandemics rapid diagnostic testing for influenza influenza viruses world health organization polymerase chain reaction is more sensitive than viral culture and antigen testing for the detection of respiratory viruses in adults with haematological cancer and pneumonia ruling out novel h1n1 influenza virus infection with direct fluorescent antigen testing evaluation of multiple test methods for the detection of the novel 2009 influenza a (h1n1) during the new york city outbreak centers for disease control and prevention. fluview: 2009-2010 influenza season week 20 ending early administration of oral oseltamivir increases the benefits of influenza treatment efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. gg167 influenza study group efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza a and b virus infections efficacy and safety of oseltamivir in treatment of acute influenza: a randomized controlled trial. neuraminidase inhibitor flu treatment investigator group zanamivir for treatment of symptomatic influenza a and b infection in children five to twelve years of age: a randomized controlled trial zanamivir for the treatment of influenza a and b infection in high-risk patients: a pooled analysis of randomized controlled trials randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza a and b: pooled efficacy analysis the mist (management of influenza in the southern hemisphere trialists) study group. randomized trial of efficacy and safety of inhaled zanamivir in treatment of influenza a and b virus infections effects of oseltamivir on influenzarelated complications in children with chronic medical conditions pandemic 2009 influenza a (h1n1) virus illness among pregnant women in the united states antiviral therapy and outcomes of influenza requiring hospitalization in ontario antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes national advisory committee on immunization statement on seasonal trivalent inactivated influenza vaccine (tiv) for 2010-2011. an advisory committee statement (acs) guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings guidance: infection prevention and control measures for healthcare workers in acute care and long-term care settingsseasonal influenza epidemic-and pandemic-prone acute respiratory diseases: infection prevention and control in health care. epidemic and pandemic alert and response. world health organization respiratory protection 1910.134. personal protective equipment guidelines and recommendations prevention strategies for seasonal influenza in healthcare settings the ontario health plan for an influenza pandemic in brief. ontario ministry of health and long-term care novel swine-origin influenza a (h1n1) virus investigation team. emergence of a novel swine-origin influenza a (h1n1) virus in humans implications of the emergence of a novel h1 influenza virus older age and a reduced likelihood of 2009 h1n1 virus infection what is the difference between the ordinary/seasonal influenza -or "flu" -and an influenza pandemic early detection of severe emerging or re-emerging respiratory infections through severe respiratory illness (sri) surveillance. public health agency of canada appendix 1: references for table 4 manufacturer's product information or product insert comparison of binax now and directigen for rapid detection of influenza a and b evaluation of three immunoassay kits for rapid detection of influenza a and b comparison of rapid diagnostic techniques for respiratory syncytial virus and influenza a virus respiratory infections in young children comparison of a new neuraminidase detection assay with an enzyme immunoassay, immunofluorescence, and culture for rapid detection of influenza a and b viruses in nasal wash specimens application of directigen flu-a for the detection of influenza a virus in human and nonhuman specimens comparison of directigen flu-a with viral isolation and direct immunofluorescence for the rapid detection and identification of influenza a virus comparison of rapid detection methods for influenza a and their value in health care management of institutionalized geriatric patients evaluation of a rapid enzyme immunoassay for detection of influenza a virus clinical features and rapid viral diagnosis of human disease associated with avian influenza a h5n1 virus evaluation of the directigen flua1b test for rapid diagnosis of influenza virus type a and b infections clinical evaluation of the zstatflu-ii test: a chemiluminescence rapid diagnostic test for influenza virus comparison of the directigen flu a1b test, the quickvue influenza test, and clinical case definition to viral culture and reverse transcription-pcr for rapid diagnosis of influenza virus infection comparison of lateral-flow immunoassay and enzyme immunoassay with viral culture for rapid detection of influenza virus in nasal wash specimens from children comparison of the denka seiken influ a-b quick and bd directigen flu a1b kits with fluorescent-antibody staining and shell vial culture methods for rapid detection of influenza viruses suboptimal detection of influenza virus in adults by the directigen flu a1b enzyme immunoassay and correlation of results with the number of antigen-positive cells detected by cytospin immunofluorescence comparison of four clinical specimen types for detection of influenza a and b viruses by optical immunoassay (flu oia test) and cell culture methods evaluation of a rapid optical immunoassay for influenza viruses (flu oia test) in comparison with cell culture and reverse transcription-pcr evaluation of biostar flu oia assay for rapid detection of influenza a and b viruses in respiratory specimens evaluation of an optical immunoassay for the rapid detection of influenza a and b viral antigens a flu optical immunoassay (thermobiostar's flu oia): a diagnostic tool for improved influenza management simultaneous detection and typing of influenza viruses a and b by a nested reverse transcription-pcr: comparison to virus isolation and antigen detection by immunofluorescence and optical immunoassay (flu oia) evaluation of diagnostic tests for influenza in a pediatric practice evaluation of a rapid test (quickvue) compared with the shell vial assay for detection of influenza virus clearance after antiviral treatment influenza virological surveillance in children: the use of the quickvue rapid diagnostic test quickvue influenza test for rapid detection of influenza a and b viruses in a pediatric population clinical evaluation of an immunochromatography test for rapid diagnosis of influenza evaluation of immunochromatography method for rapid detection of influenza a and b viruses evaluation of new rapid influenza virus detection kit-quick s-influ a/b "seiken comparison of a new lateral-flow chromatographic membrane immunoassay to viral culture for rapid detection and differentiation of influenza a and b viruses in respiratory specimens evaluation of a neuraminidase detection assay for the rapid detection of influenza a and b virus in children new point of care test is highly specific but less sensitive for influenza a and b in children and adults evaluation of an immunochromatography test using enzyme immunoassay for rapid detection influenza a and b viruses comparison of three rapid diagnostic kits using immunochromatography for detection of influenza a viruses evaluation of an immunochromatography test kit for rapid diagnosis of influenza evaluation of flow-through immunoassay for rapid detection of influenza a and b viruses key: cord-342919-ls2q1g0v authors: balsamo, michela; carlucci, leonardo title: italians on the age of covid-19: the self-reported depressive symptoms through web-based survey date: 2020-10-16 journal: front psychol doi: 10.3389/fpsyg.2020.569276 sha: doc_id: 342919 cord_uid: ls2q1g0v the pandemic of coronavirus disease 2019 (covid-19) has affected the italian community. the widespread use of quarantine had the desired impact of controlling the epidemic, although it caused many psychological consequences. to date, compliance of the italian public with voluntary home quarantine has been very high, but little is known about the impact of psychological health on sociodemographic categories during the quarantine. the purpose of this study was to assess the prevalence of depressive symptoms in specific sociodemographic categories during the covid-19 quarantine lockdown and the potential factors that contribute to, or mitigate, these effects. in the very early stage of the nationwide lockdown, 3,672 quarantined italian adult residents (65% females, ranging from 18 to 85 years) participated in a web-based cross-sectional survey, including measures of depressive symptoms, which were measured by the teate depression inventory, and state anxiety levels. the overall prevalence was 27.8% for moderate and 9.3% for severe levels of depressive symptoms. a generalized logistic model was used to identify the factors associated with mental health problems. among these factors, sociodemographic variables (e.g., sex, age, employment status) and adherence to quarantine guidelines were analyzed. females, younger people, students, singles, residents in northern italy, people who were reluctant to adhere to quarantine guidelines, and people less worried about being infected with covid-19 were at high risk of developing depressive symptoms during the covid-19 epidemic, also after controlling for state anxiety. these findings showed that public levels of depressive symptoms did not increase the greater likelihood of being infected. our study suggested that the monitoring of psychological outcomes for outbreaks could identify groups at higher risk of psychological morbidities due to the current pandemic in order to target future psychological interventions for implementation. the pandemic of coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2, previously known as 2019-ncov) has affected the italian community since late january. according to the imperial college covid-19 response team (ferguson et al., 2020) , cumulatively, 5.9 (1.9-15.2) million people had been infected as of march 28, giving an infection rate of 9.8% (3.2-25%) of the italian population. to contain the rapid spread of this pandemic, the italian government ordered nationwide lockdown by march 11: all public places were closed (included educational, religious, and public/cultural institutions, such as schools, universities, museums, and law courts), all public events and any form of congregation were banned, and a distance of at least 1 m had to be maintained (government of italy, 2020). all italian people were in quarantine at home (#iorestoacasa) until may 4: people had to stay at home apart from essential tasks. the slowing growth in daily reported deaths in italy was consistent with the significant impact of these restrictions. the effective reproduction number, rt, dropped to close to 1 around the start of the lockdown, with 38,000 (13,000-84,000) deaths averted. the widespread use of quarantine had the desired effect of controlling the epidemic, this was also due to the fact that the compliance of the italian public with quarantine guidelines had been very high (carlucci et al., 2020) . yet, the pandemic created a breeding ground for direct psychological consequences, suddenly throwing many individuals into daily lives filled with health threats, existential depression, and generalized stress (holmes et al., 2020) . a recent review of the psychological impact of quarantine, due to earlier outbreaks, suggested that there were high rates of negative psychological effects among the public, including post-traumatic stress symptoms, persistent depression, substantial anger, panic attacks, and suicidality (liu et al., 2003; maunder et al., 2003; brooks et al., 2020) . social distancing and isolation exacerbate the burden of stress, and often cause effects on immune, cardiovascular, and mental health because these measures frustrate the deep-seated human instinct to connect with others. on this point, social connection helps people to regulate negative emotions, remain resilient during difficult times, and cope with stress (rimé, 2009; hawkley and cacioppo, 2010; haslam et al., 2012; doré et al., 2017; jetten et al., 2017) . remarkably, the mental impact of quarantine can depend largely on the characteristics of participants and the quarantine variables selected. as documented by reynolds et al. (2008) , taylor et al. (2008) , and brooks et al. (2020) , while compliance with quarantine guidelines requirements are significant factors behind a higher level of post-traumatic stress disorder (ptsd), healthcare workers were more likely to be affected than the public. in italy, in the early phase of quarantine (7-10 days after the decree of nationwide lockdown), deleterious consequences on the population's psychological health were analyzed in a nationally representative survey of 3,452 participants (barari et al., 2020) . different demographic groups were struggling with different aspects of quarantine. older adults expressed worry or anxiety, while those who were likely working parents (40-49 years) cited consistent economic distress and struggles with home-schooling and smart-working, compared to other groups. younger people were struggling with increased boredom, perceived immobility, and conflicts within family, while vulnerable groups, like the elderly and health-compromised people, cited consistent loneliness relative to others. overall, the average level of anxiety surrounding the crisis in the italian population was high: no respondents reported being completely without anxiety. according to barari et al. (2020) , the negative psychological consequences of the quarantine were beginning to wear on people and seemed likely to become more serious over time. further findings derived from an online survey showed the prevalence of psychiatric symptoms in 2,766 participants drawn from the general population from march 18 to 22 2020. female gender, negative affect, and detachment were associated with higher levels of stress, anxiety, and depression. having an acquaintance infected was associated with increased levels of both depression and stress, whereas a history of stressful situations and medical problems was associated with higher levels of anxiety and depression. finally, those with a family member infected and young people who had to work outside their domicile presented higher levels of anxiety and stress, respectively. thus, it is important that the potential advantages of home quarantine are weighed against the possible mental costs (rubin and wessely, 2020; torales et al., 2020) . quarantine as an efficacious public health measure also needs to lower the psychological strain associated with it. research evidence aims of this study were to explore (1) the likely effects of quarantine on mental health (anxiety and depressive symptoms), immediately after the nationwide lockdown issued by the italian government, and (2) the factors that contribute to, or mitigate, these consequences. among these factors, sociodemographic variables (gender, age, employment status, marital status, education, geographic area, and income per year), worry about being affected by covid-19, and adherence with quarantine guidelines were analyzed. depression was the principal outcome, while anxiety was used as a covariate, given its close association with depression (clark and watson, 1991; barlow and campbell, 2000) . respondents were italian quarantined adults aged 18 and older with access to a networked computer. an online cross-sectional study was conducted from march 21 to 26, immediately after the nationwide lockdown issued by the italian government on march 11 (#iorestoacasa). a virtual snowball sample via social media was used within a wider web-based study including other psychological measures (carlucci et al., 2020) . this study has been approved by the department of psychological sciences, health and territory, university of chieti, italy review board. written informed consent was obtained from all the participants included in the study. of psychiatric illnesses and medical problems (e.g., hospitalizations) were collected. the 21-item teate depression inventory (tdi; balsamo et al., , 2018b , developed via rasch analysis (rasch, 1960) , was employed to evaluate depressive symptoms in participants in the past 2 weeks. respondent answers were measured on a 5point likert scale ranging from "never" to "always." cronbach's α coefficient in our study was 0.90. the 21-item state scale of the state-trait inventory for cognitive and somatic anxiety (sticsa) (ree et al., 2008; balsamo et al., 2016; carlucci et al., 2018) was administered to evaluate cognitive (e.g., "i have trouble remembering things") and somatic (e.g., "my muscles are tense") symptoms of state anxiety. individuals rated how often a statement was true in the past 2 weeks, from 1 "not at all" to 4 "very much so." cronbach's α coefficient was 0.89. adherence to quarantine guidelines in response to the covid-19 outbreak was measured by a global index composed of 11 items classified into preventive (i.e., handwashing with soapy water/alcohol-based solution) and avoidant (i.e., avoidance of gatherings in public or open to public places, handshaking) disease behaviors (carlucci et al., 2020) . respondents were asked about the frequency of which they had carried out quarantine restrictions on a 5-point likert scale from 0 "never" to 4 "always." cronbach's α coefficient was 0.70. worry about being infected with covid-19 was assessed by a single item drawn from a multidimensional questionnaire of risk perception for the covid-19 infectious disease outbreak. responses were classified according to three levels of worry severity: none ("not worried at all"), moderate ("slightly worried"), and quite a lot ("really worried"). descriptive statistics were computed for sociodemographic characteristics, physical symptoms and health service utilization variables, knowledge and concern-related variables, precautionary measure variables, and additional health information variables. prevalence of depressive and anxiety symptoms during the covid-19 outbreak in the italian population were also computed for sex and age. in line with similar studies (e.g., giallonardo et al., 2020; wang et al., 2020) , the tdi outcome score was categorized into "minimal, " "mild, " "moderate, " and "severe" depression levels . a sticsa-s score of 40 points or greater was indicated as the cut-off point for the presence of anxiety symptoms (van dam et al., 2013) . sensitivity analysis was conducted using the hmisc r package (harrell and dupont, 2006) in order to assess the power and sample size of ordinal outcomes under the proportional odds ordinal logistic model. next, generalized linear regression (glms) was applied to the explanatory model to analyze whether the severity of depression during the covid-19 quarantine could be predicted by high levels of adherence to quarantine guidelines and worry about being infected with covid-19, and by sociodemographic variables (model 1), that resulted as significant in our previous study (carlucci et al., 2020) . since depression was measured in terms of severity levels, we specified multinomial (ordinal) as the distribution and cumulative logit as the link function. predictors were selected according to a two-step process. firstly, a potential set of considered variables were correlated with the outcome variable. all the potential variables that correlated significantly with the outcome were selected as predictors in the glms model. hence, based on the test of model effects (wald chi-square statistic and p-values), the predictors were compared (guisan et al., 2002) . only the resulting significant predictors (p < 0.05) were retained in the model. a wald test (and its 95% confidence interval) based on robust estimates of the coefficients and covariance matrix were used to assess the models, and residual deviance as a goodnessof-fit statistic was applied to evaluate model overdispersion (mccullagh, 2018) . the model with the deviance/df ratio closest to the unit was retained as the most parsimonious model (mccullagh, 2018) . in addition, due to the high comorbidity between depression and anxiety symptomatology (clark and watson, 1991; barlow and campbell, 2000) , the model was re-estimated controlling for anxiety as the covariate (model 2), in order to increase the ability to detect differences on dependent variables (depression severity levels) by an independent variable inserted as the covariate. differences between the two models were interpreted in terms of unique contribution of any independent variable on depression severity symptoms. the data were statistically analyzed with spss for windows 21.0 (ibm corp, 2018). statistical significance was set by p-values of less than 0.05. the characteristics of the participants are shown in table 1 . of the 3,672 respondents, 1,282 (34.9%) were male and 2,390 (65.1%) were female. the mean (±sd) age of the participants was 33.27 ± 14.29 years. a total of 45.2% of them were located in the south of italy (n = 1660). among these, 1,817 (49.5%) respondents held a high school diploma, while 1,535 (41.8%) held a higher education qualification (bachelor/master/doctorate). in terms of occupational status and income per year, 1,138 (31.20%) participants were students, 232 (6.3%) were healthcare workers, and 1,742 (47.4%) were employed. concerning marital status, 2,249 (61.2%) participants were unmarried/single, 901 (24.5%) were married, 103 (2.8%) were divorced/separated, 366 (10%) were cohabiting, and 53 (1.4%) were widowed. most of the subjects had a high level of health: 2,616 (71.2%) were found to show no physical disease, while 24 (0.7%) were detected as "fragile, " having more than three diseases, and with a long history of chronic medical illness. a total of 967 (26.3%) participants had previously carried out psychotherapeutic treatment. among these, 97.2% of respondents had carried out at least one psychotherapy treatment (individual, family/couple, and/or group treatment), 20.9% had undergone psycho-pharmacological treatment, and 0.6% had participated in other psychological treatments. most (84.2%) of the participants spent their quarantine period with family members. a total of 1,787 (48.7%) were found to be highly adherent to quarantine guidelines, and 2,326 (63.34%) reported that they were worried about being infected with covid-19. a sample size of 3,672 was used for the statistical power analyses, and a 1:2 odds ratio was used as a baseline. the alpha level used for this analysis was p < 0.05. the post-hoc analyses showed that the statistical power for this study was 0.859. thus, there was an adequate power at the moderate to large effect size level. an n of approximately 4,182 would be needed to obtain statistical power at the recommended 0.90 level (cohen, 1988) . the overall prevalence was 6.4% for severe, 24.2% for moderate, 39.7% for mild, and 29.7% for minimal depressive symptoms. the overall prevalence of anxiety symptoms was 13.6%, using the cut-off of >40. taking together, the prevalence of depressive symptoms and state anxiety severity was significantly higher in female participants, and those younger than 30 years compared to participants aged 31 years or older (p < 0.001, as shown in tables 2, 3 ). in addition, those who received psychotherapeutic treatment in the past reported higher severity levels of depressive [χ 2 = 45.58 (3), p < 0.001] and anxiety [χ 2 = 47.43 (1), p < 0.001] symptoms relative to the general public. preliminarily, nonparametric correlations (spearman's rho) were performed in order to select independent variables as predictors in the glms. as expected, all the sociodemographic variables, as well as worry were found to correlate negatively with the outcome variable (depressive symptom severity levels) ranging from rho = 0.298 (age, p < 0.01) to rho = −0.040 (education, p < 0.05), except for sex and worry (rho = 0.113, p < 0.01 and 0.037, p < 0.05, respectively). parameter estimates of the generalized linear model and the exponentiated values of the coefficients [the "exp(b)" column] are displayed in table 4 . the first model resulted in an underestimation of the data with no statistical association for education [wχ 2 (df ) = 3.19 (3), p = 0.372], and income per year [wχ 2 (df ) = 7.306 (3), p = 0.063] as predictors of depressive symptoms. to improve model fit, we discharged them and reestimated the model. the omnibus test [χ 2 (df ) = 526.21 (20); p < 0.001], and residual deviance/df ratio (deviance/df = 1.038) of the re-estimated models suggested that the refined model fit significantly better than the proposed model (mccullagh, 2018 as expected, a preliminary analysis showed that depression and anxiety symptoms shared approximately 38% of the common variance, as derived by the spearman rho coefficient (rho = 0.62, p < 0.001). thus, state anxiety, as measured by the state sticsa, as the covariate was inserted in our model (model 2). compared to the previous model, no statistical differences were found in sex, age, and adherence level to quarantine guidelines groups when predicting depression symptom severity, when controlling for anxiety (see appendix a). statistically significant differences were maintained in depression symptom severity for marital status, geographic area, and occupational status groups, after controlling for anxiety. in detail, divorced/separated participants were less likely to experience depressive symptoms compared to single people, with a significant decreased risk of depressive symptoms (odds ratio: 0.654 [95% ci, 0.434-0.983]). on the other hand, no statistical differences on depressive symptom severity was found in cohabiting participants compared to unmarried participants in the second model. concerning geographic area, the participants living in central italy were found less likely to experience severe depressive symptoms (odds ratio: 0.794 [95% ci, 0.641-0.984]) compared to those living in north-west italy, after removing anxiety effects. far from the previous model, the healthcare professionals' group were not found to differ from other occupational groups in predicting high levels of depressive symptoms compared to unemployed participants. interestingly, participants "moderately" worried about being infected with covid-19 were more prone to experience high levels of depressive symptoms (odds ratio: 1.252 [95% ci, 0.953-1.643]) compared to participants who were "quite a lot" worried, after controlling for the state anxiety effect. we fitted both the glms models (without and with anxiety as the covariate) in the subsample of participants with healthcare professionals (β = −0.797; se = 0.280; p < 0.01) were less depressed compared to unemployed participants, with a decreased risk of depressive symptom severity (odds ratio: 0.450 [95% ci, 0.260-0.780]). next, those who reported to adhere to the quarantine guidelines had significantly lower levels of depressive symptoms compared to those who were not adherent (β = −0.475; se = 0.133; p < 0.001), with a decreased risk of depressive symptoms (odds ratio: 0.622 [95% ci, 0.479-0.809]). no statistical association was found for worry about being infected with covid-19 and geographic area. surprisingly, in model 2, no statistically significant differences were maintained in depression symptoms for the sex, marital status, and occupational status groups, after controlling for anxiety. participants aged from 30 to 39 years reported significantly lower levels of depression scores compared to the younger participants (β = −0.5.04; se = 0.194; p < 0.01), with a decreased risk of depressive symptoms (odds ratio range: 0.604 [95% ci, 0.413-0.884]). concerning geographic area, the participants living in south italy were less likely to experience severe depressive symptoms (odds ratio: 0.688 [95% ci, 0.493-0.962]) compared to those living in north-west italy, after removing anxiety effects. as expected, participants "moderately" and "none" worried about being infected with covid-19 were more prone to experience high levels of depressive symptoms (odds ratio: 1.757/1.722 [95% ci, 1.292-2.391/1.063-2.791]) compared to participants who were "quite a lot" worried, after controlling for the state anxiety effect. quarantine has been used extensively in all countries of the world to lower the spread of the covid-19 infection and to protect individuals' health, at different times (sohrabi et al., 2020) . quarantine includes the separation and restriction of movement of people who have potentially been exposed to a contagious disease to ascertain if they become unwell, so reducing the risk of them infecting others. it is an unpleasant experience for those affected (hiremath et al., 2020) . imposed isolation and separation from loved ones, loss of mental health needs (freedom, social contacts, stimulation), uncertainty over disease status, family conflict, and boredom can, on occasion, contribute to the onset of psychological disorders (brooks et al., 2020) . due to the fact that the psychological impact of quarantine depends largely on the characteristics of participants and the quarantine variables selected, several sociodemographic characteristics have been selected here, with depressive symptoms measured by the tdi as the outcome. in the second model, anxiety, as measured by the sticsa state scale, was inserted as the covariate, given the close relationship with depression (brooks et al., 2020) . about gender, depressive symptoms were more likely to occur in female participants, with a risk of developing depressive symptoms higher 1.6 compared to male participants in our sample. this finding was in accordance with studies by qiu et al. (2020) and wang et al. (2020) among the chinese general population in the first 2 weeks following the outbreak, as well as broche-pérez et al. (2020) among the cuban population. also, among the italian general population higher levels of psychological distress were reported in the female gender compared to their male counterparts rossi et al., 2020) . sex differences in depression were not caused by a higher prevalence of covid-19 infection in women because mortality and vulnerability to the covid-19 disease indicated that more men are dying from covid-19 (lancet, 2020) . thus, these differences seem to be caused by the fact that women carry a different kind of burden from this epidemiological emergency. gender inequities disproportionately affect the wellbeing and economic resilience during lockdown. households are under strain, but children and elderly care, as well as housework generally fall on women (cluver et al., 2020) . by increasing caregiving needs, covid-19 has intensified the pressure on women to uphold prescriptive feminine norms. women have to bear more of the burdens of providing additional support for children's distance learning, and alleviating children's emotional tedium, isolation, and anxiety of shelter-in-place (rosenfeld et al., 2020) . in addition, increased intimate partner violence has grown during the quarantine due to covid-19 because women are required to stay uninterruptedly with their partners and away from those people who can give help or at least validate their experiences and, particularly if these women live in small houses (bradbury-jones and isham, 2020; van gelder et al., 2020) . indeed, some studies suggest that sudden forced proximity with their immediate household members is a risk factor for domestic violence, and aggression (taylor et al., 2008; brooks et al., 2020) . in italy, since the beginning of the covid-19 quarantine, three domestic homicides and 11 murder-suicides have been registered to date. furthermore, while covid-19 has coincided with greater rises in unemployment for women than men, the rise in unemployment for men remains substantial (bureau of labor statistics, 2020). about the age groups, depressive symptoms were most likely to occur in younger people (aged 18-29 years). with increasing age, depressive symptoms were less prevalent during the italian lockdown due to the covid-19 outbreak. our results were similar to those from previous studies, such as a study during the sars outbreak in taiwan (su et al., 2007) , a study of horse owners quarantined because of equine influenza (taylor et al., 2008) , and one recent study during the covid-19 epidemic in china (huang and zhao, 2020) . as well, like gender, for this sociodemographic variable, the prevalence of the depressive symptoms in different age groups and the probability of risk of developing depressive symptoms depending on age do not relate to the greater likelihood of being infected. being elderly has been reported to correlate with adverse clinical outcomes, including hospitalization and mortality (applegate and ouslander, 2020; zhou et al., 2020) . indeed, in italy the mean age of covid-19 patients who died was 81 years (remuzzi and remuzzi, 2020) and the case fatality rate was 16% from 60 to 79 years, 19.7% from 80 to 89 years, and 16% for 90 years and older (livingston and bucher, 2020) . despite this, respondents older than 60 years had the lowest risk for developing depressive symptoms compared to the younger age groups. in a population where loneliness and isolation have already been described as an epidemic (luo et al., 2012) , the impact of even short-term social distancing measures and the resulting distress did not influence the vulnerability to mental health issues (jeste et al., 2020; vahia et al., 2020) . this finding is in accordance with part of the literature. although mixed results derive across current and previous studies on the association between participants' age and depression as a psychological outcome of health-related emergency (hawryluck et al., 2004; qiu et al., 2020) , some authors reported that only young age was found to be associated with increased distress as a psychological outcome of the covid-19 quarantine (barari et al., 2020; and of the sars quarantine (hawryluck et al., 2004) . the higher psychological distress reported by the younger population could be due to their greater and uncontrolled access to the amount of information ("infodemic") through social media, which can easily trigger distress (cheng et al., 2014) . as regards marital status, unmarried/single people were the most depressed group with quarantine policies in the event of this outbreak. it is plausible that single people had greater difficulty in relying on or obtaining the assistance of others during the italian lockdown, thus are at risk of depressive symptoms and lower self-confidence more than cohabiting and married participants. this datum is in line with part of previous literature reporting that being married was protective for depression or associated with a lower risk of depressive symptoms (inaba et al., 2005; yan et al., 2011; bulloch et al., 2017) , although other studies conducted during the sars outbreak suggested that demographic factors such as marital status, as well as living with other adults, and having children were not associated with psychological outcomes (hawryluck et al., 2004; mihashi et al., 2009) . as to geographic area of residence, people living in the south of italy showed the lowest risk of developing depressive symptoms among all the groups, followed by participants from regions of central italy compared to residents from northern regions and the islands. as expected, residents in the most severely affected regions are at the highest risk of developing depressive symptoms. southern and central regions recorded a smaller number of deaths and diagnosed cases (1,812 and 2,730 deaths, respectively), compared to the north-east and north-west regions (6,935 and 21,009 deaths, respectively), where the disease spread first on a large scale. to explain this datum, it should be considered that the authorities introduced control measures in the northern regions (the "red zone"), before any other region and carried out extraordinary efforts to restrict the movement of people (carlucci et al., 2020) . in addition, residents from northern italy were found less adherent to restrictive measures compared to the those from the south of italy. people who have shown more adherence were found less at risk of depressive symptoms compared to people with less adherence (see under). as for occupational status, this study highlighted students as suffering from the highest level of psychological distress among all the other groups, including the unemployed group. also, in this case, the public's level of depressive symptoms did not increase with an increased probability of contracting the disease. since the physical spaces of universities were closed, students' mental well-being was affected by the sudden interruption of social interactions. however, the possibility of having online lessons and maintaining social contacts through social networks would not explain the onset of the depressive symptoms compared to other groups, for example employees who had been laid off or were retired. the reason for students' greater risk of depressive symptoms, reported also by wang et al. (2020) among the chinese population, could lie in a sense of uncertainty toward the future that this emergency, not only in health, but also in economic, social, and political areas, is eliciting all over the world (chong et al., 2004; wenzel et al., 2005; tan and enderwick, 2006) . compared with other professions and the general population, healthcare workers were associated with a lower risk of psychological outcomes compared to the unemployed in our sample. "learned helplessness" (seligman, 1972) could explain why health professionals were the least depressed group. after being exposed to inescapable difficult events, people become passive and stop trying after being exposed to events such as uncontrollable bursts of noise (alloy et al., 1984) and as a result show greater levels of anxiety and depression. on the contrary, health professionals, considered the real heroes of this emergency, were associated with a lower risk of psychological outcomes compared to unemployed participants. through the practice of their profession, they felt more useful to society, despite their increased risk for infection and transmission (al-rabiaah et al., 2020) . after students, the unemployed were at a higher risk of depressive symptoms compared to the other groups (stuckler et al., 2009; reeves et al., 2012) . this datum is inserted within the context of the covid-19-related risk unemployment and economic losses and insecurity with the closure of community services and the collapse of industries negatively impacting the national economy. it should be a critical public health priority to prevent suicide. indeed, during the most recent economic recession, a 1% rise in unemployment was correlated with a rise in the suicide rate of 0.99% in the united states (95% ci: 0.60-1.38, p < 0.001) (reeves et al., 2012) . similarly, each percentage point increase in unemployment was accompanied by 0.79% rise in suicide (95% ci: 0.16-1.42, p = 0.016) in europeans aged 65 years or less. as to adherence, people with low adherence were more likely to exhibited depressive symptoms relative to people with a great level of adherence to covid-19 preventive measures. as expected, adherence has been found to be a protective factor against mental health problems (hawryluck et al., 2004; koenig and schultz, 2010; brooks et al., 2020) . adopting the preventive behaviors contribute to lower the uncertainty of the epidemic progression which would cause higher psychological pressure on the public. as to worry about being infected with covid-19, people with more worry were more depressed than people with a low level of worry. as for the whole sample, also in the subsample of participants with psychotherapeutic treatment history, the same sociodemographic factors and behaviors that contribute to, or mitigate mental effects of the quarantine in terms of depressive symptoms were reported. however, when anxiety symptoms or concomitant stressful events were present in comorbidity, these participants were found to experience higher levels of worry associated with increased depression symptomatology, compared to the whole sample. current evidence showed similar results. a history of stressful situations and medical problems was associated with a greater degree of depression and anxiety during the covid-19 quarantine in the italian population (hao et al., 2020) . again, psychiatric patients were significantly more likely to experience a higher degree of the negative mental impact of the outbreak, including stress, anxiety, and depression, compared to the general public (hao et al., 2020) . during the covid-19 quarantine outbreak in italy, female participants, younger people, single people, students, people living in northern regions, and who were less compliant with quarantine guidelines and less worried about being infected with covid-19 were at a high risk of displaying psychological issues. these findings suggest public levels of depressive symptoms did not increase with the greater likelihood of being infected. for example, although female and younger people reported a lower risk of covid-19 infection, they experienced higher levels of depressive symptoms during the covid-19 quarantine in italy. therefore, ongoing monitoring of the psychological strain associated with outbreaks of epidemic-potential, life-threatening diseases should become routine as part of preparedness efforts worldwide by establishing early targeted mental health interventions. in other words, more vulnerable groups, likes those cited above, should benefit from personalized "moraleboosting" interventions. or, intervention research could be valuable to combat amplifications of gender inequalities, particularly to address the added challenges women are likely to face. this research can provide timely insights for government agencies toward improving and safeguarding the psychological well-being of women, younger people, and categories of subjects at a higher risk of suffering from psychological distress on the occasion of subsequent waves of the spread of covid-19 or other epidemic diseases. this study has several limitations. firstly, the analyses presented here were derived from a crosssectional design, thus it is difficult to make causal inferences. secondly, given that the research was conducted in close temporal proximity to the period of the covid-19 quarantine, a webbased survey method was necessary to recruit a convenience sample by avoiding possible infections. this limited sampling in our study. as a consequence, a self-selection effect may have occurred and should be considered with those people who were experiencing the greatest or least levels of distress responding to the survey (saggino et al., 2017) . in addition, participants were required to access the internet and to be familiar with online devices to respond, which suggests that they might be more educated, younger or/and have a higher socioeconomic status than the overall surveyed quarantined population. thirdly, due to the uncontrolled occurrence of this health-related emergency, an accurate picture of the individual's psychological conditions before the covid-19 outbreak was not conducted. although it would been interesting to conduct pre-post analyses, these data could provide a baseline for future research on the psychological consequences of quarantine in the italian population throughout the rest of the current covid-19 pandemic. fourthly, depressive and state anxiety symptoms were measured by means self-report inventories that are notably biased by response set, such as social desirability (innamorati et al., 2014; carlucci et al., 2015; balsamo et al., 2018a,b) . thus, future research should include methods, such as observational methods and psychophysiological or behavioral assessment, in order to objectively record the levels of these mood states (campbell and fiske, 1959) . fifthly, the assessment of state anxiety could be completed or replaced by adding the specific fear of covid-19 scale (ahorsu et al., 2020; broche-pérez et al., 2020; soraci et al., 2020) . in addition, it should be acknowledged that the study was carried out was not sufficiently heterogeneous for sex, with marked female preponderance, and age sample, with a prevalence of juveniles. hence, these findings may not translate accurately to the public at large. finally, it could not evaluate whether the outcomes considered in this study will be long-lasting after the covid-19 outbreak. however, follow-up with these participants will continue in order to facilitate our understanding about how long these outcomes will last. a deeper understanding of how the epidemic affects italians' psychological health by identifying which groups were at a high risk of psychological morbidities due to the current pandemic can help to guide and target future psychological intervention implementations. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher. the studies involving human participants were reviewed and approved by the department of psychological sciences, health and territory, university of chieti, italy, review board. the patients/participants provided their written informed consent to participate in this study. both authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. we thank maria pia pugliese, ines d'ambrosio, and gianluca balsamo for their assistance and support in data collection and writing assistance. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyg.2020. 569276/full#supplementary-material the fear of covid-19 scale: development and initial validation attributional style and the generality of learned helplessness middle east respiratory syndrome-corona virus (mers-cov) associated stress among medical students at a university teaching hospital in saudi arabia covid-19 presents high risk to older persons a new measure for trait and state anxiety: the state trait inventory of cognitive and somatic anxiety (sticsa). standardization in an italian population assessment of anxiety in older adults: a review of self-report measures assessment of late-life depression via self-report measures: a review building a new raschbased self-report inventory of depression determining a diagnostic cut-off on the teate depression inventory evaluating covid-19 public health messaging in italy: self-reported compliance and growing mental health concerns. medrxiv mixed anxiety-depression and its implications for models of mood and anxiety disorders the pandemic paradox: the consequences of covid-19 on domestic violence gender and fear of covid-19 in a cuban population sample the psychological impact of quarantine and how to reduce it: rapid review of the evidence the depression and marital status relationship is modified by both age and gender the employment situation convergent and discriminant validation by the multitrait-multimethod matrix demographic and attitudinal factors of adherence to quarantine guidelines during covid-19: the italian model religious fundamentalism and psychological well-being: an italian study dimensions of anxiety, age, and gender: assessing dimensionality and measurement invariance of the state-trait for cognitive and somatic anxiety (sticsa) in an italian sample psychological health diathesis assessment system: a nationwide survey of resilient trait scale for chinese adults psychological impact of severe acute respiratory syndrome on health workers in a tertiary hospital tripartite model of anxiety and depression: psychometric evidence and taxonomic implications parenting in a time of covid-19 statistical power analysis for the behavioral sciences released 2012. ibm spss statistics for windows helping others regulate emotion predicts increased regulation of one's own emotions and decreased symptoms of depression impact of non-pharmaceutical interventions (npis) to reduce covid-19 mortality and healthcare demand the impact of quarantine and physical distancing following covid-19 on mental health: study protocol of a multicentric italian population trial decree of the president of the council of ministers 11 generalized linear and generalized additive models in studies of species distributions: setting the scene do psychiatric patients experience more psychiatric symptoms during covid-19 pandemic and lockdown? a case-control study with service and research implications for immunopsychiatry the hmisc package the social cure: identity, health and well-being loneliness matters: a theoretical and empirical review of consequences and mechanisms. anna sars control and psychological effects of quarantine covid 19: impact of lock-down on mental health and tips to overcome mental health strategies to combat the psychological impact of covid-19 beyond paranoia and panic multidisciplinary research priorities for the covid-19 pandemic: a call for action for mental health science generalized anxiety disorder, depressive symptoms and sleep quality during covid-19 outbreak in china: a web-based cross-sectional survey depression in the united states and japan: gender, marital status, and ses patterns factor validity of the beck hopelessness scale in italian medical patients battling the modern behavioral epidemic of loneliness: suggestions for research and interventions advancing the social identity approach to health and well-being: progressing the social cure research agenda koenig and schultz's disaster medicine: comprehensive principles and practices the gendered dimensions of covid-19 recommendations on diagnostic criteria and prevention of sars-related mental disorders coronavirus disease 2019 (covid-19) in italy loneliness, health, and mortality in old age: a national longitudinal study the immediate psychological and occupational impact of the 2003 sars outbreak in a teaching hospital a nationwide survey of psychological distress among italian people during the covid-19 pandemic: immediate psychological responses and associated factors danger in danger: interpersonal violence during covid-19 quarantine generalized linear models predictive factors of psychological disorder development during recovery following sars outbreak a nationwide survey of psychological distress among chinese people in the covid-19 epidemic: implications and policy recommendations probabilistic models for some intelligence and attainment tests (reprint, with foreword and afterword by distinguishing cognitive and somatic dimensions of state and trait anxiety: development and validation of the state-trait inventory for cognitive and somatic anxiety (sticsa) increase in state suicide rates in the usa during economic recession covid-19 and italy: what next? understanding, compliance and psychological impact of the sars quarantine experience emotion elicits the social sharing of emotion: theory and empirical review conducting social psychological research in the wake of covid-19 covid-19 pandemic and lockdown measures impact on mental health among the general population in italy the psychological effects of quarantining a city a validation study of the psychometric properties of the other as shamer scale-2 learned helplessness world health organization declares global emergency: a review of the 2019 novel coronavirus (covid-19) validation and psychometric evaluation of the italian version of the fear of covid-19 scale the public health effect of economic crises and alternative policy responses in europe: an empirical analysis prevalence of psychiatric morbidity and psychological adaptation of the nurses in a structured sars caring unit during outbreak: a prospective and periodic assessment study in taiwan managing threats in the global era: the impact and response to sars. thunder. int factors influencing psychological distress during a disease epidemic: data from australia's first outbreak of equine influenza the outbreak of covid-19 coronavirus and its impact on global mental health covid-19, mental health and aging: a need for new knowledge to establishing a trait anxiety threshold that signals likelihood of anxiety disorders covid-19: reducing the risk of infection might increase the risk of intimate partner violence immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china lessons from severe acute respiratory syndrome (sars): implications for infection control marital status and risk for late life depression: a meta-analysis of the published literature clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 balsamo and carlucci. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-330831-3b7vfv9b authors: hao, fengyi; tam, wilson; hu, xiaoyu; tan, wanqiu; jiang, li; jiang, xiaojiang; zhang, ling; zhao, xinling; zou, yiran; hu, yirong; luo, xi; mcintyre, roger s.; quek, travis; tran, bach xuan; zhang, zhisong; pham, hai quang; ho, cyrus s. h.; ho, roger c.m. title: a quantitative and qualitative study on the neuropsychiatric sequelae of acutely ill covid-19 inpatients in isolation facilities date: 2020-10-19 journal: transl psychiatry doi: 10.1038/s41398-020-01039-2 sha: doc_id: 330831 cord_uid: 3b7vfv9b this study examined the neuropsychiatric sequelae of acutely ill patients with coronavirus disease 2019 (covid-19) infection who received treatment in hospital isolation wards during the covid-19 pandemic. ten covid-19 patients who received treatment in various hospitals in chongqing, china; 10 ageand gender-matched psychiatric patients; and 10 healthy control participants residing in the same city were recruited. all participants completed a survey that collected information on demographic data, physical symptoms in the past 14 days and psychological parameters. face-to-face interviews with covid-19 patients were also performed using semi-structured questions. among the covid-19 patients, 40% had abnormal findings on the chest computed topography scan, 20% had dysosmia, 10% had dysgeusia, and 80% had repeated positivity on covid-19 reverse-transcription polymerase chain reaction testing. covid-19 and psychiatric patients were significantly more worried about their health than healthy controls (p = 0.019). a greater proportion of covid-19 patients experienced impulsivity (p = 0.016) and insomnia (p = 0.039) than psychiatric patients and healthy controls. covid-19 patients reported a higher psychological impact of the outbreak than psychiatric patients and healthy controls, with half of them having clinically significant symptoms of posttraumatic stress disorder. covid-19 and psychiatric patients had higher levels of depression, anxiety and stress than healthy controls. three themes emerged from the interviews with covid-19 patients: (i) the emotions experienced by patients after covid-19 infection (i.e., shock, fear, despair, hope, and boredom); (ii) the external factors that affected patients’ mood (i.e., discrimination, medical expenses, care by healthcare workers); and (iii) coping and self-help behavior (i.e., distraction, problem-solving and online support). the future direction in covid-19 management involves the development of a holistic inpatient service to promote immune and psychological resilience. the world health organization (who) declared the coronavirus disease 2019 (covid-19) outbreak a pandemic on 11 march 2020 1 . as of may 30, the number of confirmed cases was more than six million, with the number of death cases at >366,000, and the number of recovered cases at more than two million worldwide 2 . the symptoms of covid-19 include general symptoms, such as fever; chills and malaise; respiratory symptoms including cough, breathing difficulty and coryza; gastrointestinal symptoms including vomiting and diarrhea; and neurological symptoms including headache and giddiness 3 . in a recent report, some patients with covid-19 complained of olfactory and taste disorders 4 . differential levels of psychological distress as a result of vicarious traumatization from covid-19 were found in different groups of people, ranging from the general public 5 , to psychiatric patients 6 , individuals under quarantine 7 and healthcare workers 8 . however, there is currently limited research on the neuropsychiatric sequalae and psychological impact of covid-19 patients, with one study so far reporting that most clinically stable patients suffered from significant posttraumatic stress disorder (ptsd) symptoms 9 . the emotional and psychological needs of covid-19 patients could be very much different from those with pre-existing psychiatric illnesses and people in the community. several hypotheses exist to explain why covid-19 patients may suffer from neuropsychiatric ramifications. covid-19 is postulated to infect the central nervous system 10 via the peripheral trigeminal or olfactory nerves following intranasal inoculation 11 . it then invades regions of the cerebral cortex, basal ganglia, and midbrain that are closely linked to the olfactory bulb. from psychological perspectives, the perceived threat, susceptibility, and illness severity coupled with physical discomfort, loneliness and psychosocial stressors may evoke emotional disturbances, such as anger, fear, hysteria, depression, anxiety, and other psychological issues, in patients acutely infected with covid-19. these psychological factors may in turn reduce innate immunity through cell-mediated immune activation via the release of several inflammatory markers, such as il-6, il-12, and tumor necrosis factoralpha, which are implicated in the pathogenesis of depression 12 and ptsd 13 . this therefore suggests the possibility of immune dysregulation as a shared pathogenesis in covid-19 infection and psychiatric disorders. there has been an increasing number of qualitative studies that examined the in-depth effects of covid-19 pandemic on the feelings, behavior, and attitude of healthcare workers 14 and caregivers 15 . however, there is still a paucity of research on the psychological mechanisms and impact of covid-19 on infected patients, and how they cope through the isolation period. this highlights a pertinent knowledge gap that needs to be addressed that is essential for holistic management. the present study performed a quantitative evaluation of the neuropsychiatric sequelae of patients with acute covid-19 infection who received treatment in the hospital isolation wards, and compared these patients with psychiatric patients and healthy controls during the covid-19 pandemic. we hypothesized that covid-19 patients would exhibit more neuropsychiatric symptoms than psychiatric patients and people in the community. we also performed face-to-face semi-structured interviews with patients to explore other possible symptoms that may be missed in quantitative studies 16 , understand their subjective experience, and the psychological impact of contracting covid-19. findings obtained from this study will be invaluable in setting up a service that can adequately address the biopsychosocial needs of the covid-19 pandemic 6, 17 . the present study obtained the best quality data using face-to-face interviews with acutely ill covid-19 patients during their hospitalization in various hospitals in chongqing, china. the interviews were performed from 18 to 26 march 2020. interviewers wore full personal protective equipment (ppe) when performing the interviews with covid-19 patients in the isolation ward. patients were interviewed while they were still covid-19 positive in status and that they were on supportive treatment. a series of standardized validated questionnaires were used for the quantitative component of the study. for the qualitative component of the study, the interviewers performed semi-structured interviews using open-ended questions to examine patients' perception and feelings during the current outbreak. patients were encouraged to speak openly, highlight issues pertinent to them, and elucidate their responses with examples. patients were allowed to withdraw their consent at any time during the interview. the interviews were audiorecorded and kept strictly confidential. each interview took~40-90 mins and the interviewers were instructed to remain neutral during the data collection process and establish a rapport with the patients using the techniques of acceptance, active listening and clarification to ensure the authenticity of the information and minimize bias. in the event that the patients became emotional during the interview, psychological support and intervention were provided to them. age-and gender-matched psychiatric patients and healthy control participants residing in the same city were recruited during the covid-19 epidemic and used as a comparison. they did not undergo confirmatory covid-19 testing as they did not have any symptoms that were suggestive of covid-19 infection or had positive contact history, and the supplies of confirmatory kits in the hospital were limited. the ethics review committee of the first people's hospital of chongqing liang jiang new area approved this project (irb no. 2020-02-002). informed consent was obtained from all subjects. covid-19 patients were aged 18 years or older and hospitalized during the time of assessment. the diagnosis of covid-19 was made using reverse-transcription polymerase chain reaction (rt-pcr) testing and chest computed tomography (ct) for evaluation of covid-19. to be included, patients could not have any pre-existing psychiatric illnesses or unstable medical conditions. patients with severe complications requiring oxygen supplementation or who were medically unstable were excluded from the study. the inclusion criteria were different for psychiatric patients and healthy controls. all the psychiatric patients were aged 18 years or older and were previously diagnosed by psychiatrists with f32, major depressive disorder -single episode; f33, major depressive disorder-recurrent episodes; f41, other anxiety disorders, including generalized anxiety disorder and panic disorder; and f41.8, mixed anxiety and depressive disorder, based on the 10th revision of the international statistical classification of diseases and related health problems (icd-10) criteria. healthy control subjects were aged 18 years or older and did not have a history of psychiatric illnesses. the exclusion criteria included the presence of chronic medical disorders, including neurological, cardiovascular, respiratory, endocrine and inflammatory disorders, or suspected or confirmed cases of covid-19. the structured questionnaire covered several areas: (i) demographic data; (ii) physical symptoms and self-rated physical health status in the past 14 days; (iii) impact of event scale-revised (ies-r), (iv) depression, anxiety and stress scale (dass-21), (v) the insomnia severity index (isi), and (vi) other psychiatric symptoms. sociodemographic data were collected regarding gender, age, education, and household size. physical symptom variables in the past 14 days included fever, chills, headache, myalgia, cough, difficulty breathing, dizziness, coryza, sore throat, persistent fever, nausea, vomiting and diarrhea. respondents were asked to rate their physical health status. the psychological impact of the covid-19 outbreak was measured using the ies-r. the ies-r is a selfadministered questionnaire that is well-validated in the chinese population for determining the extent of the psychological impact after exposure to a public health crisis within one week of exposure 18 . this 22-item questionnaire is composed of three subscales and aims to measure the mean avoidance, intrusion and hyperarousal 19 . the total ies-r score was divided into 0-23 (normal), 24-32 (mild psychological impact), 33-36 (moderate psychological impact) and >37 (severe psychological impact). mental health status was measured using the depression, anxiety and stress scale (dass-21), and the scores were calculated based on previous studies 20 . the total depression subscale score was divided into normal (0-9), mild depression (10) (11) (12) , moderate depression (13) (14) (15) (16) (17) (18) (19) (20) , severe depression (21) (22) (23) (24) (25) (26) (27) and extremely severe depression (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) . the total anxiety subscale score was divided into normal (0-6), mild anxiety (7-9), moderate anxiety (10) (11) (12) (13) (14) , severe anxiety (15) (16) (17) (18) (19) , and extremely severe anxiety . the total stress subscale score was divided into normal (0-10), mild stress (11) (12) (13) (14) (15) (16) (17) (18) , moderate stress (19) (20) (21) (22) (23) (24) (25) (26) , severe stress (27) (28) (29) (30) (31) (32) (33) (34) and extremely severe stress (35) (36) (37) (38) (39) (40) (41) (42) . the dass is a reliable and valid measure for assessing the mental health of the chinese population 21, 22 . both the ies-r and dass were previously used in research related to the covid-19 pandemic [5] [6] [7] [8] . the sleep quality of respondents was measured using the insomnia severity index (isi) 23 . the isi has seven questions that are summed to produce a total score. the total isi score was divided into no clinically significant insomnia (0-7), subthreshold insomnia (8) (9) (10) (11) (12) (13) (14) , moderately severe clinical insomnia (15) (16) (17) (18) (19) (20) (21) and severe clinical insomnia (22) (23) (24) (25) (26) (27) (28) . as for the semi-structured interviews for covid-19 patients, eight questions were included: (i) describe a situation in which you experienced negative emotions (unpleasant feelings) during the outbreak and how you felt and thought at the time; (ii) describe a situation in which you experienced positive emotions during the outbreak and how you felt and thought at the time; (iii) how did you feel and react after your first infection (thinking, feelings, behavior, any bodily sensation)?; (iv) how did you feel and react after you were tested positive again (thinking, feelings, behavior, any bodily sensation)?; (v) what worries do you have about the future?; (vi) what enlightenment will this experience bring to your life and why is that so?; (vii) what advice, if any, would you give to countries and people experiencing a new epidemic?; and (viii) what do you think you, your family and friends did to help you recover physically and emotionally? all the interviews were audio-recorded with prior consent given by the patients. the audio recordings were transcribed within 24 hours of each interview and reviewed by the interviewers to safeguard accuracy. as the interviews, transcriptions, and analyzed data were in chinese, they were translated into english by some study team members and back translated by another group of study team members to ascertain that the meaning was retained. descriptive statistics were used to summarize the variables, means and standard deviations were used for continuous variables, and frequencies and percentages were used for categorical variables. inferential statistics, including the independent sample t test and pearson's chi-squared test, were used to examine differences in the outcome variables between the psychiatric patient and healthy subject groups. multiple linear regression with a backward selection method was used to examine the association between the outcome variables, the two groups of subjects and the demographic variables. all analyses were performed using ibm spss statistics 22, and the level of significance was set at 5%. as for the qualitative component of the study, the interview was transcribed, and a detailed reading and re-reading of the transcripts was performed to identify significant key words and phrases. understanding and validating the expressed meanings of these words and phrases were done through research team meetings to arrive at a consensus. then, codes were assigned and arranged into themes and sub-themes using the concepts of grounded theory for data analyses. the sociodemographic characteristics of the patients and healthy control participants are presented in table 1 . covid-19 and psychiatric patients were age-and gendermatched with healthy subjects. patients significantly differed from healthy controls with regards to the physical symptoms experienced (p = 0.014), with a higher proportion of covid-19 patients than psychiatric patients and healthy controls reporting at least one symptom (60% vs 30% vs 0%). there was no difference between the three groups in self-reported health status. all of the covid-19 patients were clinically stable without the need for respiratory support. they were given supportive treatment and there was no clinical indication for any specific intervention. 40% of patients had abnormalities on chest ct, 20% had dysosmia, and 10% had dysgeusia. 80% of patients had repeat positivity for covid-19 in rt-pcr testing and had been in isolation for 2 months when interviewed. the remaining 20% of patients were in isolation few days prior to the interview. the psychological symptoms experienced by the study participants in the last 7 days are presented in table 2 . covid-19 and psychiatric patients were significantly more worried about their health than healthy controls (p = 0.019), with more covid-19 patients reporting moderate levels of worry (40%) and some psychiatric patients reporting serious level of worry (20%). although the three groups were not statistically significant in regard to the parameter of discrimination, more covid-19 patients reported feeling discriminated, ranging from a mild to very serious level (p = 0.160). more covid-19 patients were impulsive as compared with psychiatric patients and healthy controls (p = 0.016), with half of the covid-19 patients experiencing a mild level of impulsivity, and 20% of psychiatric patients experienced moderate to very serious levels of impulsivity. the psychological impact of the covid-19 pandemic on participants are presented in table 3 . the psychological impact as measured using the ies-r scale, revealed that the covid-19 patients had a higher mean score (22.3, sd = 16.3) than psychiatric patients (18.4, sd = 19.4) and healthy controls (14.7, sd = 7.9), although there was no significant difference between the three groups. a greater proportion of covid-19 patients (50%) than the other two groups experienced a psychological impact of at least mild and above severity in keeping with clinically significant symptoms of ptsd, as indicated by ies score of 24 and above, although this result was not statistically significant. covid-19 and psychiatric patients had higher dass-21 sub-scores of anxiety, depression and stress than healthy controls, with higher scores of anxiety (6.4 vs 5.0) and depression (7.8 vs 7.0) for psychiatric patients than for covid-19 patients. the dass-21 sub-score of stress was higher for covid-19 patients than for psychiatric patients (9.2 vs 7.8). all three p values were however insignificant. there were also no significant differences in the severity dichotomization of anxiety, at least one symptom 6 (60%) 3 (30%) 0 (0%) self-reported health status 0.263 healthy or better 7 (70%) 3 (30%) 7 (70%) very serious 0 (0%) 1 (10%) 0 (0%) felt anxious 0.207 very serious 0 (0%) 1 (10%) 0 (0%) felt upset 0.309 very serious 0 (0%) 0 (0%) 0 (0%) felt meaningless 0.201 very serious 0 (0%) 0 (0%) 0 (0%) worried about health 0.019 felt being discriminated 0.16 very serious 1 (10%) 0 (0%) 0 (0%) heard voices 0.355 very serious 0 (0%) 0 (0%) 0 (0%) felt being followed 0.117 very serious 0 (0%) 0 (0%) 0 (0%) felt impulsive 0.016 serious 0 (0%) 0 (0%) 0 (0%) depression, and stress among the three groups. for sleep quality, a higher proportion of covid-19 patients (50%) reported insomnia than psychiatric patients (30%) and healthy controls (0%), and this difference was statistically significant (p = 0.039). three main themes emerged from the covid-19 patients' accounts of their experiences of the outbreak: (i) emotions of the patients after covid-19 infection; (ii) external factors that affected patients' mood; (iii) coping and self-help behavior. each main theme and its subthemes are discussed and illustrated in some of the participants' verbatim accounts. theme 1: emotions of the patients after covid-19 infection 1.1. emotions generated by the infection all patients reported that the covid-19 infection was a major stress event for them. this stress was particularly due to the high infectivity and potential lethality of the viral infection. emotional disturbances occurred in patients, especially in the initial period after diagnosis with the infection, and some of the first emotions included surprise, fear, bewilderment, and questioning why the virus had infected them. "i feel so scared and stressed. i'm afraid that i'm going to break down and i won't be able to hold on anymore." (patient 9) "i was actually quite surprised i got infected because i did a good job protecting myself… i had no contact with anyone from foreign countries, i only went downstairs to buy daily necessities twice in 14 days, and i wore a mask the whole time. so, i was surprised to find out i was infected." (patient 10) after the initial realization and acceptance of contracting the disease, patients began to feel depressed, and some individuals had desperate thoughts, such as the fear of being unable to leave the hospital or of dying. very serious 0 (0%) 0 (0%) 0 (0%) however, once past the initial phases, some patients accepted their predicament and adjusted their mindset to receive treatment. "at first, i was very worried and felt miserable…then i stopped thinking about these because i knew it was meaningless to think about them now. the key was to get well quickly." (patient 6) patients who tested positive for covid-19 repeatedly during their stay in the hospital might have experienced a sense of hopelessness and helplessness that their chances for recovery had been "dashed". this feeling might have triggered previous fears and worries of their condition deteriorating. there was also increased stress of waiting for repeated test results. with the absence of a viable cure and the limited understanding of the consequences of the novel viral infection, there was much apprehension, and some patients diverted excessive attention to their body, which led to the manifestation of somatic symptoms. "i have always been a little worried about my health. but now, my concerns about my health are more serious. i previously had high levels of uric acid, so i stopped eating meat or drink any soup… despite the doctor telling me that it is actually appropriate to eat. in the hospital, i don't eat the apples that they provide me at night… i think they are cold, and it is bad to eat at night. i also don't let my wife eat fruits at night. i'm worried that my illness is because of my underlying poor health constitution." (patient 1) with the stabilization of their disease, patients started worrying about people close to them and also longer-term issues, such as employment, financial problems and vaccine development. the long hours that patients spent alone in a closed environment with their freedom limited may have led to a feeling of isolation, boredom, and a depressed mood. "it is too boring staying here, and it is making me irritable and restless, which i wasn't before. if i test positive again, i'm going to go crazy. and i'll find a way to get out somehow…." (patient 7) "the accommodation conditions in the last hospital was very limited. after my neighboring patients were discharged, i was alone in the room, with weak cell phone signal and no tv, so i was really bored. every day i wonder -when will this life ever end?" (patient 1) during this unprecedented time of the covid-19 pandemic, and living in a relatively special environment, various events might have affected the patients' mood. the provision of systematic and sound national policies on protective and supportive measures for citizens might have mitigated the psychological burden of patients. patients felt their own safety was guaranteed when the country that they lived in demonstrated it cares about the well-being of its people. "the government has exempted the medical expenses of patients suffering from this disease, so that people can concentrate on recovering without worries. the government has developed the right policies to guide us in the fight against the epidemic, and we are moving towards the right path. this shows the merits of the whole country in being able to focus on big things. what is there to worry about living in such a country and with such people?" (patient 4) furthermore, the care and warmth of the medical staff experienced by the patients made them realize that their feeling of isolation was due solely to the virus and not due to a lack of love and comradeship. the care and assistance provided by the medical staff made patients feel solidarity and warmth between people. "the nurse sister made me feel a lot of warmth every day… telling me to take my medicine and checking my temperature. during my illness, i learned that everyone was helping and supporting each other in need." (patient 4) "the nurses are like angels. one day, i was hungry before the scheduled mealtime as i had diarrhea prior. i asked for a bowl of noodles, and the nurse immediately brought me noodles. the medical staff taught us to dance and sing… it was really fun, and we learned a lot. these nurses are very young in their 20 s to 30 s, and they haven't been home for more than 30 days… it's pretty hard for them too." (patient 6) despite the inability to physically meet, family members and friends also provided psychological support and motivation to the patients via remote communication. patients were also able to more deeply appreciate the value of kinship and friendship in the midst of this outbreak. "i am very grateful to my wife for her continued encouragement. during the period when i was staying in isolation, i felt lonely and sad. due to changes in the environment, my state was worse than before, but she was always there encouraging me." (patient 2) "i received a bunch of flowers and a letter from my friend. the content of the letter was simple and reassuring, which moved and made me feel good. i did not expect to encounter so many heartening moments during my stay in the hospital." (patient 5) there is much panic about the infectivity and lethality of the virus. patients reported discrimination and abuse by non-infected individuals. excessive worry for family members also increased the psychological burden of patients. "after being discharged from the hospital the last time, we returned to our neighborhood and continued to be quarantined at home. somehow our private information including our address and telephone number was leaked. residents in the neighborhood said a lot of nasty things in the neighborhood wechat group and regarded us as monsters. people who live in the same building are very worried about getting infected merely by passing by our door. in the group chat, they even talked about their fear to go downstairs. in the future, when we want to visit your clinic for review, i wonder if you will also avoid us?" (patient 1) "…he (family member) calls me every day and then passed the negativity to me. he feels better after talking to me, but it is actually hard for me. i absorbed his negative emotion and passed positive emotions to him." (patient 3) in addition to the negative comments of other people, patients spent more time on the internet due to the lack of face-to-face communication opportunities during their stay in the hospital. when they saw negative news on the internet, such as foreign communities' lack of understanding of the chinese measures and discrimination against chinese people, they also felt angry and upset. "i have some foreign friends who believe that china's reaction to the outbreak is an overkill and overly paranoid. perhaps they underestimated the epidemic or they have never experienced the situation in wuhan. they think that china is making a mountain out of a molehill and its measures are ridiculous. there are those who laugh at our policies and precautionary measures. these make me feel uncomfortable." (patient 9) "from the beginning of the outbreak, leaders of some countries claimed that the virus originated from china and that china spread the virus across the world. as a result, the chinese are loathed by other ethnic groups overseas. many of china's efforts to combat the outbreak have been deliberately ignored. i felt hated, discriminated against and that my life is threatened." (patient 10) due to the isolation, patients felt anxious and worried about their unfinished matters. their original social role was replaced by the patient sick role, which caused them to feel bored, irritated, and depressed. "i have been living here for two months, and i feel that there is no longer meaning to life. sometimes i feel that my life and memories are not real, and i don't know what i can achieve in the future. i used to be a person who's very active with activities." (patient 6) "over the past two months, i have to pay my house mortgage, and my small business has been affected by the economic situation. my children have to go to school… my son is still very young… i worry that when i am not around, he cannot take care of himself." (patient 7) in the face of stressful events, such as the pandemic, patients sought ways to adjust their emotions to help themselves. first, they comforted themselves by believing that the government and the medical staff would do their best to help them. "i try not to think too much. i constantly tell myself that young people such as myself don't have medical illnesses, so covid-19 will have a very small impact on me. i have confidence in my body, so i don't have to worry so much, and this is the most important." (patient 3) "i will always encourage myself to think positively and try my best to adjust my mindset. an integral part of recovery is the mental attitude, so psychologists play a key role in the process. (patient 5) in addition to comforting themselves, patients also tried to maintain a regular routine that included proper exercises and an adequate mastering of disease knowledge to feel more empowered and in control. "i am one of the younger patients in isolation. at present, the inpatient isolated lifestyle requires one to go to bed and wake up early, and doing some gentle physical exercises planned by the ward team, which are more for middle-aged people and not particularly suitable for me… i have to find ways to enrich my life. other people whom i know who are also in isolation are actively looking for ways to adjust." (patient 9) patients also attempted to divert their attention from their situation via other activities. "distraction is a great way, whether it's talking to someone or finding something to do on your own. for example, when i was first admitted to the hospital, i always felt that i had breathing difficulties. but when i talked to you on the phone, i didn't feel any difficulty at all. when i get distracted, the physical symptoms disappear…the more attention i pay to my breathing, the more obvious the shortness of breath becomes." (patient 5) with limited interpersonal communication during isolation, some patients created ways to make friends with other patients to expand their social contact and comfort one another. "when i just got admitted, i remembered walking along a corridor and seeing the door of a ward open. there was a fellow patient inside. i said: "friend, let's add each other on wechat." at that time, i needed friends, someone to understand me, to talk to me." (patient 7) our study sample of covid-19 patients had mild-moderate severity with less than half of them having abnormal findings on the chest ct. the paucity of abnormal findings on chest ct could possibly be due to an earlier pick-up rate with a shorter time after the onset of symptoms 24 . furthermore, only a small proportion of them had olfactory and gustatory dysfunction. there has been increasing reports of smell and taste alterations as concurrent symptoms of covid-19 infection. interestingly, those with dysnomia and dysgeusia were found to have less-severe manifestations of other symptoms and tended to recover more quickly 11 , raising the possibility of olfactory and gustatory dysfunctions as potential markers of structural or functional morbidities 25 . the majority of our patients were retested positive for covid-19. although the exact causes of this phenomenon remain uncertain, there is a possibility that the viral infection can provoke an inflammatory milieu that results in aberrant immune responses. such immune responses may trigger the propagation of host antibodies and lymphocytes that cross-react with both viral antigen and self-antigen, causing persistent infections, and potentiate the development of autoimmune neuropsychiatric sequelae particularly impulsivity and insomnia 26, 27 . a higher proportion of covid-19 patients was found in our study to be impulsive as compared to psychiatric patients and healthy controls. these feelings might have been related to patients staying in isolation rooms for a prolonged duration with limited social interaction, lack of stimulation and loss of freedom, which may result in anger, fear, restlessness, and irritability. staying in isolation rooms can negatively impact psychological wellbeing, in which previous studies highlighted higher scores for anger-hostility 28 , in addition to depression, anxiety, fear, and loneliness 29, 30 . the acute stress experienced by patients can activate immune system responses via amplification of the corticotropin-releasing factor system that regulates impulsivity 31 and releases pro-inflammatory cytokines such as il-6 and tnf-α that evoke behavioral changes aimed to protect self from injury or harm 32 . sleep disturbances was also a prominent feature found in covid-19 patients compared with psychiatric patients and healthy controls. this finding was consistent with other studies that found sleep problems occurring in people with naturally occurring respiratory infections 33 . physical stress inflicted on the body by the infection coupled with psychological stress trigger off a cascade of system responses including cortisol release from the hypothalamic-pituitary-adrenal axis, and catecholamine, norepinephrine, and epinephrine release by the peripheral sympathetic-adrenomedullary system 34 . these systems in turn stimulate pro-inflammatory cytokine release targeting sleep-related functions among others such as metabolic and cardiovascular changes. although these physiological mechanisms in the acute phase facilitate stress adaptation to "fight-or-flight" in the event of adversity, chronic activation of these mechanisms may cause detrimental bodily and psychological effects, such as obesity, depression, and even elevating the risk of developing a rhinovirus infection 35 . higher levels of depression, anxiety, stress, and ptsd were found in covid-19 patients than healthy people, though in our study, these results were not statistically significant. several reasons for the depressive and anxiety symptoms in our study include the perception of vulnerability to the virus, uncertainty and fear about the consequences of the infection, treatment outcome and death in the absence of a definitive treatment, the inability to resume their routine activities, worries about unfinished matters and loved ones, worries about their financial situation and stigma. cognitive features of depression such as helplessness and hopelessness 36, 37 , and somatic symptoms 38 as part of the anxiety spectrum with hypervigilance on bodily sensations were also exemplified in the interviews. as for ptsd symptoms in covid-19 patients, many expressed concerns about their health, family, livelihood, and future, which was disrupted, and displayed emotions that resembled the various stages of grief, ranging from denial, anger, bargaining, and depression to acceptance. with the possible shared immune dysregulation pathogenesis of covid-19 and psychiatric disorders with bidirectional implications, it may be worthwhile to stabilize each condition to prevent worsening of the other, and medications that modulate the immune system to counteract covid-19 could potentially be used as an antidepressant and vice-versa 39 . anti-inflammatory drugs have been found to have antidepressant effects in clinical trials 12 , whereas antidepressants are also found to reduce central and peripheral levels of il-1β with the alleviation of depressive symptoms 40 , suggesting their anti-inflammatory properties. antidepressants with its relatively safe side-effect profile and affordability than other immunomodulators could therefore be a potential new therapeutic candidate in the treatment of covid-19 41 . psychiatric patients on the other hand, had higher scores of depression and anxiety than covid-19 patients, which may be owing to their pre-existing poorer adaptive coping to acute stressful events. this result also raised the concern that more psychological support should be rendered to psychiatric patients despite their lack of infection; and psychiatric patients if infected with covid-19, could be at higher risk of complications considering their emotional state and lowered immunity status. it is important to reiterate that we were unable to measure the inflammatory markers of participants and correlate them with the psychological parameters in our study, and owing to the crosssectional nature of the study, it would not be possible to elucidate the causal relationship between mental illness and the inflammatory effects of covid-19 infection. nevertheless, this is an important research area that warrants further investigation. there is a wide spectrum of emotions experienced by patients, and the heterogeneity in disease response could be contributed by various psycho-socio-economic factors, pre-existing medical comorbidities, differences in the immune system maturity that underline the immune response differences to the infection, temperament, and attachment styles 42, 43 . those with pre-existing chronic medical conditions and older adults may have lower innate immunity with greater susceptibility to the virus and risk having worse outcomes. anxious, depressive, and cyclothymic temperaments as well as the insecureanxious attachment dimension temperament have been found to predict psychological distress, whereas secure and avoidant attachment styles are protective 43 . shock, fear, despair, and hope as found in our study are wellrecognized symptoms of traumatization 44 , whereas boredom in relation to restlessness and irritability are especially relevant for those in isolation and quarantine. boredom if entrenched and severe, can manifest as a neurotic disorder that may erode self-control, leading to impulsivity, and risk-taking behavior 45 . feeling discriminated was a pertinent issue encountered by covid-19 patients, which is consistent with previous studies that highlighted the stigma experienced by infected patients 46 who may be shunned by their loved ones, friends, and communities for being a carrier of the virus, or as part of a nationality or ethnic group that contributed to its transmission 47 . in addition, internalized stigma may also occur in which infected people view themselves as inferior to others, which leads to self-loathing as a result of their disease status 48, 49 . discrimination and stigmatization often lead to feelings of abandonment and loneliness 50 , which are further compounded in covid-19 patients by staying in an isolation room and may last beyond discharge from the hospital 51 . in our study, covid-19 patients utilized the tripartite framework of positive coping style, cognitive appraisal, and social support to mitigate stress, promote positive emotions, and enhance perceived self-efficacy 52 . these factors facilitate psychological adaptation and resilience in the backdrop of an infectious outbreak 53 . the pressure of the pandemic prompted them to utilize coping strategies, which included distraction techniques (exercise, talking to others, engaging in activities) and mental avoidance to keep themselves busy while disengaging from their own plight. problem-solving strategies such as mastering knowledge of the disease allowed patients to proactively empower themselves and gain control of their health, which minimized their feelings of uncertainty 54 and improved their mental health 55 . positive cognitive appraisals of the outbreak situation together with a positive mindset enable one to seizure control of the situation and constructively plan ahead. some patients re-evaluated the situation based on past outbreaks and experiences in life to anticipate possible scenarios, and assessed the situation to be manageable, which reduced distress 56 . some patients placed confidence in the government and healthcare systems to manage the outbreak and believed that they would receive good treatment if they needed it 57 . having faith and trust in the government and health authorities to manage covid-19 may reduce their fears and perceived vulnerability to the virus 58 . seeking support from various sources, including family and friends, fellow patients and healthcare providers, are integral in cushioning the psychological complications of the outbreak. the dedicated care and concern shown by healthcare workers positively impacted patients and made them feel supported. all of these factors contribute to enhanced optimism, which favorably alleviates psychological trauma in disasters, and enhances psychological rehabilitation of ptsd 59 . guided by findings of this study, which identified the psychological distress and mental health needs of covid-19 patients, it is paramount for hospitals moving forward, to set up a novel holistic inpatient service with appropriate prevention measures to promote immune and psychological resilience. this is done by catering to the individualized physical and mental health needs of covid-19 patients who are kept in prolonged isolation. several principles of this service that could be considered are as follow. (1) maintain regular physical exercise regimes, especially those that elevate cardiorespiratory fitness at moderate intensity, as they have been found to reduce inflammation and boost immunity 60 . exercise can be delivered through online instructor-led platforms or via exergaming, which is a hybrid form of physical activity that combines exercise and video games. (2) develop healthy lifestyle habits with proper nutrition that includes antioxidants, high fiber content, whole grains, and unsaturated fats, which have rapid anti-inflammatory effects that boost immunity, counteract vulnerability to covid-19 and promote recovery 61 . (3) educate on proper safety precautions including hand hygiene, wearing of face masks and social distancing to minimize community spread after hospital discharge. (4) use of online and smartphone-based platforms to deliver various types of psychotherapy to enhance patients' adaptive and coping capability. an example is trauma-focused-cognitive behavior therapy with emphasis on cognitive reframing of the mindset to help remove unhelpful thoughts about covid-19 and perceived discrimination, trauma narrative to process personal traumatic experiences during the pandemic, grief therapy to handle potential losses, and relaxation techniques to counteract anxiety, irritability, anger, and ptsd-like symptoms 62 . sleep hygiene advice can also be provided to improve circadian rhythm and sleep quality. (5) allow patients the peace of mind to recover from the infection. this includes ensuring data protection and confidentiality of patient details to minimize potential discrimination by others, and ensure affordability of medical care. (6) provide emotional support to healthcare workers taking care of covid-19 patients. the mental health of healthcare workers can directly impact the quality of care and psychological wellbeing of patients. (7) monitor the association of blood pro-inflammatory cytokine levels with severity of covid-19 physical and neuropsychiatric symptoms. this may have implications in monitoring disease progression and treatment response, considering the potential bidirectional relationship between covid-19 and psychiatric disorders. furthermore, the application of biological markers may better elucidate the yield of using antidepressants as a novel treatment modality for covid-19. the present study has merits in being the first study to quantitatively and qualitatively evaluate the neuropsychiatric sequalae and psychological impact of patients with active covid-19 infection. the qualitative component of the study provides a more personalized account of the perspectives and challenges faced by patients, and strengthens the findings obtained from quantitative measures. the study performed face-to-face interviews as compared with other studies 9 , and was challenging logistically and safety-wise for the interviewers. nevertheless, this study provided patients with a better interview experience to elicit more authentic information. furthermore, the comparison of covid-19 patients to psychiatric patients and healthy individuals in the community provided further clarity that covid-19 patients had more neuropsychiatric psychiatric symptoms than psychiatric patients and the general population, which could be due to their enhanced pro-inflammatory state and increased stress. on the other hand, this study has several limitations. first, the sample size of the study was small, and thus results from our study are at risk of type 2 errors and could not be generalizable to all psychiatric and covid-19 patients. we were unable to recruit a larger sample owing to the potential risk of infection to the interviewers. furthermore, the psychiatric and covid-19 patients whom we recruited had low to moderate severity of their psychiatric condition and stable medical condition without complications, respectively. it would not be ethical and feasible to recruit patients who were psychiatrically and medically unstable. therefore, our sample participants were not representative of the spectrum of psychiatric disorders and covid-19 infection. second, no biological markers such as cytokines were measured to correlate with the neuropsychiatric symptoms. thus, we were unable to elucidate the relationship between the two, and whether the psychiatric symptoms experienced by covid-19 patients were the result of the inflammatory effects of covid-19 infection or owing to other causes such as the psychological effects from being isolated. third, this study was a cross-sectional study that performed assessments at a particular time point. it would be pertinent to longitudinally review their condition with monitoring of their cytokine levels and neuropsychological data as part of the intervention. nevertheless, the current data are valuable to provide a preliminary in-depth understanding of the psychological issues faced by covid-19 patients and serve as a foundation for further studies in this area. this study has provided a comprehensive and in-depth exploration of the neuropsychiatric sequalae and psychological impact of acutely infected covid-19 patients through quantitative and qualitative approaches. covid-19 patients had higher levels of neuropsychiatric symptoms than psychiatric patients and healthy individuals in the community in terms of impulsivity and insomnia, which could be secondary to their enhanced pro-inflammatory state. covid-19 patients also experienced emotions including shock, fear, boredom, and hope during their course of treatment, and common concerns about discrimination, medical expenses, care by healthcare workers, and means of self-help behavior were highlighted. the future direction for covid-19 management involves the setting up of a dedicated holistic service that incorporates preventive measures on exercise, nutrition, safe hygiene practices, psychotherapy, and use of cytokine markers to monitor disease progression and treatment response, coupled with financial and healthcare support. world health organization. who director-general's opening remarks at the media briefing on covid-19 covid-19 coronavirus pandemic nervous system involvement after infection with covid-19 and other coronaviruses self-reported olfactory and taste disorders in sars-cov-2 patients: a cross-sectional study immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china do psychiatric patients experience more psychiatric symptoms during covid-19 pandemic and lockdown? a case-control study with service and research implications for immunopsychiatry is returning to work during the covid-19 pandemic stressful? a study on immediate mental health status and psychoneuroimmunity prevention measures of chinese workforce a multinational, multicentre study on the psychological outcomes and associated physical symptoms amongst healthcare workers during covid-19 outbreak posttraumatic stress symptoms and attitude toward crisis mental health services among clinically stable patients with covid-19 in china nervous system damage after covid-19 infection: presence or absence? dysosmia and dysgeusia due to the 2019 novel coronavirus; a hypothesis that needs further investigation. maxillofac inflammatory markers in depression: a meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls symptom severity impacts sympathetic dysregulation and inflammation in post-traumatic stress disorder (ptsd) experiences and psychosocial problems of nurses caring for patients diagnosed with covid-19 in turkey: a qualitative study experiences and needs of caregivers of persons with dementia in india during the covid-19 pandemic-a qualitative study medically unexplained symptoms in the times of covid-19 pandemic: a case-report using psychoneuroimmunity against covid-19 usage of social media and smartphone application in assessment of physical and psychological wellbeing of individuals in times of a major air pollution crisis methodology of developing a smartphone application for crisis research and its clinical application multi-level predictors of psychological problems among methadone maintenance treatment patients in difference types of settings in vietnam relationship of anxiety and depression with respiratory symptoms: comparison between depressed and non-depressed smokers in singapore misophonia in singaporean psychiatric patients: a crosssectional study validation of the insomnia severity index as an outcome measure for insomnia research chest ct findings in coronavirus disease-19 (covid-19): relationship to duration of infection traumatic brain injury and olfaction: a systematic review nervous system involvement after infection with covid-19 and other coronaviruses are we facing a crashing wave of neuropsychiatric sequelae of covid-19? neuropsychiatric symptoms and potential immunologic mechanisms psychological impact of the management of methicillin-resistant staphylococcus aureus (mrsa) in patients with spinal cord injury adverse effects of isolation in hospitalised patients: a systematic review impact of isolation on hospitalised patients who are infectious: systematic review with meta-analysis innately activated tlr4 signal in the nucleus accumbens is sustained by crf amplification loop and regulates impulsivity anger and fear responses to stress have different biological profiles sleep during naturally occurring respiratory infections: a pilot study exploring the multidimensional complex systems structure of the stress response and its relation to health and sleep outcomes association of insufficient sleep with respiratory infection among adults in the united states psychological distress among ebola survivors discharged from an ebola treatment unit in monrovia, liberia-a qualitative study adjustment to severe acute respiratory syndrome (sars): roles of appraisal and post-traumatic growth adjustment outcomes in chinese patients following onemonth recovery from severe acute respiratory syndrome in hong kong three insights on psychoneuroimmunology of mood disorders to be taken from the covid-19 pandemic chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression current status of potential therapeutic candidates for the covid-19 crisis one size does not fit all-patterns of vulnerability and resilience in the covid-19 pandemic and why heterogeneity of disease matters affective temperament, attachment style, and the psychological impact of the covid-19 outbreak: an early report on the italian general population vicarious traumatization in the general public, members, and nonmembers of medical teams aiding in covid-19 control risk-taking increases under boredom addressing disease-related stigma during infectious disease outbreaks the h1n1 pandemic: media frames, stigmatization and coping towards a sustainable theory of health-related stigma: lessons from the hiv/aids literature from conceptualizing to measuring hiv stigma: a review of hiv stigma mechanism measures narrative synthesis of psychological and coping responses towards emerging infectious disease outbreaks in the general population: practical considerations for the covid-19 pandemic an exploratory study of nurses suffering from severe acute respiratory syndrome (sars) mental health and emotional impact of covid-19: applying health belief model for medical staff to general public of pakistan a qualitative study on the psychological experience of caregivers of covid-19 patients qigong practice among chronically ill patients during the sars outbreak the effect of training problem-solving skills on coping skills of depressed nursing and midwifery students the h1n1 pandemic: media frames, stigmatization and coping population-based post-crisis psychological distress: an example from the sars outbreak in taiwan the singaporean response to the sars outbreak: knowledge sufficiency versus public trust effects of optimism on recovery and mental health after a tornado outbreak the immunological case for staying active during the covid-19 pandemic the impact of nutrition on covid-19 susceptibility and long-term consequences a longitudinal study on the mental health of general population during the covid-19 epidemic in china the research was supported by chongqing science and technology dissemination and popularization project (cstc2019kpzx-kphda0014) for fengyi hao the authors declare that they have no conflict of interest.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.received: 10 june 2020 revised: 12 september 2020 accepted: 1 october key: cord-022155-9759i9wr authors: nag, pranab kumar title: sick building syndrome and other building-related illnesses date: 2018-08-18 journal: office buildings doi: 10.1007/978-981-13-2577-9_3 sha: doc_id: 22155 cord_uid: 9759i9wr sick building syndrome (sbs) and building-related illnesses are omnipresent in modern high-rise buildings. the sbs is a complex spectrum of ill health symptoms, such as mucous membrane irritation, asthma, neurotoxic effects, gastrointestinal disturbance, skin dryness, sensitivity to odours that may appear among occupants in office and public buildings, schools and hospitals. studies on large office buildings from usa, uk, sweden, finland, japan, germany, canada, china, india, netherlands, malaysia, taiwan, and thailand, substantiate the occurrence of sbs phenomena. the accumulated effects of a multitude of factors, such as the indoor environmental quality, building characteristics, building dampness, and activities of occupants attribute to sbs. a building occupant manifests at least one symptom of sbs, the onset of two or more symptoms at least twice, and rapid resolution of symptoms following moving away from the workstation or building may be defined as having sbs. based on the peer-reviewed documentation, this chapter elaborates the magnitude of building-related health consequences due to measurable environmental causations, and the size of the population affected. the mechanisms and causative factors of sbs and illnesses include, for example, the oxidative stress resulting from indoor pollutants, vocs, office work-related stressors, humidification, odours associated with moisture and bioaerosol exposure. related regulatory standards and strategies for management of sbs and other illnesses are elaborated. challenging lawsuits to redress grievances. the term sbs has been in use for some time now and widely recognized, in spite of suggestions for alternative names, such as problem buildings, building-related occupant complaint syndrome, abused building syndrome. acknowledging that the incidences of sbs symptoms are straightforward, its characterization and linkages to an indoor exposure require more in-depth analysis. an impediment towards this effort is to make the primary distinction as to whether the problem is chemical, biological, physical, or psychogenic. the questions to examine are the mechanism how workplace or environmental processes trigger physical health symptoms, and whether some individuals are more prone to illnesses. further, it calls for a review on the kind of critical work settings that precipitate illness conditions, and how the work or environmental aspects influence building occupant's psychophysiological threshold, making oneself hypersensitive even to mild irritants. priority is placed on exploring organizational interventions to restrict the spread of the syndrome and efficiently manage causes of building-related illnesses. several researchers indicate the sbs as a phenomenon that occurs among building occupants, perhaps one out of five building occupants reports symptoms associated with their respective place of work and attributed to the iaq. the interactions of a multitude of factors, such as the site, climate, building system, construction materials, building dampness, contaminant sources, activities of occupants, affect the quality of indoor air. typically, maintaining allowable iaq in office buildings depends on effective ventilation systems in operation. ineffective or inadequate ventilation systems result in inefficient removal of pollutants from indoor air and display signs of sbs among the occupants. health impact assessment addresses qualitative or quantitative evaluation of the magnitude of health consequences due to measurable environmental causation or metric, and the size of the population affected (fehr et al. 2012; mesa-frias et al. 2014) . apparent relationships exist between the external stimuli, kinds of human responses and about the type of building environment. therefore, the discomfort and symptoms of occupants in the building require acknowledging that an exposure scenario exists, and the discomfort and disease have a strong association with psychologic or physiological components. a structured questionnaire (table 3 .1) may be used to ascertain the sbs of the respondents in an office building. the office workers who had at least one symptom of sbs and onset of two or more symptoms at least twice weekly, overnight resolution of symptoms after leaving the workstation or building, and the absence of known medical causes, may be defined as having sbs (ooi et al. 1998 ). the prevalence of symptoms among building occupants is linked to personal exposure to the indoor environment. the symptoms may vary during the day, in the course of changes in the concentrations of indoor pollutants. further, the prevalence of syndrome might differ with the specificity of criteria for the definitive diagnosis of a case. accordingly, there may be a shift in the frequency distribution of affected workers when the requirements were changed to one symptom, instead of two or more symptoms (ooi et al. 1998) . for measuring the concentration of indoor air pollutants, one may adopt area sampling by placing an environmental monitoring device in general building locations and placing a personal sampling device close to the nose of the person that better represents the inhaled dose of individuals. chapter 10 is dedicated to indoor environmental quality (ieq) assessment, concerning primary exposures. the exposure assessment based on area sampling and recording of symptoms of occupants from the vicinity of the samplers may indicate some dose-response relationships between exposures and symptoms. however, there are limitations to extrapolate the relation to other buildings, since the problem situations in buildings are unlikely to be similar. epidemiological evidence is abundant of the occurrence of sbs in real-world settings all over the world. within the limited scope, and the author's comprehension on the subject, only a selected number of cross-sectional studies that have been reported in the recent years are briefly summarized in table 3 .2. different research groups emphasized on the association of prevalence of sbs symptoms among the office workers with the organic floor dust concentration, the floor covering of the workplaces, the age of the building, and the kind of ventilation system in operation. the size of the office and the number of occupants in the office were critical, presumably because of likely rise of pollutants during the day. the shelf factor was identified as a risk factor for mucosal irritation, and the fleece factor, such as fleecy surfaces, paper, and cardboard was recognized for general symptoms in the office buildings (skov et al. 1990; mølhave 2011) . despite that carpets give a cozy atmosphere and an aesthetic acoustic environment in a building, carpet fibres and accumulated dust, especially the organic part of the dust, have been found to be associated with sbs, namely mucosal irritation. further details of work and building-related respiratory illnesses are elaborated elsewhere in the chapter. the us epa building assessment survey and evaluation (base) study (apte and erdmann 2003 ) is a landmark study covering 100 large office buildings and extensive measurements of both sbs symptoms and environmental monitoring. the occupant must have reported an occurrence of one sbs symptom, at least 1-3 days per week during the month, and resolution of the symptoms when the occupant moves away from work. analysis indicated dose-dependent associations in many of sbs symptoms with the delta change in indoor and outdoor co 2 concentrations. voc sources had a direct association with mucous membrane and lower respiratory irritation. the whitehall ii sbs study is a longitudinal health survey of uk office-based civil servants, commenced with 10308 males and females, exploring the significance of the physical and psychosocial work environment to the occurrence of sbs. analysing ten sbs symptoms among 4052 participants from 44 buildings, marmot et al. (2006) did not observe the significant relation between most aspects of the physical work environment and sbs symptom prevalence. the features of the psychosocial work environment, such as high job demands and low support, appear to be more determining in explaining differences in the prevalence of sbs symptoms, than those attributed to local aspects of the physical environment of office buildings. examined the occurrence of sbs related symptoms, chronic respiratory symptoms, and respiratory infections, using a questionnaire survey of 342 office workers in finland. a case definition of sbs was taken as symptoms of nasal (dryness or itching of nose, blocked or a runny nose, or sneezing), eye (dryness and irritation, watering, or redness), throat (dry irritative cough, sore throat, or hoarseness), skin (dryness, irritation, redness patches, itching, sore skin, or urticaria), and non-specific symptoms (headache and fatigue), which workers had more sbs symptoms in buildings that were humidified or air-conditioned. complaint: lethargy (57%), nasal congestion (47%), dry throat (46%), headache (46%). symptoms (mean building sickness index) were more in women than in men and were independently more frequent in clerical workers, secretaries than in technical and professional employees and managers skov et al. (1989) were more among females than males might have occurred during the past year, at least 1-3 days per week and mainly during workdays or work shifts. there were significant health effects due to office work exposures, adjusting confounders such as psychosocial factors at work. exposures to paper dust and carbonless paper that contains solvents and colour-forming chemicals increase the risk of a headache and fatigue, chronic breathlessness, and chronic bronchitis (a chronic cough and phlegm production). exposure to carbonless paper through its touching can cause sinus infections, middle ear infections, and increased risk of eye symptoms and diarrhoea. gupta et al. (2007) undertook a questionnaire-based investigation on the prevalence of the sbs at a multi-story centrally air-conditioned airport authority of india building in new delhi. qualitative analysis included the relationships between sbs score, co 2 and other parameters related to building and work environment. quantitative analysis included monitoring of pollutants, namely no x , so 2 , co, and suspended particulate matter. despite that the concentrations of pollutants complied with iaq standards were generally within limits, the prevalence of sbs (a headache-51%, lethargy-50%, and dryness in body mucous-33%) was higher in the third floor as compared to other floors and the control tower. the third floor and the control tower of the airport were affected by infiltration, mainly from entrance doors. hengpraprom et al. (2010) showed the influence of airborne fungi on allergic rhinitis among office occupants (49%) of a high-rise building in bangkok. allergic rhinitis was defined as having the symptoms of nasal congestion, an itchy nose, sneezing, and running nose without a cold in the past 12 months (teeratakulpisarn et al. 2000) . work-related allergic rhinitis was defined as (a) having the above symptoms with a cold at least twice in the past month; (b) expressing the manifestation at work or seeing it worsen at work; and (c) the frequency of manifestation occurred at least 1-3 days per week. indoor humidity was strongly correlated with airborne fungi concentrations. however, the fungal concentration was not associated with work-related allergic rhinitis. asthma and asthma-like symptoms among office workers, respiratory sensitization with exposure to hot or cold weather, the presence of visible mould, and carpeting resulted in a positive association with allergic rhinitis. syazwan et al. (2009) compared the data of sbs and iaq of 176 office workers in old and new buildings in kuala lumpur city. the investigators suggested that improvement in ventilation effectiveness and increase in ventilation rates per person may reflect on the reduction of indoor pollutants and also reduction in the prevalence of sbs in buildings. norhidayah et al. (2013) investigated associations between iaq parameters and sbs in three buildings in malaysia. the prevalence of sbs symptoms, having 1 to 3 symptoms per week, was similar in the buildings. the co concentration and fungal counts were not significantly different between the buildings. however, the observed co 2 concentration and climatic factors suggest that the predictors of sbs might be ventilation and accumulation of contaminants within the indoor environment. many abiotic agents from building materials and interiors like wall coverings, synthetic paints (a&b-pinene), thinners, glue, floor coatings of linoleum and pvc, solvents, such as formaldehyde, hairspray, perfume, photocopiers and printers, disinfectants and detergents (members of linear alkylbenzene sulphonates), and soap as cleaning agent (sodium or potassium salts mixed with fatty acids) add to air pollution to cause sbs symptoms (guo 2011; mcdonnell and burke 2011) . therefore, it may be reiterated from reviewing voluminous literature that no one single cause explains most sbs complaints, but instead assumes that multiple factors interact to manifest occupant complaints. the symptoms typically grow worse during the workday and disappear or diminish after the person leaves the building. women appeared to show a higher prevalence of sbs symptoms as compared to men in the same buildings. individual characteristics, such as education level, working conditions, job characteristics, and other psychosocial factors, can also influence sbs prevalence positively or negatively in men and women. the technical factors associated with the increased prevalence of sbs are the building factors, such as the age of the building, indoor dampness, presence of some photocopiers and humidifiers in the building (sundell 1996) . zweers et al. (1992) examined 7043 occupants (65% female) in 61 office buildings in the netherlands and noted that occurrence of sbs symptoms was related to air conditioning and humidification in buildings. females had more prevalence of sbs (e.g., skin/eye/ nasal symptoms) and complaints of indoor climate, such as temperature, air quality, lighting, and noise. carrying out of study on 4943 office workers (53% female) in sweden, stenberg and wall (1995) observed a higher prevalence of sbs among females (or = 3.4) than males. questionnaire survey and ergonomic data from the german proklima-project (brasche et al. 2001 ) also substantiated a significantly higher prevalence of sbs symptoms among women, as compared to men folks, both under the most favourable and most unfavourable job characteristics. undoubtedly, the physical and psychological disposition, on the one hand, and work-and job-related factors, on the other hand, are risk factors on the perception of the indoor environment and the pathogenesis of complaints. with a sample size of 368 office workers (*77% females) from 6 office buildings in the usa, reynolds et al. (2001) observed that the psychosocial factors were positively correlated with the incidences of sbs in females. however, the environmental factors were correlated with symptoms in males. by examining 877 occupants (50% female) in 12 office buildings in quebec, canada, donnini et al. (1997) observed no significant differences in thermal neutrality between males (23.5°c) and females (23.8°c). females expressed significantly higher thermal dissatisfaction (63% female vs. 37% male). nakano et al. (2002) examined 406 japanese office workers (37% females) and noted a significant difference in thermal neutrality, i.e., females (25.1°c) and males (22.9°c), while females reported a higher frequency of sbs symptoms, as compared to the male group. in a study on 935 office occupants (48% female), in 22 office buildings in australia, cena and de dear (1999) noted the votes of thermal unacceptability, and females complained of significantly higher thermal dissatisfaction than those of males. choi et al. (2010) had a similar observation by studying 402 office workers (*53% females) from 20 office buildings in the usa. runeson et al. (2003) investigated the prevalence and change of sbs symptoms in buildings with suspected indoor air problems about antonovsky's sense of coherence (soc), a psychological measure of life attitude. the study was conducted on a cohort of 194 workers from 19 swedish buildings with indoor environmental problems between 1988 and 1998. information on 16 sbs symptoms was gathered, as well as the soc measure was administered in a postal follow-up. after adjusting for age, gender, history of atopy, and ets, runeson et al. (2003) noted that sbs was more common in women, younger ones, and those with a history of atopy. a low soc was related to a higher prevalence of ocular, nasal, and throat symptoms, tiredness, and headache. also, subjects with a low soc developed more symptoms during the follow-up period. saijo et al. (2009) undertook postal self-administered questionnaire survey to 1,582 dwellings from 40 municipal, and 24 prefectural apartment buildings in the city of asahikawa, japan, and 480 questionnaires were finally analysed. from the questionnaire about moisture condensation and visible mould on window panes, walls, closets, bathrooms, the perception of mouldy odour, and water leakages, a building dampness index was defined as the sum of positive dampness indicators. sbs symptoms recorded for the preceding 3-month period were-fatigue, feeling heavy-headed, headache, nausea/dizziness, difficulty in concentrating, irritation of the eyes, running nose, dry throat, cough, dry or flushed facial skin, itching of the scalp, ears, and hands. the symptoms were significantly higher among females than males. the building dampness index was also significantly related to all sbs symptoms, as also noted by engvall et al. (2001) in the study covering 609 multi-family buildings (14,235 dwellings) in stockholm. saijo et al. (2009) noted allergic diseases as risk factors for sbs development, and therefore, the history of allergic diseases was taken as a confounder for sbs symptom analysis. the us niosh study in 80 office buildings also found a positive association between moisture and debris in the ventilation systems and lower respiratory tract symptoms (mendell et al. 2003) . kim et al. (2013) undertook a comprehensive literature survey, based on north american post-occupancy evaluation (poe) database (n = 38,257). the survey indicated that the satisfaction levels of female occupants were significantly lower than males on all fifteen ieq factors (such as thermal comfort, air quality, lighting, acoustics, office layout, furnishings, cleanliness, and maintenance). the results were consistent, even after controlling the potential confounders, such as age and work characteristics. chronic fatigue syndrome (cfs) manifests as a clinical entity characterized by prolonged severe and disabling fatigue (fukuda et al. 1994) . the syndrome usually occurs sporadically, but occasionally may appear as epidemics. typically, the syndrome follows a cyclical course, alternating between periods of illness and relatively good health. the onset of cfs has been related to a variety of psychological, environmental, and behavioral factors (pizzigallo et al. 1999) , and exposure to pesticides, organophosphates, solvents, and other chemicals (bell et al. 1998) . in tropical areas, many cfs-like cases follow an episode of gastroenteritis due to food toxins from ciguatoxic fish (pearn 1995) . ciguatera consists of a food-chain disease that starts with a reef-dwelling dinoflagellate, gambierdiscus toxicus (gillespie et al. 1986 ), which is heat-stable. individuals can be poisoned from eating fresh or frozen fish, or fish products. symptomatology of some outbreaks of sbs resembles cfs, associating with building characteristics, such as old buildings, inadequate ventilation, non-functioning windows, and inefficient hvac system (chester and levine 1997) . thousands of gulf war veterans, even 5 years after the operation desert storm in 1991, remained ill with vague symptoms that resemble cfs. these veterans were exposed to an array of hazards, such as extremes of climate, dust, and smoke from oil well fires, petroleum fuels and products, depleted uranium (used in artillery shells), chemical warfare agents, pesticides, infectious diseases, and pervasive psychological and physical stress. the veterans were administered with pyridostigmine bromide (as pre-treatment for potential poison gas exposure), anthrax and botulinum toxoid vaccines (landrigan 1997) . haley et al. (1997) identified six different syndromes among the war veterans, namely: syndrome 1 (impaired cognition)-reported by veterans wearing flea collars during the war than those who never wore them; syndrome 2 (confusion-ataxia)-reported by veterans involved in chemical exposure (e.g., pyridostigmine bromide); syndrome 3 (arthro-myo-neuropathy)-exposure to insecticides containing 75% deet (n,n-diethyl-m-toluamide); syndrome 4 (phobia-apraxia); syndrome 5 (fever-adenopathy); and syndrome 6 (weakness-incontinence). the case definition of cfs (fukuda et al. 1994) a. persistent or recurrent fatigue (lasting >6 months) 1. recent and or well-defined onset; 2. not secondary to excessive physical activity; 3. not resolved by rest; and 4. inducing reduction of previous levels of physical and mental activities. b. presence of more than four symptoms (for >6 months), not previous to fatigue onset: 1. impaired memory or concentration; 2. a sore throat; 3. tender cervical or axillary lymph nodes; 4. muscle pain; 5. multi-joint pain; 6. new headaches; 7. unrefreshing sleep; and 8. post-exertion malaise. if the combined number of elements of a and b present exceeds 4, a case of cfs would be considered. the multifactorial aetiology of sbs in office buildings is yet to understand clearly. evidence favours that the accumulated effects of building characteristics and ieq manifest in health outcomes, including sbs symptoms, allergy, asthma, and other respiratory illnesses. the health effects, in turn, cause adverse impacts on job satisfaction, work performance, productivity, and healthcare costs (fisk 2000) . the potential environmental stressors that might be responsible for causing sbs symptoms are briefly mentioned herewith. further details of iaq associated with different pollutants in the indoor environment are described in chap. 10. indoor air pollutants include oxides of nitrogen (no x ), co, co 2 , vocs, and particulates, which are emitted from building materials, office equipment, and as combustion by-products. the intrusion of pollutants from the outdoor air through leakages and ventilation systems is a critical component. the build-up of co 2 may be considered as a surrogate for many occupant-generated pollutants in the indoor built environment. review of studies of sbs symptoms in office buildings indicated increased indoor co 2 levels were associated with an increase in the prevalence of one or more sbs symptoms (seppänen et al. 1999) . findings from more mechanically ventilated and air-conditioned buildings indicated a significant association between an increase in co 2 and sbs symptoms, and total symptom scores. as mentioned earlier, the base dataset (1994-98) yielded significant dose-response relationships between the delta change in indoor and outdoor co 2 concentrations, and the sbs symptoms, such as a sore throat, nose/sinus irritation, mucous membrane symptoms, and tight chest (apte et al. 2000) . headaches represent the single most common symptom in almost all indoor environmental studies ). the current knowledge highlights different forms and mechanisms of a headache, such as a migraine, or a tension-type headache, or any plausible exposure to chemical toxicants, e.g., co or pesticide poisoning. whereas, many of the events do not provide a precise characterization of the office environment (schneider et al. 1999) , such headaches are no less significant given the productivity implications, and the potential for active intervention in the office environment. volatile organic compounds (vocs)-vocs are ubiquitous indoors, due to human activities, building product emissions, including floorings, linoleum, carpets, paints, surface coatings and furniture, and infiltration of the outdoor air. for new or renovated buildings, vocs are primarily emitted from building products. secondary emissions of vocs result from ageing of building products, by chemical decomposition (e.g., moisture build-up or inadequate maintenance) or physical damage due to heat and uv light (wolkoff 1999) . furniture coatings release nearly 150 vocs (aliphatic and aromatic aldehydes, aromatic hydrocarbons, ketones, esters, and glycols) (salthammer 1997) . office equipment and supplies, such as laser printing toners, emit vocs, ozone, formaldehyde, resin, and other particles. use of perfumes indoors may release vocs. indoor fungi are also a source for the production of vocs. many vocs are known toxic compound, with potential for carcinogenicity, mutagenicity, or teratogenicity. documented evidence strongly affirms that occurrence of sbs follows predictable dose-response relationships with increasing concentrations of mixtures of vocs. the vocs, such as o-xylene, styrene, d-limonene and other terpene compounds may readily react with ozone and no x entrained from outdoors and produce highly reactive compounds, including aldehydes and ultrafine particles, leading to sensory irritant symptoms (sarwar et al. 2002; sundell 2004 ). these effects have been observed in case of carpet emissions, latex paint off-gassing, and other office pollutants. it has been viewed that sbs may be related to the lost vocs, i.e., the difference in the concentration of vocs entering the room to that leaving the room. in california healthy buildings study, brinke et al. (1998) adopted an approach in developing voc metrics and identified relationships between sbs symptoms and clusters of vocs by its possible emission sources. the principal component analysis (pca) allowed to cluster vocs into a reduced set of principal component (pc) vectors and further estimated the association between sbs symptoms and the voc exposure metrics, using logistic regression analysis. a similar approach was taken by apte and daisey (1999) in exploring the causal associations between sbs and environmental stressors, using a subset of data from 28 office buildings of the us epa base study. four source-based pc vectors were derived that identify sources as photocopiers, automotive emissions, ets, and latex paints. regression analyses indicated significant associations between mucous membrane-related symptoms and the photocopier vector, after adjustment for age, gender, smoking status, the presence of carpeting, and thermal exposure. sore throat symptoms were associated with the paint vector. analysis of dataset of all 100 base buildings revealed 36 vocs, formaldehyde and acetaldehyde corresponded to 41 buildings, whereas 19 vocs were available in all buildings. the pca yielded ten pcs identified as the voc sources (apte and erdmann 2003) . seven components referred to as furniture coatings (pc1), paint (pc2), construction materials (pc3), printing materials and processes (pc4), carpet and undercarpet (pc5), parking garage (pc6), and cleaning products (pc7) met the criterion of having eigenvectors 1.0. oxidative stress and sbs-several studies suggest that a shallow concentration of vocs in indoor environment may cause sbs symptoms, but how such symptoms generate disability at such low levels remains unexplained. little is known about the likely oxidative stress that can attribute to the occurrence of sbs due to exposure risks of air pollutants or other factors of the environment. reactive oxygen species (ros) are components found in many of the air pollutants and can cause oxidative damage to lipids, proteins, and nucleic acids. urinary 8-hydroxydeoxyguanosine (8-ohdg) is a known biological marker of oxidative stress on dna. accumulation of ets, vocs, formaldehyde in the building due to insufficient ventilation can result in the rise of urinary 8-ohdg levels among occupants (calderon-garciduenas et al. 1999) . lu et al. (2007) gathered data from self-reported questionnaires and analysis of on-site air pollutants and urinary 8-ohdg of 389 employees in 87 government offices of eight high-rise buildings in taipei city. the urinary 8-ohdg was significantly associated with vocs and co 2 levels in offices, and the 8-ohdg level were significantly higher among the employees with sbs symptoms than in those without such complaints. a positive dose-response effect between 8-ohdg levels and the number of symptoms was suggestive that the urinary 8-ohdg as a viable non-invasive marker can be taken as a predictor for sbs. office exposures and work stress-office work-related exposure to paper dust emanated from carbonless copy paper and fumes from photocopiers and printers are health concerns, including respiratory illness among office occupants. observations of substantiated that the exposure to paper dust and carbonless papers carries potential risks of chronic respiratory symptoms, respiratory infections, and other health concerns in an office environment. the stress of work, including extended hours of work, reflects as different work stressors and consequent health impacts among occupants in modern office buildings. there are multiple aspects of work, including physiological, motivation, technical, psychosocial, environmental, perceptual as well as organizational that attribute to work stress. as mentioned earlier, outbreaks of psychogenic illness (sbs) are perhaps a symptom of underlying stress at work and workplace (selvamurthy and ray 1996) . mizoue et al. (2001) carried out a cross-sectional survey of 1281 municipal employees from different buildings in a japanese city. findings indicated that both ets exposure and overtime work contributed to the development of sbs. working overtime for 30 or more hours per month was also associated with sbs symptoms, but the occurrence of sbs reduced by 1/5th after adjustment for variables associated with overtime work and about an-half after further adjustment for perceived work overload. runeson et al. (2006) undertook a postal questionnaire survey as regard to sbs on a sample of 1000 subjects (20-65 years of age), including the three-dimensional model of demand-control-support, regarding social support in actual work situations. results indicated that males and females perceived psychosocial work conditions differently and reacted differently to job stressors. that is, the psychosocial work environment was as important as gender and atopy as a predictor of sbs symptoms. nag and nag (2004) examined the work stresses of women vdt-cum-telephone operators in selected office buildings (telephone exchanges) and observed that the behavioural response to the work stressors, and health and well-being dimensions did vary with the work schedules. the pca analysis of the ergonomics checkpoints yielded five aspects of work, as organizational (pc1-describing job design needs, workplace interventions, and constraints of vdt workstations), environmental (pc2-covering illumination-, climate-, and noise-related hazards), mechanistic (pc3-referring to job specialization, pace of work, information handling), perceptual and motor (pc4-describing visual and auditory displays and controls), and motivational (pc5-referring to personal job characteristics and core dimensions). the loading of the work stressors explained in pc1 to pc3 appeared autonomous, irrespective of the shift schedules at which the women were engaged. the operators in the rotating shift had higher sensitivity to the stressors related to pc4. the day workers responded greater to the stressors related to the core job dimensions that reflect growth needs (pc5). the sleep disturbance, flexibility to sleeping habits, and personality dimension (neuroticism) were negatively correlated with pc1. the digestive problems, social and domestic disruption, and languidity dimensions were positively correlated to pc4 and pc5. the operators in rotating shift had increased demand in the perceptual and motor, and the motivational aspects of work, and thus causing greater negative influence on physical health symptoms, and social and domestic disruption. the job design interventions tailoring to delay the morning shift and adjust the shift length based on the work and climatic load (that is, reduce work hours in the evening shift to avoid peak workload, and extend hours of day work during the hot summer months) might alleviate work stress and enhance health and well-being. manifestations of work-related stress call for organizational analysis and job design interventions in structuring the workplace. thermal discomfort-exceedance beyond the thermal comfort range is associated with increased symptoms, such as a headache, fatigue, and mucosal irritation. besides the relative effectiveness of ventilation systems, uses of increasing numbers of electronic devices in the offices add to the heat loads in buildings. in real-life work environment, a significant proportion of the population remains in uncomfortable situations and shows thermal discomfort. clothing habits in different seasons may also contribute to the causes of thermal discomfort in a hotter environment. humidification-a sensation of air dryness and irritative symptoms from eyes, skin, and upper airways are common factors in the sbs (stenberg et al. 1993) . by examining 104 employees from four geriatric hospital units in southern sweden, nordstrom et al. (1994) evaluated the effect of steam air humidification on sbs and perceived air quality during the heating season. air humidification was raised to 40-45% rh in two units during a four-month period, whereas the other two units were maintained at 25-35% rh. after four months of air humidification during the heating season, 24% of the employees reported a weekly sensation of dryness in humidified units, compared with 73% in controls, indicating that air humidification during the heating season in colder climates can decrease symptoms of sbs and perception of dry air. in a tropical environment, rh remains at a much higher level even in an indoor office environment; therefore, incidences of sbs in such situations may be attributed to factors other than air dryness or humidification. odours-odours associated with moisture and bioaerosol exposure are familiar in buildings and best considered in the context of disease with physiological indicators. the odour characteristics are the basis to investigate the possible adverse effects of moulds on human health, in what is often referred to as sbs. from mouldy buildings, the fungal vocs (such as 1-octen-3-ol and 3-octanone) can produce a range of musty odour (morey et al. 1997) , as listed (table 3 .3). odour recognition thresholds are usually several orders of magnitude below the irritant thresholds (cometto-muniz and cain 1996) . fanger (1988) proposed an unit of pollution, olf (for olfactory) for arbitrarily defining the emission rate of air pollutants from a standard person (white male, 18-30 years of age, showering 0.7 time/day, wear no perfumes, and energy expenditure equivalent of one met for person sitting at rest). the number of olfs is indicated on the initial perception of the odour, referring to discomfort from irritation and annoyance from odour, and overall acceptability. this method was deployed in a project assessing air quality in 20 offices/assembly halls in copenhagen, and 54 external judges adjudged the air quality in unoccupied and occupied, and with or without ventilating systems in buildings. about 42% of the perceived defects in air quality was due to ventilation systems, 38% was due to combined occupant activities and occupants themselves, and 20% due to building materials. the stated method has limitations of efficacy since the raters assess the pollution level in a site within minutes of entering the site. the majority of the occupants may not be able to rate odours consistently, and also the odour annoyance is generally perceived most severe early on first exposure and recedes over time. the building professionals may be amazed at recognizing how the proliferation of fungi in buildings damages the building materials and affects the health of occupants, and more importantly to the causation of sbs and building-associated illness. inadequacy in the ventilation system, moisture controls, and dirt management thrive microbial proliferation in the hvac systems and office carpeting. water incursion into the building envelope is a common cause of moisture build-up and fungal growth. there could be visible mould growth on surfaces, the wall behind wallpaper or under the floor covering, suspended ceiling panels, localized damp areas between a wall and a large item of furniture, and in cavity wall spaces (lugauskas and krikstaponis 2004) . through the routes of inhalation or ingestion, propagules of fungi and bacteria may elicit symptoms of illness, like bronchial irritation and allergy (britton 2003; beezhold et al. 2008 ). broadly, bioaerosol contains fungal and bacterial cells and cellular fragments, and by-products of microbial metabolism build-up in the buildings. particles that range in size from 1 to 5 µm remain suspended in the air, whereas larger particles are deposited on the surfaces (martinez et al. 2004; horner et al. 2004 ). it is not within the present scope to elaborate on the classification of fungi, which are grouped by phylum (division), class, order, family, genus, and species, in the order. khan and karuppayil (2012) indicated that *600 species of fungi are in contact with humans and *50 of them are frequently described in epidemiologic studies on indoor environments. in the present context, several fungal species have been referred to by the researchers about an infestation in building materials and contamination of the indoor environment. some of the species are listed in table 3 .4. wood, wooden building materials, and kiln dried wood surfaces are vulnerable to fungal attack, with infestation by cladosporium and penicillium (penicillium brevicompactum and penicillium expansum) (sailer et al. 2010) . acylated wooden furniture, plywood, and polyurethanes used in wood composites for insulation are found to be susceptible to infestation by aspergillus, trichoderma harzianum, paecilomyces variotii, and penicillium species (yazicioglu et al. 2004; doherty et al. 2011) . prefabricated gypsum board that is used as inner wall materials in buildings favours the growth of stachybotrys chartarum. sterflinger et al. (2013) examined five different indoor insulation materials, i.e., bloated perlite plaster, bloated perlite board, loam and reed, soft wooden board, and sprayed cellulose, for their biosusceptibility. a. versicolor, alternaria, cladosporium, and penicillium species grow in fibreglass insulation and ceiling tiles (erkara et al. 2008) . galvanized steel accumulated with dust or lubricant oil residues allows the growth of fungi (rene et al. 2010; yau and ng 2011) . dampness can cause chemical degradation of polyvinyl chloride (pvc) floor coverings, including formation and emission of 2-ethyl-1-hexanol, 1-butanol (tuomainen et al. 2004) . acrylic painted surfaces are attacked by alternaria, cladosporium, and aspergillus (shirakawa et al. 2011) , and also aureobasidium pullulans can deteriorate the paints (lugauskas et al. 2003) . moisture damage of building frames was characterized by meklin et al. (2003) , studying 17 wooden and 15 concrete or brick school buildings. aspergillus versicolor, stachybotrys, and acremonium were detected in samples from moisture-damaged buildings. observations indicate that moisture damage of the building did not alter the fungal concentrations in wooden school buildings, whereas, in concrete schools, the effect of moisture damage was seen with higher fungal concentrations. the presence of oidiodendron and elevated concentrations of cladosporium and actinobacteria were associated with moisture damage in concrete schools. most fungi are mesophilic, and the optimum temperature for fungal sporulation (number of conidiophores and conidia formed in each conidiophore) is within the range of 20-25°c (burge 2006) . incidently this temperature range corresponds to the human comfort indoors, at which fungi flourish in working environments (burge 2006) . the relative humidity and air currents influence the release of conidia. fungal growth is favoured at a water activity (a w ) of 0.95-0.99, which is a ratio of the partial vapour pressure of water in a substance to the standard state partial vapour pressure of water. ph range of 5-6.5 in building materials allows better growth of most of the fungi (vacher et al. 2010; hoang et al. 2010) . the thermophilic and xerophilic (dry tolerant) fungi are found more in hot-dry climates, than in cooler wetter environments. in tropical and subtropical places, thermophilic and xerophilic fungi tend to be abundant in outdoors with optimal heat and moisture. however, an array of factors are necessary for optimal growth of different kinds of fungi. cladosporium, penicillium, and aspergillus produce high numbers of small and light spores (<10 µm in size). penicillium and aspergillus can grow in substrates with water activity lower than 0.80. the smaller particles can penetrate into the alveolar region when inhaled, evade phagocytosis by macrophages, and transport through systemic circulation (reponen et al. 2007; seo et al. 2009 ), whereas the larger spores and other fragments get deposited in the nasopharynx. kildeso et al. (2003) studied the release of particles from indoor fungi growing in wetted wallpapered gypsum boards, for 46 weeks. when penicillium chrysogenum were subjected to air currents, only spores were released from the colonies, but with aspergillus versicolor, both spores, and fragments were released. with trichoderma harzianum, particles released are-groups of spores (5-6 µm), individual spores (2-3 µm) and fragments (0.7-1 µm). seo et al. (2009) reported the release of fragments and spores from aspergillus versicolor and stachybotrys chartarum growing on the surface of ceiling tiles, wallpapered gypsum board, and culture medium. the studies are suggestive that long-term mould damage in buildings may increase the contribution of fungal fragments to the overall mould exposure. in non-culture-based methods, fungal spores in samples and its morphological identification are determined by light microscopy. components or metabolites of fungi can also be used to quantitate fungi population. specific assays can detect extracellular polysaccharides for partial identification of fungal genera in indoor environments (jovanovic et al. 2004) . polyclonal antibody-based assays detect a broad range of fungal antigens but cannot detect the spores (mitchell et al. 2007 ). molecular methods for quantitation of fungi include the use of genus-/ species-specific probes, polymerase chain reaction (pcr)-based methods, restriction endonuclease analysis, and karyotyping. mitochondrial dna can be used for restriction enzyme analysis and dna fingerprinting for fungal identification. the typical approach for fungal detection in a building utilizes culture and microscopy. different surface and air sampling methods are used for detection and counting of fungi, fungal spores and fragments in ambient air and settled dust, pieces of wallboard, duct linings, carpets (asadi et al. 2011; reponen 2011) . surface sampling allows determining the degree and the types of microbial growth on environmental surfaces (cabral 2010) . adhesive tape sampling method examines the fungi and the hyphal fragments in the specimens using a compound microscope (aydogdu et al. 2010) . in air sampling of fungi, the principles of impaction, impingement, and air filtration have been used. in the impactor method, the airstream is passed through progressively narrower slits into a culture medium and microscopic glass slides covered with an adhesive substance or tape strip is used to collect the sample, and counted by optical microscopy (zhen et al. 2009 ). andersen six-stage impactor is used for collection of particles on culture medium. in andersen sampler, in a petri dish could grow 400 colonies. fast-growing colonies may grow above the slow growing and hinder in counting colonies (stetzenbach et al. 2004 ). the dichloran-glycerol-18 agar (dg-18) culture medium with fungistatic properties prevents the growth of the fast-growing fungi (horner et al. 2004) . liquid impingers collect the samples into the fluid, and the micro-organisms are retained in the liquid until they are cultivated, or evaluated by techniques like biochemical or immunoassays (jo 2011) . shipe sampler, agt-30 glass impinger, midget, multi-stage, and micro impingers are common impinger devices (gralton et al. 2011) . air filtration is used to collect the samples of indoor air in volume. in this method after sampling, the filters are agitated or sonicated in a solution (bazaka et al. 2011) . readers may refer to standard manuals for analytical details. however, the choice of air or surface sampling techniques depends on the purpose of measurement (jung et al. 2011) . air sampling by impingement has some advantages over impaction on solid surfaces; for example, if the concentration of microbes in the atmosphere is too high, the liquid could be diluted before adding to the culture medium. collection of the cells in a liquid avoids desiccation resulting from impaction on solid surfaces (stetzenbach et al. 2004 ). impaction directly onto agar plates may maximize survival of culturable organisms. in addition to impaction and impingement, other methods like filtration by aspiration and sedimentation sampling have been used. in filtration, three types of filter media are used, such as porous fibrous filters with overlapping fibres, porous gel membrane filters, and capillary pore filters. filter materials include glass fibre, mixed cellulose esters, polytetrafluoroethylene, polyvinyl chloride, gelatin, and polycarbonate (martinez et al. 2004) . membrane filters can be placed directly on the surface of culture medium or washed with a liquid, and this added to culture medium. specific filters (namely gelatin) are dissolvable in warm liquids, and the resulting suspension can be plated on agarized medium. that is, filtration devices are adaptable for air sampling of wall cavities or roof spaces to pinpoint foci of contamination. sedimentary sampling (e.g., the gravity slide and the settle plate techniques) is the simplest of all methods. in the gravity slide method, microscopic glass slides, smeared with an adhesive substance, are exposed during a specified period. in the settle plate method, open petri dishes with appropriate culture medium are left open for a given time, depending on the air contamination load. after a certain period of incubation, colonies are counted. an index of microbial air (ima) contamination was proposed; that is, a standard petri dish (dia: 9 cm) containing plate count medium is left open to the air, for 1 h, 1 m from the floor and at least 1 m away from walls. after 48 h incubation at 36°c, the colonies are counted, and the number of colonies is the ima. five ima classes were defined, as 0-5 very good; 6-25 good; 26-50 fair; 51-75 poor; and >76 very poor. the conventional sampling apparatus gives values for fungal particles present in the atmosphere, at the time of sampling; however, other spores and fragments can be attached to the colonies and be released later. the fungal spore source strength determines the maximum amount of fungal particles that can be released from contaminated materials by the action of air currents. from the counting of released particles, the maximum fungal load for a given indoor environment can be calculated (gorny 2004; sivasubramani et al. 2004a, b) . damp concrete floor and visible mould in buildings are constant sources of risk of respiratory tract symptoms, infections, and exacerbation of asthma (lanier et al. 2010; araki et al. 2010) . mucociliary clearance represents the first strategy for removal of fungi/mould from the human respiratory tract. hypersensitivity syndromes, such as hypersensitivity pneumonitis (both acute and chronic) or extrinsic allergic alveolitis, can occur in individuals exposed to conidia, hyphae, or fungal fragments, mycotoxin (trichothecene) (eduard 2009; franks and galvin 2010) . hypersensitivity pneumonitis is generally associated with high igg antibodies concentrations in response to alveolar or bronchiolar inflammation caused by fungi or other allergens. the patients may present neutrophilic inflammation with increased production of tnfa and il-6, and symptoms such as fever, chilliness, dry cough, dyspnoea, changes in nodular bilateral x-ray, fatigue, and headache (eduard 2009 ). aspergillus spp. develops allergic bronchopulmonary aspergillosis and pulmonary aspergilloma (kawel et al. 2011) . undoubtedly, exposure to fungi in indoor environments elicits an ige-mediated hypersensitivity response that precipitates into rhinitis and other forms of the allergic syndromes, such as upper airway irritation, eye irritation, and sinusitis (yike 2011) . during this process, antigen-specific ige is produced that attaches to receptors on mast cells which are concentrated on the gastric and respiratory mucosa. the principal fungal allergens, such as (1-3)-b-d glucan or water-soluble glycoproteins, may become airborne and when its concentration exceeds 4 ng/m 3 , susceptible individuals may show non-specific inflammatory airway reactions and that affect the immune system (kalyoncu 2010; tercelj et al. 2011) . (1-3)-b-d glucan, a cell wall component of filamentous fungi, is readily detected in moisturedamaged building materials, dust samples, and textile floor coverings (reponen et al. 2010; rylander 2010) . ergosterol is found in the cell membranes of fungi, but its content varies with the fungal species (heinrich 2011) . besides, people who inhabit mouldy buildings (presence of s. chartarum and aspergillus spp. in air samples) were reported with cognitive defects and difficulties in concentration (drappatz et al. 2007 ). in mouldy buildings, occupants complain of dermatological symptoms, gastrointestinal problems, reproductive effects, rheumatologic, and other immune diseases. breda et al. (2010) recorded that the rheumatic diseases (inflammation and stiffness in muscles, joints, or fibrous tissues) are exacerbated by indoor environmental conditions, including dampness and fungi infestation. rheumatoid arthritis, ankylosing spondylitis, sjogren's syndrome, and psoriatic arthritis have been observed among occupants in water-damaged buildings with mould growth (muise et al. 2010 ). various fungi produce mycotoxins that are low molecular weight and non-volatile compounds, and potentially carcinogenic, teratogenic, and mutagenic. mycotoxins can also be isolated from fungi-contaminated building materials and house dust (engelhart et al. 2002) . the production of mycotoxins by indoor fungi growing in building materials is usually lower than that cultivated in vitro in building materials (e.g., gypsum board, chipboard) (nielsen 2003; nieminen et al. 2002) . aflatoxins, trichothecenes, and ochratoxins are common mycotoxins in indoor environments (zain 2011; halios and helmis 2010) . other toxins (e.g., t-2, ht-2, deoxynivalenol (don), nivalenol, diacetoxyscirpenol, satratoxins, trichoverrols, verrucarol, verrucarins, trichoverrins) have been described in this group. trichothecenes are a family of mycotoxins produced by species such as cladosporium, aspergillus, penicillium, fusarium, trichoderma, myrothecium, trichothecium, stachybotrys, cephalosporium, giberella, memnoniella (tuomi et al. 2000) . a possible causal relationship exists between mycotoxin exposure and building related illnesses (sen and asan 2009; di giulio et al. 2010) . the effects of trichothecenes exposure in humans include internal burning, vomiting, and diarrhoea with blood, cutaneous necrosis, and internal haemorrhages. evidence gathered that exposure to higher concentrations of penicillium and aspergillus in the indoor environment could induce health problems and sbs symptoms. severe asthma and acute exacerbations of asthma have been associated with alternaria sensitivity and increased airborne concentrations of alternaria spores (salo et al. 2005) . vance and weissfeld (2007) warned that the presence of s. chartarum indoors is a concern since its growth requires water saturation of cellulose-based materials such as paper, cardboard, wood, and gypsum board (menetrez and foarde 2004; gottschalk et al. 2006) . it is likely that plumbing and roof leaks provide the needed moisture for the fungus to grow. the small size, ellipsoid shape stachybotrys spores can reach the lower respiratory tract (murtoniemi et al. 2003) . the causal relationship between s. chartarum and sbs has been debated, with the view that health effects may be due to the presence of other pollutants, like vocs (mvocs), endotoxins, respirable dust, and other compounds in the indoor environment (bloom et al. 2007 ). don, a trichothecene mycotoxin mainly produced by fusarium molds, like other mycotoxins, is an immunomodulator that can enhance or suppress the immune system depending upon the dose and duration of exposure (lee et al. 1999; zhou et al. 1999 ). the t2-toxin, which is produced by species of fusarium and diacetoxyscirpenol, has been shown to modulate apoptosis in human promyelocytic leukaemia cells (yoshino et al. 1996; yang et al. 2000) . several types of research explore the potential association of sbs with particular microbes, biotoxins, or other complex exposure mixture components observed in the water-damaged buildings . trichothecene mycotoxins produced by stachybotrys, satratoxin, and roridin have been identified in serum using an elisa assay. generally viewed that the mixture components, including fungi, bacteria, mycotoxins, endotoxins, and lipopolysaccharides, interact synergistically, through the feedback control of pro-inflammatory cytokine production and induce sbs (huttunen et al. 2004 ). the onset of sbs is typically observed following chronic exposure in water-damaged buildings, extending for many months. needless to mention that health risk assessment for sbs has many uncertainties, such as the extent of toxin accumulation in tissues, interspecies differences in susceptibility, and threshold shifts of the repair mechanisms during chronic exposure (shoemaker and house 2005; . there is an evident need to make the focus on innovative and effective therapeutic interventions (e.g., cholestyramine (csm) therapy) to remove biotoxins from the body, caused by toxic mould exposure. there are nearly 250 vocs of fungal origin that often referred to as microbial vocs (mvocs). these mvocs produce mixtures of simple hydrocarbons, heterocycles, aldehydes, ketones, alcohols, phenols, thioalcohols, thioesters, and their derivatives, including benzene derivatives, and cyclohexanes (korpi et al. 2009; ortiz-castro et al. 2009 ). currently, gas chromatography-mass spectrometry (gc-ms) is the primary method for the detection of mvocs (matysik et al. 2009 ). the electronic nose (e-nose) is an alternative non-invasive technique to detect essential fungi and mvocs. the instrument combines an array of electronic chemical sensors, a pattern recognition processing unit, and a reference library for recognizing odours baietto 2009, 2011) . molhave (2008) emphasized the exposure to mvocs as the aetiological agents associated with sbs, including lethargy, headache, as well as irritation of the mucous membranes. however, the types and concentrations of mvocs in mould-infested buildings vary with the ventilation rate indoors, moisture level, the composition of mould population, and other parameters (schleibinger et al. 2008) . for example, penicillium, aspergillus, and stachybotrys are vocs as well as mycotoxin producers (matysik et al. 2008) . mvocs are produced by the cells and released to the indoor environment, whereas mycotoxins are present inside the cells and fragments (reponen et al. 2007 ). in healthy individuals, the fungal spores and fragments are destroyed by cells of the immune system, but a small number of mycotoxins can still enter in the systemic circulation with possible chronic or sub-chronic toxic effects (straus 2009 ). the fungal release of vocs is sometimes referred to like products of secondary metabolism, and these compounds remain reasonably stable in a range of growth media and conditions (moularat et al. 2011) . moularat et al. (2008a, b) described the assay of vocs produced by aspergillus niger, a. versicolor, and penicillium brevicompactum and identified nineteen compounds resulting from fungal metabolism. mvocs also cause indirect metabolic effects. fungal colonization in urea formaldehyde insulation materials results in the cleavage of urea from the polymer releasing formaldehyde (shinoj et al. 2011; asan et al. 2010) . like other sources of vocs, the exposure of mvocs even at deficient concentrations has been linked to symptoms such as a headache, nasal irritation, dizziness, fatigue, and nausea, independent of exposure to other allergenic fragments and toxins (weinhold 2007; burton et al. 2008 ). researchers have attempted to distinguish between the sbs and building-associated illness tsai et al. 2012) . as discussed, the sbs represents multiple non-specific symptoms among the building occupants, but its occurrence is correlated with some factors, such as the type of ventilation and the condensation or the leakage of water in building indoors. on the other hand, building-associated illness consists of different diseases with known aetiologies (craig and mindell 2011) ; for example, allergic alveolitis, with specific aetiologies, is usually linked to ventilation-based, wet microbial breeding places, such as humidifiers, air washers, heater/cooler units. in multifactorial causal situations, however, several components attribute to creating complex environmental conditions. ventilation inadequacy in indoor spaces may aggravate ieq, resulting in health symptoms, sbs or br and other communicable respiratory illnesses, such as allergy and asthma symptoms, respiratory infections and cardiovascular diseases. the literature emphasizes association of building characteristics, iaq, and inhaling of bioaerosol with the prevalence of respiratory illnesses among building occupants. for easy understanding by the professionals from other building sciences, some common forms of respiratory illnesses are briefly described herewith. details of the respiratory illnesses are found in several online sources, e.g., http://www.mayoclinic.org/ diseases-conditions/copd/symptoms-causes/dxc-20204886. increased prevalence of asthma has long been known as the impacts of outdoor and indoor exposures to air pollutants, and lifestyle habits, as well (eder et al. 2006 ). asthma can be adult onset or occupational in origin. from a clinical point of view, bronchial asthma is a well-known lung condition, defined as a chronic inflammatory disease, due to the contraction of the bronchial muscles, increased mucous production or decreased clearance, and muscle tightening, causing variable airflow obstruction (fig. 3.1) . coughing, wheezing, chest tightness, shortness and shallow breathing, anxiety, and tachycardia are the common signs and symptoms of asthma. the inflammation causes airway hyper-responsiveness and is the reason for the appearance of variable and reversible airflow obstruction. occupational asthma is caused by breathing substances present at workplaces, such as chemical fumes, gases or dust which are irritating or sensitizing. exposure to these substances develops an immune response either to respiratory irritants (gas, fume, or vapour), usually of low molecular mass at high concentration, referred to as irritant-induced occupational asthma, or to sensitizing agents (e.g., high molecular mass-glycoproteins of biological origin), referred to as sensitizer-induced occupational asthma. these exposures are characteristically associated with symptoms at work with relief on weekends and holidays. with early diagnosis and treatment, occupational asthma may be reversible. table 3 .5 includes the most common asthmagen agents. irritant-induced acute occupational asthma (also termed as reactive airway dysfunction syndrome-rads) may occur following a short-duration single high-level irritant exposure to substances, such as chlorine or oxides of nitrogen, or multiple exposures to gas, smoke, fume, or vapour characterized by irritant capacity. respiratory symptoms (a cough, wheezing, chest tightness, and dyspnea) may persist for 3 months. low-molecular mass agents probably become antigenic after conjugation with a body protein (e.g., serum albumin), and its response clinically manifest as direct epithelial cell injury. the procedure to diagnose rads includes analysis of occupational history, inventory of exposures in the workplace, pulmonary function tests (pft), serial peak expiratory flow measurement on work days and days off, histamine or methacholine challenge, and immunological tests, such as specific ige and skin prick, epicutaneous tests (fishwick et al. 2008; tarlo et al. 2008 ). the pft may show evidence of airway obstruction (fev 1 /fvc ratio less than 0.7), although the absence of airway obstruction does not exclude a diagnosis of the disease. for irritant-induced asthma due to indoor environmental exposures, specific bronchial challenges may not diagnose; also the peak expiratory flow (pef) is not diagnostically specific. however, conventional approach of observing an elevated diurnal variation in pef might suggest the presence of asthma. bronchodilator response may be seen in individuals with acute irritant-induced asthma. a chest radiograph is usually normal, although it may show no specific signs associated with coexisting respiratory infection. a bronchial biopsy may indicate possible inflammation with lymphocytes and plasma cells, as a manifestation of epithelial cell injury. sensitizer-induced occupational asthma is characterized by a latency period, which may last from several weeks to months or years, between first occupational exposure to a respiratory sensitizer and the development of immunologically isocyanates (e.g., toluene diisocyanate), acid anhydrides (e.g., phthalic anhydride), amines (e.g., ethylenediamine), fluxes (e.g., colophony), metals (e.g., platinum salts), drugs (e.g., penicillin), plastics (e.g., acrylates), wood dust (e.g., western red cedar) auto-spray painting, varnishing, metal grinding, platinum refineries, pharmaceutical manufacturing, sawmill work, woodworking, other chemicals biocides (e.g., glutaraldehyde), polyvinyl chloride fumes, organophosphate insecticides janitorial work, meat packaging mediated symptoms. once the subject is sensitized, asthma attacks are provoked even with exposure to a shallow concentration of the sensitizing agent. diagnosis is typically achieved from the evidence of reversible variable airway limitations, along with asthmatic trends between periods of work and rest. pft may become normal rapidly after the cessation of the exposure. a serial pef (about four recordings a day) over three weeks has high specificity and sensitivity in making the diagnosis of occupational asthma. serum-specific ige may assist in making a diagnosis, due to its likely presence in persons exposed to allergens with high molecular weight and some chemical agents. skin prick tests may also be positive for the workplace allergen. increased bronchial reactivity to challenge with the agents, such as histamine, methacholine, is evidence of sensitizer-induced occupational asthma, and this may be carried out sequentially over time. allergens that cause occupational asthma can also cause allergic rhinitis (nasal symptoms) that may precede the onset of occupational asthma symptoms or may commence at the same time as asthma symptoms. simoni et al. (2010) showed that upper respiratory tract symptoms were more prevalent in poorly ventilated classrooms. that is, with co 2 levels exceeding 1000 ppm had a higher risk of a dry cough and rhinitis. increased ventilation rate (>0.7 l h −1 ) was associated with a decreased prevalence of allergic symptoms among college students living in dorms in china (sun et al. 2011a ). the occurrence of wheeze decreased with the increase in ventilation rates when co 2 concentration reduced from 1359 to 915 ppm. the prevention of occupational asthma requires environmental intervention and medical management. the primary prevention of exposure, such as improved ventilation and dust control for elimination of the formation of dust, and localized aspiration, is the direct approach towards reducing the incidences of the disease. avoiding cold temperature and air dryness, wearing ppe, and in some cases, adopting prophylactic pharmacological treatments can mitigate asthma symptoms. population screening for early detection is the secondary prevention. the term asthma-like (suspected asthma) is indicative that all asthma-like symptoms are not associated with asthma. these include chronic obstructive pulmonary disease, chronic bronchitis, chronic cough, hyperventilation, mechanical obstruction of the airways, congestive heart failure, pulmonary embolism, gastro-oesophageal reflux, multiple chemical sensitivity/idiopathic environmental illness, sbs, sjogren's syndrome, vocal cord dysfunction. the chronic obstructive pulmonary disease is characterized by a slowly progressive reduction of pulmonary ventilation due to a combination of emphysema and bronchiolitis with obstruction of the small airways. ets is a critical aetiological factor. chronic cough has different aetiologies-a cough at night or associated with physical exercise may be indications of asthma. the asthma tests such as reversibility to a bronchodilator and increased levels of exhaled nitric oxide should be positive (chatkin et al. 1999) . hyperventilation syndrome is indicated by symptoms induced by physiologically inappropriate hyperventilation or voluntary hyperventilation. shortness of breath, accelerated/deepened breathing, and feeling of inability to breathe deeply are asthma-like. symptoms reproduced by a hyperventilation test and a slow recovery of co 2 in blood or expired air are the two criteria for establishing the diagnosis (ringsberg and akerlind 1999) . rads is an illness with asthma-like symptoms that may occur as the direct consequence of excessive toxic inhalation exposure. the bronchial histological changes show an increase in inflammatory cells. however, eosinophils and mast cells do not dominate. multiple chemical sensitivity (also named as idiopathic environmental intolerance) is a disease caused due to some low dose of exposure to chemical toxicants, manifesting diverse symptoms (e.g., headache, weakness, memory problems, inability to concentrate, throat soreness, abdominal pain, and discomfort). one may suffer from nasal congestion and asthma-like symptoms such as cough and chest tightness. as elaborated earlier, sbs is a complex disease caused primarily due to building characteristics of the indoor environment, including inadequacies in air-handling systems. sjogren's syndrome is a systemic rheumatic disease. vocal cord dysfunction is characterized by episodic or acute attacks of breathing troubles similar to attacks of asthma. in asthma-like disorder, treatment compliance with conventional therapy is low (schmier and leidy 1998; chan et al. 1998) . medication with steroids are the most potent drugs in the treatment of asthma. sensory hyper-reactivity (earlier referred to as functional breathing disorder) manifests common symptoms, such as heavy breathing, cough, and increased secretion, difficulty in getting air, and chest pressure (lowhagen et al. 1997) . the symptoms are often induced by trigger factors, such as allergens, chemical irritants, ets and strong scents, cold air, viral infections, physical exercise (millqvist and lowhagen 1998) . symptoms, such as difficulty in breathing and breathlessness, which indicate asthma, may also be indicators of sensory hyper-reactivity. the diagnosis of sensory hyper-reactivity is a clinical challenge; pft is sometimes difficult to obtain due to inability to perform an adequate forced expiration, giving a false indication of bronchoconstriction (ringsberg et al. 1997) . asthma-like symptoms can be provoked by a sensory nerve-mediated disturbance of the respiratory pattern; for example, a capsaicin inhalation test provokes these kinds of symptoms . extrinsic allergic alveolitis (eaa, also termed as hypersensitivity pneumonitis) is type iii and iv hypersensitivity reaction of the alveolar and bronchiolar tissue and interstitium of the lungs, in response to inhaled antigens. a range of environmental allergens, including fungi, bacteria, plant proteins, and other reactive chemicals, may be related to the occurrence of eaa (simon-nobbe et al. 2008; robertson et al. 2007 ). farmer's lung caused by mouldy forage is a well-studied form of eaa. microbiological contamination of air conditioners or humidifiers has been reported to cause of eaa in an office environment. the eaa may manifest as an acute, sub-acute, and chronic form. the former form is more natural to recognize, with symptoms, like a cough, chest tightness, febrile chills, and flu-like illness appear 3-8 h after exposure, fades away gradually over a few hours, and may reappear on subsequent exposure. the sub-acute form presents as progressive shortness of breath, dry cough, and weight loss. the chronic form may show the slow development of interstitial fibrosis. diagnosing eaa requires identifying the source of exposure to contaminants, recording exposure history, including worksite visit and environmental measurements. in physical examination, crackles in the lower fields of the lungs may be noticed. a chest x-ray may show fine interstitial infiltrates in acute and sub-acute forms of the disease, whereas in the chronic form, irregular scarring may indicate diffuse pulmonary fibrosis. in pft, typically patients may show restrictive impairment, i.e., the fev 1 /fvc ratio reduced in comparison with its normal range. the eaa is a diffuse parenchymal disease, and thus, the diffusion capacity of the lungs is affected (both dl co and k co ). bronchoscopy with bronchoalveolar lavage (bal) and transbronchial biopsy may be carried out when investigating a patient with suspected eaa. bal typically shows increased total cell count, with an increased proportion of lymphocytes (>40%). t-helper to t-suppressor ratio is usually reduced to less than 1. after acute exposure, neutrophils are transiently increased. the histopathologic findings include diffuse interstitial infiltrate, scattered non-caseating granulomas, and cellular inflammation of the bronchioles. an inhalation provocation test with the specific antigen can be performed to confirm the diagnosis; a worksite challenge test is a conventional approach, with pft before and after workplace exposure. management of eaa primarily demands to remove the affected persons from the source of exposure. drug intervention with corticosteroids is given at the acute episodes. any dampness or mould problems in buildings should be repaired promptly. humidifier fever, like in eaa, is also termed as a disease related to bioaerosol exposure from contaminated humidifier water, often referred to as monday morning fever. the affected person experiences fever, nausea, sweating, and myalgia, sometimes with breathlessness, about 3-8 h after exposure, which is very similar to those described in outbreaks of eaa. the symptoms diminish towards the end of the working week, and over the weekend, for example, the episode may be worse again. humidifier fever differs from eaa in that the affected person may have specific igg antibodies to the micro-organisms growing in water reservoirs as a sign of exposure. regular maintenance of humidifiers and air conditioners is the best approach to prevent humidifier fever (pal et al. 2000) . legionnaires' disease presents as pneumonia, due to infection with legionella pneumophila, a bacterial micro-organism that may be found in wet surroundings and capable of forming colonies in cooling towers and hot water systems in hospitals and office buildings. an outbreak of legionella pneumophila in philadelphia in 1976 (fraser et al. 1977) with the source identified at the ventilation and humidification system of a hotel, affected 221 persons, with about 20% mortality. the incubation period of the disease is about a week. the early symptoms include illness, headache, myalgia, fever and mild cough, blood in the sputum, and watery diarrhoea (cunha 2008) . there may be a neurological symptom of severe encephalopathy. a chest x-ray may show unilateral lobe infiltrate, with rapidly progressive infiltrations of legionella. complete recovery of the infiltrates may take several weeks to months. urinary antigen detection is a rapid test. however, it is less sensitive than culturing respiratory secretion. superheating of hot water to >50°c and flushing the water distribution systems are crucial to prevent legionella infections. office environment exposures through handling of self-copying paper that contains ink, solvent and dust, acrylate glues used in flooring, pvc, phthalate compounds, and wall-to-wall carpet might induce airway inflammation in humans jaakkola and knight 2008) . professional cleaners in buildings are regularly exposed to cleaning chemicals containing ammonium, bleach, chlorine, and some disinfecting substances, and these people may develop irritant-induced asthma (zock 2005) . table 3 .6 includes different environmental, physical, and social factors, which may cause one or more signs and symptoms related to sbs. second-hand tobacco smoke exposure (shs), containing irritant substances, can potentially induce mucus hypersecretion and inflammation in the airways (jaakkola et al. 2003; gilmour et al. 2006) . in adults with asthma, shs exposure is related to increased occurrence of respiratory symptoms, reduced lung functions, increased use of bronchodilator and steroid medications, and increased bronchial hyper-responsiveness (jaakkola and jaakkola 2002) . fisk et al. (2007) from a meta-analysis of 33 epidemiological studies on dampness and mould problems revealed 30-50% increased risk of asthma about indoor dampness and mould problems in buildings. the ige-mediated hypersensitivity reactions to fungal allergens and mycotoxins produced by fungi and inflammatory reactions caused by fungal cell wall components (1,3-b-d-glucan, ergosterol) are the suggested mechanisms that could lead to asthma. there is a whole range of airborne pathogens, such as aspergillus and bacillus spp., that may be found in the built environment and also during construction or renovation activities (balm et al. 2012; fournel et al. 2010) . particular focus is on hospitals and healthcare buildings, to create healthy conditions. natural ventilation and availability of sunlight in buildings serve as effective strategies in infection control of diseases, such as measles, tuberculosis, smallpox, chickenpox, influenza, sars and h1n1 . the transmission of pathogen takes place through contact, dust, respiratory droplets, and droplet nuclei, e.g., inhalation of large droplets from contagious individuals or contaminated surfaces. the transmission depends upon the number and size of particles produced, the velocity at which they are produced, micro-organisms contained within the droplets, and proximity of a susceptible target (gralton et al. 2011) . the longevity of the pathogens depends on temperature and humidity, ultraviolet (uv) radiation, and atmospheric pollutants (tang 2009 ). depending on the size and density, residues of suspended droplet nuclei can remain suspended and penetrate deep into the lung tissues. droplet nuclei that are exhaled during normal breathing are only a small fraction than those aerosols produced when coughing or sneezing (gralton et al. 2011) . factors, such as local ventilation, the activity of occupants indoors, and thermal gradients produced due to office equipment influence the movement of the suspended droplets (nielsen 2009; eames et al. 2009; clark and de calcina-goff 2009) . towards controlling infection in healthcare and other building facilities through sunlight and natural ventilation, transmission and control of some pathogens are briefly described herewith. influenza is assumed to be transmitted by large droplets. however, the aerosol transmission, such as h5n1 avian influenza that demonstrates high virulence and lethality involves the lower respiratory tract (tellier 2009; tang and li 2007) . direct contact with diseased poultry and other birds may cause h5n1 transmission through the air, without recombination in an intermediate host (herfst et al. 2012) . severe acute respiratory syndrome (sars) epidemic in 2003 was assumed direct contact as the primary transmission route. the hong kong, amoy gardens outbreak, is an affirmative indication of the airborne transmission of the sars virus (mckinney et al. 2006) , such as transmission of virus-laden aerosol through inadequate ventilation, the ventilating shaft of adjacent buildings, floor drainage. before the sars epidemic, hantavirus transmission causing the pulmonary syndrome in humans has been demonstrated, due to the inhalation of aerosolized excreta and saliva from wild rodents (kimmel et al. 2010; clement et al. 2008) . the primary prevention is to clean the ventilation system of buildings that show signs of rodent infestation. norovirus that causes gastrointestinal illness is transmitted via contact with food materials, contaminated surfaces, and the spread of aerosolized particles from vomiting or liquid diarrhoea (marshall and bruggink 2011; greig and lee 2012) . tuberculosis is mainly contracted through airborne droplets; that is, transmission of m. tuberculosis to a non-infected person is possible if there are overcrowding and confined environment, and poor indoor ventilation (beggs et al. 2003) . earlier it was presumed that smallpox virus spreads by face-to-face contact. however, airborne transmission of the virus is evident now. occupants in hospital, health care, and allied facilities are at potential risk from staphylococcus aureus (kerr 2010 ) that get deposited throughout a room. nasal cavities of susceptible adults become colonized with s. aureus by inhaling particles from the air. there are many other pathogens found in an aerial spread in building facilities, such as escherichia coli, klebsiella, acinetobacter, pseudomonas, clostridium difficile (wu et al. 2011) . persons infected with c. difficile may shed spores in faeces, and therefore, when a toilet is flushed without a closed lid, aerosol production may contaminate the surrounding environment (best et al. 2012 ). office goers and building occupants are usually not exposed to high levels of physical, chemical, or biological compounds potentially hazardous to health. office environments have traditionally been considered as safe. however, an ample body of the literature is available on sbs and building-associated illnesses (bri) from different kinds of studies, including epidemiological cohort and cross-sectional studies, population questionnaire surveys, and experimental studies. the risk of sbs may occur at different levels, for example, (a) building level-indoor environmental quality, different sources pollutants, and exposure to bioaerosols, (b) personal level -interpersonal differences (women, younger and the elderly people, persons predisposed with chronic disease show more sbs related complaints), and (c) workplace stressors-aspects of work and psychosocial environment of the building occupants, and ones' ability to cope with the conditions of workplace and workspace. since all these levels are simultaneously present, one major problem emerges in sbs and bri is its lack of generalizability. on a simplistic way, the overall impression of the building environment may be rated by the occupants on an ordinal 100 point scale, against the stated levels of ieq, personal characteristics, aspects of work and the psychosocial environment. the summated scores are scaled into an overall dissatisfaction score for the building occupants. mitigation of iaq problems may require the involvement of building management and related people of responsibility in facility operation and maintenance, housekeeping, policy-making, and staff training. three methods have been suggested to improve the iaq, namely source control, increase ventilation, and air cleaning. the source control is the most cost-effective approach to mitigating iaq problems in which point sources of contaminants can be identified. conventional pollution source control method, such as adsorption by microporous activated carbon and chemical scrubbers, has reasonable efficacy to mitigate pollutants. thermal catalytic oxidation (everaert and baeyens 2004; roark et al. 2004 ) and photocatalytic oxidation (carp et al. 2004 ) are promising technologies for air purification. however, the former is not economically feasible at low pollutant concentrations. photodegradation may be more cost-effective for air purification since the process takes place at room temperature and pressure. tio 2 , a popular photocatalyst, is employed for removal of vocs from indoor air (wang et al. 2006 (wang et al. , 2007 . by incorporating tio 2 catalyst with adsorbent may yield better results for adsorption of pollutants and oxidation efficiency. this type of catalyst, however, exhibits high catalytic activity at uv light. the literature suggests a robust affirmative link between ventilation and the respiratory health of building occupants (seppänen and fisk 2004) . due to the random character of natural ventilation during different seasons of the year, emphasis among the building designers goes in installing mechanical ventilation and hvac systems. the natural ventilation no longer provides optimal distribution of fresh air in the buildings. however, several views have been put forward with regard to mechanical ventilation systems and acute health symptoms (sbs/br), asthma and allergy symptoms among occupants in buildings. mendel et al. (2003 mendel et al. ( , 2006 , examining us niosh data of 80 office building, emphasized that improperly maintained ventilation systems increase the adverse health effects among the occupants, particularly the asthmatics, due to exposure to accumulated pollutants and microbiological growth. comparing with naturally ventilated systems, the presence of air-conditioning increased respiratory symptoms in office buildings located in a hot and humid climate (graudenz et al. 2005) . takahashi et al. (2008) reported that the presence of a ventilation system was associated with increased allergic symptoms, probably due to the entry of large quantities of pollen into the dwellings through the air ducts and other factors, not directly related to the ventilation system. dwellings installed with air conditioners, and those had poor maintenance of ventilation systems, resulted in increased prevalence of sbs (wong et al. 2004; coelho et al. 2005) , as compared to those in naturally ventilated dwellings. some multidisciplinary reviews on relationships between ventilation rate and health outcomes are summarized in table 3 .7. table 3 .7 case studies on the influence of indoor ventilation rate on health outcomes godish and spengler (1996) increasing the ventilation rate up to 10 l/s per person may be useful in reducing the prevalence of sbs symptoms and occupant dissatisfaction with air quality. the use of ventilation as a mitigation measure for iaq problems should be dealt with factors that may limit its effectiveness seppanen et al. (1999) ventilation rates below 10 l/s per person in different building types were associated with significant worsening in one or more health or perceived air quality outcomes. some studies determined that increasing ventilation rates above 10 l/s to *20 l/s per person significantly decreases the prevalence of acute health symptoms or improvement in the perceived air quality. the sbs symptoms continued to decrease significantly with decreasing co 2 concentrations below 800 ppm wargocki et al. (2002 wargocki et al. ( , 2004 ventilation rates below 25 l/s per person increase the risk of acute health (sbs) symptoms, increase short-term sick leave, and decrease productivity mendell and heath (2005) no substantial evidence on the causal relationships between indoor pollutants or thermal conditions in schools and the performance of students. suggestive evidence links low ventilation rates in buildings to decreased performance in children and adults seppanen et al. a 1-3% improvement in average performance was associated with an increase in ventilation rate by 10 l/s per person. the performance increase per unit increase in ventilation was more substantial with ventilation rates in the range 15-17 l/s per person, and almost negligible with ventilation rates over 45 l/s per person li et al. (2007) strong evidence of the association between ventilation, air movements in buildings, and the transmission/spread of infectious diseases. data insufficiency to define the ventilation rates that can reduce the spread of infectious diseases via the airborne route in hospitals, schools, offices, homes, and isolation rooms. overcrowding is a risk factor related to the ventilation of buildings and also infection transmission via direct contact fisk et al. (2009) reduction in ventilation rate from 10 to 5 l/s per person led to increased prevalence of sbs symptoms by *23% (12-32%). increase in ventilation rate from 10 to 25 l/s per person led to the decreased prevalence of acute symptoms by 29% (15-42%) sundell et al. (2011) ventilation rates, up toper person, were associated with reduced prevalence of sbs symptoms in offices. ventilation rates in homes above 0.5 ach are associated with a reduced risk of allergic manifestations among children in a nordic climate the above stated studies provide a fair understanding that ventilation (air change in a built environment) plays a central role to exhaust pollutants of both non-biological and biological agents of the occupied space or generate pollutants within systems. chapter 12 elucidates the design, installation, operation, and maintenance of ventilation systems in buildings. ventilation inadequacy may be due to poor building design, inadequate ventilation system, and its improper maintenance and operational strategies. lack of control of hvac systems aggravates the growth of microorganisms. besides, the quality of outdoor air, building materials, and accumulated dust are also sources of microbial contaminants in indoor environments. the presence of mould, spores, musty smell, and water intrusion are warning signs, reflecting the inefficiency of a building's ventilation system (radon et al. 2008) . it is emphasized that the strength of elimination of pollutants from building space is the determinant of exposure-associated adverse health effects of occupants. in spite of differing views, ventilation rates below 10 l/s per person would increase the risk of symptoms of sbs (jaakkola and miettinen 1995) . the assertion from the base study of the association of sbs with the increasing difference in concentration of co 2 between indoor and outdoor brings forward the suggestion that a relative increase in the ventilation rates per person in an office building may reduce the prevalence of sbs symptoms. a concentration of co 2 (800 ppm) has been suggested as a control limit value. erdmann and apte (2004) observed a remarkable reduction in mucosal symptoms ranging from 65 to 85% when co 2 levels in offices dropped in the range from 610 to 40 ppm above outdoor levels. frequent contributors to biological pollutants are water damage in buildings, leaks in plumbing, roofs or air conditioners, and humidifiers (mckernan et al. 2008; li et al. 2010) . given that some airborne moulds may always be present in the indoor environment, various guidance limits and remediation measures have been proposed (baubiologie maes 2008) . ec guidelines state that mould count greater than 500 cfu/m 3 may be considered an intermediate level of exposure for a building occupant, whereas >1000 cfu/m 3 is a high level of exposure in indoor non-industrial workplaces. levels more than these guidelines do not necessarily imply unsafe or hazardous conditions. in the usa, there are no exposure levels for airborne concentrations of mould (us osha 2003) . every country must establish the requisite legislation and environmental standards and guidance concerning building maintenance specifications. also, building-associated illnesses manifest in multiple forms of symptoms, and often in combinations of asthma, hypersensitivity pneumonitis, and interstitial pneumonitis (bornehag et al. 2001) . evidence of markers for individual susceptibility might separate normal from more sensitive groups. symptoms of allergy and asthma may be triggered by allergens in the indoor air including those from house dust mites, pets, fungi, insects, and pollens. as elaborated earlier, asthma symptoms can be evoked by irritating chemicals or sensitizing agents. there are approaches to reducing allergy and asthma symptoms via changes in buildings and indoor environments. reductions in allergy and asthma symptoms would be expected by a substantial reduction in the associated allergens and irritants, from indoors. overall, intervention and management of sbs and bri may encompass measures, as described herewith. for new buildings, the prevention measures in reducing mould contamination include, for example, (a) minimizing moisture accumulation in construction materials, (b) maintaining the integrity of building impermeable envelope, and (c) ensuring the effectiveness of hvac system to control thermal comfort and relative humidity. in the existing buildings, corrective measures include (a) repair and maintenance of water leakage in ceilings, walls, and draining systems, (b) deep cleaning of building interiors and hvac systems, (c) control of the reservoirs of visible mould in ceiling and carpets, and (d) periodic assessment of iaq. once a mould problem is established, a well-documented action plan may be followed to notify people for (a) rectifying the underlying moisture problem, (b) minimizing spread of contamination, by cleaning of ventilation pathways and enhancing ventilation to exhaust the relevant pollutants from indoors, and (c) removing mouldy materials. it is important to consider that fungal spores are continually entering into the indoor environment and a remedial measure to fungal contamination is the maintenance of dry conditions in a building. as part of remediation, an entire or part of a building may be heated to a temperature that should kill most of the fungal spores. caution is needed that heat may not damage specific equipment and plastic materials. apart from dilution of airborne pathogens, high ventilation of outdoor air results in an adverse effect on viability and virulence of micro-organisms, including influenza and the category iv pathogen, francisella tularensis (hood 2009 ). infection of rhinoviruses causes adults to suffer the frequent common cold. myatt et al. (2004) provided evidence of aerosol transmission of rhinovirus in mechanically ventilated office buildings that resulted in an increased risk of inhaling infectious droplets. in student rooms having a ventilation rate of about 1 l/s per person, the frequency of common colds was six times more among 35% of the students. the number of common colds was higher in winter. reported common colds were higher when some students shared a room. by increasing the ventilation rate to 5 l/s per person, the self-reported common colds dropped to a mere 5% (sun et al. 2011b ), suggesting that ventilation from outdoor-to-indoor bears greater significance in diluting and dispersing virus-laden droplets (mendell et al. 2002) . milton et al. (2000) observed a reduction in short-term sick leave among office workers when the outdoor air supply rates increased from 12 to 24 l/s per person in an office building. mendell et al. (2013) reported the relative decrease of illness absence of about 1.6% for each additional ventilation rate of 1 l/s per person. natural ventilation brings many advantages, whereas entry of unfiltered air containing free contaminants such as fungal spores (bartley et al. 2010; phares et al. 2007 ) is a possible disadvantage of natural ventilation. natural ventilation can be more effective than mechanical systems for preventing transmission (kembel et al. 2012) . despite that an outbreak of infectious disease is an outcome of several factors, as stated above, the evidence is supportive that ventilation is a modifying factor in the transmission of infection. following the 2001 incidents of anthrax attacks, preventive intervention is to relocate air intakes to publicly inaccessible locations, e.g., secure roofs. coughing and sneezing activities can carry infectious aerosols a long distance within a built environment (zhu et al. 2006) . intervention in building ventilation airflow patterns (chen and zhao 2010) can thwart particle transport from a source to a receiver. the exposed concentration of aerosol from sneezing, at the breathing zone of a receiver occupant is slightly higher under displacement ventilation, dv than mixing ventilation, mv system (seepana and lai 2012) , due to its low local air velocities. high discharge velocity air curtains provide a strong momentum to redirect coughing and sneezing jets and minimize cross infection (aubert and solliec 2011; nino et al. 2011) , and also influence heat gain/loss in a facility (foster et al. 2006) . with a protected occupied zone ventilation, pov system, the intake fraction of coughed particles in the breathing zone of the receiver occupant decreased to a significant extent, as compared to an mv system (liu et al. 2014) . a narrowly concentrated plane jet was more effective at reducing the direct exposure to expiratory particles than with multiple low-velocity jets. the majority of micro-organisms that cause airborne infections cannot tolerate sunlight. direct sunlight passing through an ordinary window can kill m. tuberculosis and meningococci within a few hours. streptococcus pyogenes cannot survive more than 5 min under sunlight, compared with more than an hour in diffuse daylight. lethality of sunlight against staphylococci is due to radiation at 300-380 nm; in addition to bactericidal effect, solar radiation is mutagenic. ordinary window glass absorbs solar radiation at <300 nm, which permits entry of solar uv-a and small amounts of uv-b. research indicates that uv wavelengths inactivate microbes by causing cross-links between constituent nucleic acids; the formation of intra-strand cyclobutyl-pyrimidine dimers within dna leads to mutations and cell death (maclean et al. 2010 ). exposure to high-intensity visible violet light at 405 nm is likely to be associated with photoexcitation of porphyrin molecules, resulting in the production of reactive oxidative species that are strongly bactericidal (hamblin et al. 2005) . the contemporary modern building envelopes have an overdependence on mechanical ventilation and hvac systems. as insulation levels increase, there is a risk of overheating and poor iaq (bone et al. 2010) . typically, in cold climate, the heating in new buildings is provided by warm air, whereas heating in older ones was often from a radiant source (hobday 2011) . any exclusion of sunlight in buildings, for example, in hospital and healthcare facilities increases the risk of infection, and a variety of other health problems (castro et al. 2011; hobday and dancer 2013) . the design of buildings that allow increased exposure to sunlight and outdoor air may discourage survival and spread of infectious agents with considerable health benefits to occupants. vocs and "sick building syndrome": application of a new statistical approach for sbs research to us epa base study data indoor carbon dioxide concentrations, vocs, environmental sensitivity associations with mucous membrane and lower respiratory sick building syndrome symptoms in the base study: analyses of the 100 building dataset associations between indoor co 2 concentrations and sick building syndrome symptoms in us office buildings: an analysis of the 1994-1996 base study data relationship between selected indoor volatile organic compounds, so-called microbial voc, and the prevalence of mucous membrane symptoms in single family homes windows, view, and office characteristics predict physical and psychological discomfort indoor air quality audit implementation in a hotel building in portugal airborne and soilborne microfungi in the vicinity hamitabat thermic power plant in kirklareli city (turkey), their seasonal distributions and relations with climatological factors push-pull air curtain performances for vocs containment in an industrial process indoor and outdoor airborne bacteria in child day-care centers in edirne city (turkey), seasonal distribution and influence of meteorological factors hot and steamy: outbreak of bacillus cereus in singapore associated with construction work and laundry practices protean nature of mass sociogenic illness current views of health care design and construction: practical implications for safer, cleaner environments institut fur baubiologie + okologie ibn plasma-assisted surface modification of organic biopolymers to prevent bacterial attachment prevalence of allergic sensitization to indoor fungi in west virginia the transmission of tuberculosis in confined spaces: an analytical review of alternative epidemiological models illness from low levels of environmental chemicals: relevance to chronic fatigue syndrome and fibromyalgia potential for aerosolization of clostridium difficile after flushing toilets: the role of toilet lids in reducing environmental contamination risk mass spectrometry-based strategy for direct detection and quantification of some mycotoxins produced by stachybotrys and aspergillus spp. in indoor environments will drivers for home energy efficiency harm occupant health? perspectives in public health dampness in buildings and health why do women suffer from sick building syndrome more often than men?-subjective higher sensitivity versus objective causes laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update development of new volatile organic compound (voc) exposure metrics and their relationship to "sick building syndrome" symptoms microbiological threats to health in the home how does heat affect fungi sick building syndrome: a study of 4373 office workers effect of gaseous chlorine dioxide on indoor microbial contaminants can we use indoor fungi as bioindicators of indoor air quality? historical perspectives and open questions 8-hydroxy-2'-deoxyguanosine, a major mutagenic oxidative dna lesion, and dna strand breaks in nasal respiratory epithelium of children exposed to urban pollution the effect of light on critical illness field study of occupant comfort and office thermal environments in a hot, arid climate difficult-to-control asthma: clinical characteristics of steroid-insensitive asthma exhaled nitric oxide as a noninvasive assessment of chronic cough some questions on dispersion of human exhaled droplets in ventilation room: answers from numerical investigation the natural history of concurrent sick building syndrome and chronic fatigue syndrome investigation on the impacts of different genders and ages on satisfaction with thermal environments in office buildings some aspects of the airborne transmission of infection hantaviruses: underestimated respiratory viruses indoor air pollution in old people's homes related to some health problems: a survey study physicochemical determinants and functional properties of the senses of irritation and smell. indoor air and human health health survey for england 2010. respiratory health atypical pneumonias: current clinical concepts focusing on legionnaires' disease indoor air quality in university environments value-adding to cellulosic ethanol: lignin polymers field study of occupant comfort and office thermal environments in a cold climate (no. conf-970668-) medical management of brain tumor patients movement of airborne contaminants in a hospital isolation room the asthma epidemic fungal spores: a critical review of the toxicological and epidemiological evidence as a basis for occupational exposure limit setting occurrence of toxigenic aspergillus versicolor isolates and sterigmatocystin in carpet dust from damp indoor environments sick building syndrome in relation to building dampness in multi-family residential buildings in stockholm mucous membrane and lower respiratory building related symptoms in relation to indoor carbon dioxide concentrations in the 100-building base dataset airborne alternaria and cladosporium species and relationship with meteorological conditions in eskisehir city catalytic combustion of volatile organic compounds introduction of the olf and the decipol units to quantify air pollution perceived by humans indoors and outdoors quantitative health impact assessment: taking stock and moving forward standards of care for occupational asthma health and productivity gains from better indoor environments and their relationship with building energy efficiency meta-analyses of the associations of respiratory health effects with dampness and mold in homes quantitative relationship of sick building syndrome symptoms with ventilation rates effectiveness and optimum jet velocity for a plane jet air curtain used to restrict cold room infiltration airborne aspergillus contamination during hospital construction works: efficacy of protective measures hypersensitivity pneumonitis: essential radiologic and pathologic findings legionnaires' disease: description of an epidemic of pneumonia the chronic fatigue syndrome: a comprehensive approach to its definition and study ciguatera in australia. occurrence, clinical features, pathophysiology and management how exposure to environmental tobacco smoke, outdoor air pollutants, and increased pollen burdens influences the incidence of asthma filamentous microorganisms and their fragments in indoor air-a review determination of macrocyclic trichothecenes in mouldy indoor materials by lc-ms/ms the role of particle size in aerosolised pathogen transmission: a review association of air-conditioning with respiratory symptoms in office workers in tropical climate a review of nosocomial norovirus outbreaks: infection control interventions found effective source apportionment of volatile organic compounds in hong kong homes sick building syndrome-a case study in a multistory centrally air-conditioned building in the delhi city is there a gulf war syndrome?: searching for syndromes by factor analysis of symptoms temporal evolution of the main processes that control indoor pollution in an office microenvironment: a case study helicobacter pylori accumulates photoactive porphyrins and is killed by visible light influence of indoor factors in dwellings on the development of childhood asthma indoor air quality and allergic rhinitis among office workers in a high-rise building airborne transmission of influenza a/h5n1 virus between ferrets resistance of green building materials to fungal growth indoor environmental quality in refurbishment. historic scotland technical paper roles of sunlight and natural ventilation for controlling infection: historical and current perspectives the effect of open-air factors on the virulence and viability of airborne francisella tularensis air-and dustborne mycoflora in houses free of water damage and fungal growth synergistic interaction in simultaneous exposure to streptomyces californicus and stachybotrys chartarum effects of environmental tobacco smoke on the respiratory health of children office work exposures and adult-onset asthma the role of exposure to phthalates from polyvinyl chloride products in the development of asthma and allergies: a systematic review and meta-analysis ventilation rate in office buildings and sick building syndrome occupation and asthma: a population-based incident case-control study interior surface materials and asthma in adults: a population-based incident case-control study office work exposures and respiratory and sick building syndrome symptoms bioaerosols in apartment buildings. encyclopedia of environmental health indoor fungi levels in homes of children with and without allergy history real-time measurement of uv-inactivated escherichia coli bacterial particles by electrospray-assisted uvaps spectrometry relationship between airborne fungal allergens and meteorological factors in manisa city gender differences in thermal comfort and use of thermostats in everyday thermal environments discrimination between invasive pulmonary aspergillosis and pulmonary lymphoma using ct architectural design influences the diversity and structure of the built environment microbiome controlling methicillin-resistant staphylococcus aureus infection in hospitals fungal pollution of indoor environments and its management determination of fungal spore release from wet building materials gender differences in office occupant perception of indoor environmental quality (ieq) should we recommend precautions during a hantavirus endemic microbial volatile organic compounds illness in gulf war veterans: causes and consequences airborne molds and mycotoxins associated with handling of corn silage and oilseed cakes in agricultural environment sick building syndrome. intern encyclopedia public health effects of satratoxins and other macrocyclic trichothecenes on il-2 production and viability of el-4 thymoma cells role of ventilation in airborne transmission of infectious agents in the built environment-a multidisciplinary systematic review the effect of air-conditioning parameters and deposition dust on microbial growth in supply air ducts optimal color design of psychological counseling room by design of experiments and response surface methodology asthma or asthma-like condition? oxidative dna damage estimated by urinary 8-hydroxydeoxyguanosine and indoor air pollution among non-smoking office employees filamentous fungi isolated in hospitals and some medical institutions in lithuania. indoor and built environment micromycetes as deterioration agents of polymeric materials environmental decontamination of a hospital isolation room using high-intensity narrow-spectrum light building health: an epidemiological study of "sick building syndrome" in the whitehall ii study the dynamics of norovirus outbreak epidemics: recent insights exposure assessment and analysis for biological agents determination of volatile metabolites originating from mould growth on wall paper and synthetic media determination of microbial volatile organic compounds (mvocs) by passive sampling onto charcoal sorbents disinfection: is it time to reconsider spaulding? monitoring microbial populations on wide-body commercial passenger aircraft environmental transmission of sars at amoy gardens effect of building frame and moisture damage on microbiological indoor air quality in school buildings do indoor pollutants and thermal conditions in schools influence student performance? a critical review of the literature improving the health of workers in indoor environments: priority research needs for a national occupational research agenda environmental risk factors and work-related lower respiratory symptoms in 80 office buildings: an exploratory analysis of niosh data indicators of moisture and ventilation system contamination in us office buildings as risk factors for respiratory and mucous membrane symptoms: analyses of the epa base data association of classroom ventilation with reduced illness absence: a prospective study in california elementary schools research and development of prevention and control measures for mold contamination quantifying uncertainty in health impact assessment: a case-study example on indoor housing ventilation methacholine provocations do not reveal sensitivity to strong scents sensory hyperreactivity-a possible mechanism underlying cough and asthma-like symptoms risk of sick leave associated with outdoor air supply rate, humidification, and occupant complaints current state of the science: health effects and indoor environmental quality environmental tobacco smoke exposure and overtime work as risk factors for sick building syndrome in japan volatile organic compounds and sick building syndrome sick building syndrome. encyclopedia of environmental health microbial vocs in moisture damaged buildings detection of fungal development in closed spaces through the determination of specific chemical targets detection of fungal development in a closed environment through the identification of specific voc: demonstration of a specific voc fingerprint for fungal development airborne fungal volatile organic compounds in rural and urban dwellings: detection of mould contamination in 94 homes determined by visual inspection and airborne fungal volatile organic compounds method mold spore penetration through wall service outlets: a pilot study effect of plasterboard composition on stachybotrys chartarum growth and biological activity of spores detection of airborne rhinovirus and its relation to outdoor air supply in office environments do the work stress factors of women telephone operators change with the shift schedules? differences in perception of indoor environment between japanese and non-japanese workers mycotoxin production by indoor molds control of airborne infectious diseases in ventilated spaces isolation and identification of aspergillus fumigatus mycotoxins on growth medium and some building materials submerged rectangular air jets as a particulate barrier effect of air humidification on the sick building syndrome and perceived indoor air quality in hospitals: a four month longitudinal study indoor air quality and sick building syndrome in three selected buildings epidemiology of sick building syndrome and its associated risk factors in singapore the role of microbial signals in plant growth and development exposure and acute exposure-effects before and after modification of a contaminated humidification system in a synthetic-fibre plant ciguatera-a potent cause of the chronic fatigue syndrome legionnaires' disease among residents of a long-term care facility: the sentinel event in a community outbreak clinical and pathophysiological aspects of chronic fatigue syndrome occupation and adult onset of rhinitis in the general population the diseases of workers assessment of indoor air problems at work with a questionnaire biotreatment of gas-phase voc mixtures from fibreglass and composite manufacturing industry methodologies for assessing bioaerosol exposures. encyclopedia of environmental health fungal fragments in moldy houses: a field study in homes in new orleans and southern ohio visually observed mold and moldy odor versus quantitatively measured microbial exposure in homes indoor environmental quality in six commercial office buildings in the midwest united states respiratory disease among military personnel in saudi arabia during operation desert shield presence of hyperventilation in patients with asthma-like symptoms but negative asthma test responses: provocation with voluntary hyperventilation and mental stress physical capacity and dyspnea in patients with asthma-like symptoms but negative asthma tests catalytic oxidation of volatile organic liquids clinical investigation of an outbreak of alveolitis and asthma in a car engine manufacturing plant symptoms and sense of coherence-a follow-up study of personnel from workplace buildings with indoor air problems personal and psychosocial factors and symptoms compatible with sick building syndrome in the swedish workforce organic dust induced pulmonary disease-the role of mould derived beta-glucan relation of dampness to sick building syndrome in japanese public apartment houses forming of a functional biofilm on wood surfaces dustborne alternaria alternata antigens in us homes: results from the national survey of lead and allergens in housing emission of volatile organic compounds from furniture coatings production an levels of selected indoor radicals: a modeling assessment microbial volatile organic compounds in the air of moldy and mold-free indoor environments the complexity of treatment adherence in adults with asthma: challenges and opportunities a pilot study of a headache program in the workplace: the effect of education epidemiology of tension-type headache experimental and numerical investigation of interpersonal exposure of sneezing in a full-scale chamber psychogenic mass illness-a case study in calcutta telephones fungal flora in indoor and outdoor air of different residential houses in tekirdag city (turkey): seasonal distribution and relationship with climatic factors size-fractionated (1 ! 3)-b-d-glucan concentrations aerosolized from different moldy building materials summary of human responses to ventilation association of ventilation rates and co 2 concentrations with health and other responses in commercial and institutional buildings ventilation and performance in office work oil palm fiber (opf) and its composites: a review biodeterioration of painted mortar surfaces in tropical urban and coastal situations: comparison of four paint formulations a time-series study of sick building syndrome: chronic, biotoxin-associated illness from exposure to water-damaged buildings sick building syndrome in water-damaged buildings: generalization of the chronic, biotoxin associated illness paradigm to indoor toxigenic fungi school air quality related to dry cough, rhinitis and nasal patency in children the spectrum of fungal allergy mass psychogenic illness: a social psychological analysis assessment of the aerosolization potential for fungal spores in moldy homes fungal spore source strength tester: laboratory evaluation of a new concept influence of personal characteristics, job-related factors and psychosocial factors on the sick building syndrome influence of indoor climate on the sick building syndrome in an office environment why do women report 'sick building symptoms' more often than men? a prevalence study of the sick building syndrome (sbs) and facial skin symptoms in office workers bio-susceptibility of materials and thermal insulation systems used for historical buildings detection and enumeration of airborne biocontaminants molds, mycotoxins, and sick building syndrome in china, students in crowded dormitories with a low ventilation rate have more common colds: evidence for airborne transmission ventilation and dampness in dorms and their associations with allergy among college students in china: a case-control study what we know, and dont know about sick building syndrome on the history of indoor air quality and health ventilation rates and health: multidisciplinary review of the scientific literature indoor air quality and sick building syndrome in malaysian buildings two routes for pollen entering indoors: ventilation and clothes relationship between sick building syndrome and indoor environmental factors in newly built japanese dwellings the effect of environmental parameters on the survival of airborne infectious agents transmission of influenza a in human beings diagnosis and management of work-related asthma survey of the prevalence of asthma', allergic rhinitis and eczema in schoolchildren from khon kaen aerosol transmission of influenza a virus: a review of new studies fungal exposure in homes of patients with sarcoidosis-an environmental exposure study office workers' sick building syndrome and indoor carbon dioxide concentrations indoor air quality and health problems associated with damp floor coverings mycotoxins in crude building materials from water-damaged buildings brief guide to mold in the workplace. occupational safety and health administration impact of paint and wall-paper on mould growth on plasterboards and aluminum the controversies surrounding sick building syndrome zro2-modified mesoporous nanocrystalline tio2-xnx as efficient visible light photocatalysts volatile organic compounds in indoor environment and photocatalytic oxidation: state of the art subjective perceptions, symptom intensity and performance: a comparison of two independent studies, both changing similarly the pollution load in an office the performance and subjective responses of call-center operators with new and used supply air filters at two outdoor air supply rates a spreading concern: inhalational health effects of mold applications and advances in electronic-nose technologies advances in electronic-nose technologies developed for biomedical applications how to measure and evaluate volatile organic compound emissions from building products. a perspective cluster of sars among medical students exposed to single patient quantification and analysis of airborne bacterial characteristics in a nursing care institution apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to erk, p38 mapk, and sapk/ jnk activation a comparison study on energy savings and fungus growth control using heat recovery devices in a modern tropical operating theatre indoor airborne fungal spores and home characteristics in asthmatic children from edirne region of turkey fungal proteases and their pathophysiological effects transient elevation of intracellular calcium ion levels as an early event in t-2 toxin-induced apoptosis in human promyelotic cell line hl-60 impact of mycotoxins on humans and animals impact of perceived indoor environment quality on overall satisfaction in swedish dwellings a comparison of the efficiencies of a portable biostage impactor and a reuter centrifugal sampler (rcs) high flow for measuring airborne bacteria and fungi concentrations amplified proinflammatory cytokine expression and toxicity in mice coexposed to lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol) study on transport characteristics of saliva droplets produced by coughing in a calm indoor environment world at work: cleaners health and indoor climate complaints of 7043 office workers in 61 buildings in the netherlands key: cord-019347-tj3ye1mx authors: nan title: abstract book date: 2010-02-19 journal: ann allergy asthma immunol doi: 10.1016/s1081-1206(10)61294-x sha: doc_id: 19347 cord_uid: tj3ye1mx nan introduction: the effect of anti ige has been described as a function of complexing free ige to reduce mast cell implantation and consequent reduction of mast cell degranulation upon exposure to antigen. theoretically, as total free ige drops below 10 ng/ml, improvement occurs as free and cell bound ige equilibrate and allergic reactions subside. initial observations ( togias a et al. j allergy clin immunol. 1998 ;101:s171)suggested that prick skin tests consistently reached their low point at 98 days with significant reduction in size. laynadier (leynadier f, doudou o, gaouar h, le gros v, bourdeix i, guyomarch-cocco l, trunet p : effect of omalizumab in health care workers with occupational latex allergy.j allergy clin immunol 2004;113:360-1) noted some reduction in skin testing in sixty percent of patients treated over a six month period with monoclonal antiige. but clinicians since approval of the drug in 2002 have noted that even in the presence of good clinical response to asthma, skin test reactivity is still obvious, and in many cases unchanged. methods: following the suggestions for standard clinical follow up by lanier and marshall ( annals may 2003) , routine skin prick skin testing was completed after informed consent on 24 patients at onset of anti-ige therapy, and repeated at 6-7 months. in all instances were skin tests done and photographed in a standard manner. in a few cases, skin tests were repeated on patients receiving anti ige for as long as five years. results: photographic evidence will be presented. in 22 of 24 patients on current therapy, prick skin testing remained at an almost identical photographic level to the baseline analysis, but there was a correlation between the patients with the lowest serum ige and the likelihood of apparent reduction. there was no correlation to reduction of skin testing and clinical response to anti ige since all 24 patients had experience significant quality of life improvements. conclusion: anti ige has variable effects on reducing prick skin testing, with a greater likely hood associated with low or extremely low initial total ige levels. skin testing is more sensitive for detection of allergen-specific ige than is immunoassay for allergen-specific ige. for some assay methods, the qualitative cutoff of 0.35 ku/l is inappropriately high. this study was conducted in order to determine whether a particular assay system can be used to measure lower levels of allergen-specific ige. the pharmacia unicap system was studied. all reagents were purchased from the manufacturer, and the study was approved by a local human assurance committee. to determine background of the calibration curve, the fluorescent unit (fu) response of 6 replicates of assay diluent measured with an anti-ige solid phase was determined. the background responses of 7 arbitrarily selected allergen solid phases (oak, timothy and short ragweed pollen; cat; peanut; yellow jacket venom; penicillin g) were also measured. lower detection limits (lld) were calculated using the mean background measurement + 3 standard deviations (sd). to examine linearity of a low-range calibration curve, 1:2 dilutions to extinction were made, starting with the 3.5 ku/l calibrator. the mean background of the anti-ige solid phase was 15.4 fu, sd 2.7 and coefficient of variation (cv) of 18%; the lld was 24. this lld corresponded to a level of approximately 0.01 ku/l of ige. the lld of the allergen solid phases ranged from 17.2 fu (yellow jacket venom) to 71.6 fu (short ragweed); this corresponded to about 0.08 ku/l ige. the low level dilution curve exhibited parallelism with a curve constructed using a zero (diluent) calibrator as a 7th point in the assay's reference curve. a low level method is capable of measuring specific ige levels lower than the manufacturer's 0.35 ku/l cutoff. this would seem to be particularly important in research applications, and in the analysis of certain highrisk allergens. the clinical significance of very low levels of specific ige in the serum warrants study. allergists/immunologists are often consulted on patients with rashes or recurrent infections. the differential diagnosis can comprise a variety of disorders, some of which are rare syndromes that require early diagnosis and specific management. a 3 mo old wm developed persistent rash and worsening eczema. later, he had recurrent severe skin infections, skin abscesses, recurrent sinusitis, and chronic otitis media that required multiple placement of tympanostomy tubes, yet had a persistent tympanic membrane perforation. recurrent wheezing was noted from 3-7 yr of age. he had several episodes of pneumonia since 3 yr of age affecting different lobes. he failed to shed the primary teeth and had history of periodontitis and oral thrush. he developed scoliosis and multiple fractures of the upper extremities and ribs. at 12 yr he had staphylococcal bacteremia and osteomyelitis of the acetabulum. in spite of antibiotics prophylaxis, he continued to have recurrent skin infections and lymphadenitis. laboratory evaluation revealed eosinophilia (up to 3138/mm3), normal levels of igg, iga, igm & igg subclasses, except for decreased igg2 (51 mg/dl). he had protective levels of anti s. pneumoniae and h. influenzae, but low anti-tetanus and anti-diphtheria titers. at 4 yr, total ige level was 42, 500 iu/ml which supported the diagnosis of hyper ige (hie) syndrome; it decreased to 197 iu/ml by 12 yr. rast was positive to hd mite, cat, dog, egg, milk, and pollens. flow cytomerty, nbt and phagocytic index were normal; ch50 was low (66 mg/dl). dexa scan showed osteopenia. chest x-ray showed bilateral infiltrate, atelectasis and scoliosis of the thoracic spine. during his hospitalization at 13 yr, his skin was fair, lichenified with widespread maculopapular erythematous rash. the palms and fingers showed open cracks and pustules, but no weeping lesions. in addition to coarse facial features, his face was eczematous. conclusion: hie syndrome is an autosomal dominant disorder that mimics atopic dermatitis but has severe course, multiple infections, and several complications. although a markedly elevated total ige level introduction: mannose-binding lectin (mbl) is a serum protein in the lectin complement pathway. it is important in innate immunity, and is thought to be particularly relevant in young children during the development of adaptive immunity. deficiency in mbl has been reported in population-based studies as a risk factor in children for infection and hospitalization. additionally, age-dependent variability of mbl has been previously noted. this study evaluates the prevalence of mbl deficiency in children with established recurrent infection who were referred for evaluation of immunodeficiency. method: we prospectively evaluated mbl status of children referred for recurrent infection. serum was collected from october 2002 to september 2003. children with known primary or secondary immunodeficiencies were excluded. mbl analysis was performed by standardized elisa using mbl oligomer assays. we performed chart and laboratory review for comorbid diagnoses, quantitative immunoglobulin levels and subclasses, and complement function with ch50 and ah50. results: two-hundred thirty five children were evaluated. mean age was 4.5 years (range 0.08-17 years). mean mbl was 1780 ng/ml (range 17-4806 ng/ml). thirty-one of 235 children (13.1%) were mbl deficient, levels <200, and among this group the mean mbl level was 61.3 ng/ml (range 17-163 ng/ml). mean age in this group was 3.6 years (range 0.3-16 years). of the children with mbl deficiency, 13 (5.1%) children had levels <50. the m:f ratio of children with abnormal mbl levels was 1.08. linear regression analysis showed no correlation of mbl level with age. comorbid diagnoses were variable, including asthma, allergy, and atopic dermatitis. none of the children had symptoms compatible with connective tissue disease. no child with an abnormal mbl level was found to have significant deficiency of igg, iga, or igm. several children had low igg4, which were within normal physiologic range. no other concomitant complement pathway disorders were detected. conclusions: our study did not reveal any correlation between mbl level and age. in children with recurrent infections, mbl deficiency was approximately twice the estimated rate of the general population. contrary to previous studies, no other significant immunologic disorders were identified. therefore, mbl deficiency alone is a risk factor for infection in children. t.b. fausnight * , hershey, pa. introduction: the incidence of perioperative anaphylaxis is estimated to be between 1 in 10, 000 and 1 in 20, 000 procedures. approximately 60% of cases of perioperative anaphylaxis are attributed to neuromuscular agents. very little information is reported in the literature regarding pediatric perioperative anaphylaxis. i describe a pediatric patient with suspected perioperative anaphylaxis to rocuronium. methods: a 10 year-old girl with a history of sacral agenesis and neurogenic bladder was scheduled to have bladder augmentation surgery. the patient was taken to a latex-free operating room. during induction of general anesthesia, she was found to be difficult to ventilate. she also became hypotensive. examination of the patient revealed urticaria on her right arm. she was given epinephrine, diphenhydramine, and dexamethasone. the procedure was aborted. the reaction was believed to be from either rocuronium or propofol. results: because of the high incidence of anaphylaxis to neuromuscular agents, allergy skin testing was performed for rocuronium, vecuronium, and succinylcholine. the patient had negative percutaneous skin tests (1:10) for rocuronium, vecuronium, and succinylcholine. she had a negative intradermal skin test to rocuronium at the 1:1000 dilution. she had a positive intradermal skin test to rocuronium at the 1:100 dilution. she had negative intradermal skin tests to both vecuronium and succinylcholine at the 1:1000, 1:100, and 1:10 dilutions. she underwent surgery 2 weeks after skin testing. she received a test dose of vecuronium and had no reaction. she received 3 doses of vecuronium and multiple doses of morphine without any adverse reactions. propofol was avoided. the surgery was completed without difficulty conclusions: this case illustrates the usefulness of skin testing for neuromuscular agents in a pediatric patient. introduction: extrapulmonary pneumocystis jiroveci infection is rare in non-hiv infected individuals and, to our knowledge, it has not been reported before in a patient with good's syndrome. we report a case of extrapulmonary pneumocystis in a patient with good's syndrome. case report: a 44-year-old african american male patient with a history of good's syndrome presented with left flank pain of 3 months duration. the pain was constant and associated with night sweats, fever, and chills. furthermore, the patient also reported a 20-pound weight loss. on exam, patient was found to have multiple hypopigmented areas over his abdomen and left lower extremity, bitemporal wasting, sunken eyeballs, and oral thrush. the patient was also found to have left costovertebral angle tenderness with a palpable solid fixed mass along the left mid axillary line overlying the splenic area. computedtomography (ct) scan of the chest and abdomen showed a 2.2 x 2.9 cm soft tissue mass at the left lateral aspect of the t11 vertebral body and 7.0 x 5.2 cm soft tissue parasplenic mass. the parasplenic mass involved the inferior anterior aspect of the left 11th and 12th ribs (see figure) . the giemsastained biopsy of the parasplenic mass revealed pneumocystis jiroveci and was confirmed using immunohistochemical stain with monoclonal antipnumocystis antibodies. the patient's symptoms of night sweats and loss of appetite improved within 48 hours following initiation of trimethoprim-sulfamethoxazole therapy. a ct of the chest and abdomen, repeated six months post treatment, confirmed the resolution of both the paravertebral and the parasplenic masses. conclusion: to our knowledge, this is the first case of extrapulmonary pneumocystis presenting in a patient with good's syndrome. although it is rare, extrapulmonary pneumocystis should be considered in the differential diagnosis of patients with good's syndrome and chest or abdominal mass. introduction: t cells are regulated by cellular interactions with the environment during development. they play a critical role in the regulation and development of autoimmune diseases. we report inflammatory myositis in a 10-year-old caucasian female with primary t cell-deficiency since infancy. methods: at nine months of age, our patient developed lymphoid interstitial pneumonitis. immunologic evaluation revealed isolated t-cell deficiency. during the first 3 years of life, she had failure to thrive, recurrent sinusitis, oral candidiasis, fungal skin infections, and pseudomonas pneumonia. at 5 years, autoimmune conditions, characterized by a purpuric rash over the nose; face and exposure area of elbows; knees and fingers; raynaud's phenomenon; and nasal septum perforation, developed. inflammatory markers were persistently elevated and autoantibodies detected. by age 9, she developed proximal muscle weakness with distal joint contractures. dry gangrene of the fingers from a thrombotic incident occurred. results: serial immunologic evaluation revealed low cd4 9-36%, # 153-335 (normal 36-61%, # 900-2860 cell/mm3), low cd8 5-23%, #142-237 (normal 16-34%, # 630-1910 cell/mm3) , decreased lymphocyte transformation to antigens but appropriate to mitogens. igg 1320-2560 (normal 667-1179 mg/dl); iga 470-780 (normal 79-169 mg/dl), and igm 215-340, (normal 40-90 mg/dl) with appropriate antibody responses to vaccine antigens. bone marrow and thymus biopsies were normal. further evaluation was not consistent with known primary or secondary immunodeficiencies. several skin biopsies revealed nonspecific dermatitis without vasculitis. mri of lower extremities showed abnormal signals involving bilateral muscles of thighs and calves. muscle biopsy revealed inflammatory myositis with plasma cell predominance, inconsistent with dermatomyositis or polymyositis. aldolase 8-10 iu/l (< 5), crp 8-16 mg/dl (< 0.5), esr 50-70 (< 20), rf 1:1280 (< 1:40) and type ii collagen ab 26-35 ei/ml (< 20) . ana, anca and ace were within normal range. antibodies for myositis and myositis related-antibodies were negative. diagnosis of nonspecific plasma-cell inflammatory myositis was made. a trial of monthly ivig 2 gm/kg resulted in clinical improvement. conclusion: this novel plasma cell myositis occurring in a child with primary t cell deficiency underscores the role t cells play in the development of autoimmune diseases. introduction the incidence of hypersensitivity reactions (hr) is increased in patients treated with multiple courses of carboplatin. the purposes of this investigation were to evaluate the effectiveness of a 6-hour, 12-step desensitization protocol and to characterize the immune mechanism of carboplatin hr. methods we analyzed ten consecutive patients over a two year period with documented hr to carboplatin who required continued treatment with a platinum agent. the patients were treated with carboplatin using a 6-hour, 12-step desensitization protocol. skin tests were performed on five patients. results ten patients successfully completed 35 planned courses of desensitizations to carboplatin, 31 of which were without reactions. four patients had symptoms during their first (n=3) and third (n=1) desensitizations but tolerated the re-administration of infusions without further reactions. for subsequent courses, the protocol was modified for two patients who had extracutaneous symptoms during desensitization and was unchanged for the patient who had mild urticaria. these three patients tolerated subsequent courses of desensitizations without reactions. the fourth patient with symptoms during desensitization no longer required carboplatin. of the five patients who were skin tested to carboplatin, four had positive wheal and flare reactions. in one patient, the skin test response to carboplatin became negative after desensitization. conclusions the 6-hour, 12-step desensitization protocol is safe and effective for treating patients with carboplatin hr. positive skin tests to carboplatin suggest a mast cell/ige-mediated mechanism. conversion of the positive skin test to a negative response after desensitization supports antigen-specific mast cell desensitization. hypothesis: there is an association between food allergies and acid reflux in atopic adults study design: a retrospective chart review of 60 patients was conducted. 30 people who tested positive and 30 people who tested negative for food allergy were included. the prevalence of gastroesophageal reflux disease (gerd) in the total group and each of the study arms was compared to population prevalence. methods: results of 70 allergen specific ige tests (pharmacia immunocap, nj) run for food allergies were reviewed to help locate charts of 60 atopic subjects, 30 with positive, and 30 with negative food allergy results. we reviewed charts for history of heartburn and acid regurgitation or the diagnosis of gerd, laryngopharyngeal reflux (lpr) or peptic ulcer disease (pud). population prevalence (19.8%; ci 17.7-21.9) of acid reflux was estimated from a historical comparison that studied adults in a similar geographical location. results: in the food allergy positive group, 26.7% of the subjects (95% ci 11.8-41.6) had either a history of heartburn and/or a diagnosis of gerd, lpr or pud. in the food allergy negative group, 40% (95% ci 25.1-54) had acid related disorders. in the total study group of atopic subjects, the prevalence of heartburn, gerd, lpr or pud was 33.34% ). on chi square analysis, the prevalence of acid reflux disorders was significantly higher in the total study group when compared with population prevalence (p=0.013). the prevalence of acid reflux disorders between the food allergy study group and in the population shows no significant difference (p=0.41). the prevalence of acid reflux disorders was significantly higher in the food allergy negative group when compared with the prevalence in the population (p=0.003). there was no significant difference in the prevalence of acid reflux disorders between the two study groups with and without food allergy (p = 0.27). conclusions: the prevalence of acid reflux disorders was higher in people with food allergy when compared to the population, but missed statistical significance. patients without food allergy had a significantly higher prevalence of acid reflux disorders compared to the population. atopic individuals have a statistically significant higher prevalence of acid reflux disorders, but there is no statistically significant difference between atopics with and without food allergy. abstract background: analysis of dispensing patterns of injectable epinephrine offers a method to study the characteristics of school children with allergic or anaphylactic reactions. objective: to analyze the demographics of children prescribed injectable epinephrine in massachusetts school districts with diverse racial and ethnic enrollment patterns. methods: school nurses in 44 schools (grades pk-12) enrolling 21, 870 students recorded the characteristics of students prescribed injectable epinephrine including the number and racial mix of students in each school, student age, grade level, race, sex, and allergic disorder requiring epinephrine. surveyed school districts were two predominately white (98%) suburban districts enrolling 5855 students and one urban area with a minority population of 60% enrolling 16, 020 students. the use of epinephrine for peanut allergy was analyzed in detail. results: a total of 181 of 21, 875 (0.83%) students in three school systems were dispensed injectable epinephrine. males outnumbered females (110 to 71). whites outnumbered non-whites 153 to 28. two thirds (n=116) of children dispensed epinephrine had peanut allergy. the second most common allergy was stinging insect allergy (n=34). the rate of dispensed epinephrine for peanut allergy was lowest in the urban school district (0.30%) versus the two suburban districts, 1.1% and 1.26% respectively. whites with peanut allergy outnumbered nonwhites 99 to 19. males outnumbered females 69 to 49. the lowest rate of prescribed injectable epinephrine for peanut allergy in all three school districts was found in 9612 non-white school children-0.17%. eighty-nine of 118 (75%) school children with peanut allergy were enrolled in grades pk through 5. there were twice as many white versus non-white (32 to 16) school children in the urban system with prescribed injectable epinephrine for peanut allergy. only eight (.11%) of 7209 hispanic and asian students in the were dispensed injectable epinephrine for peanut allergy. conclusions: this is the first study to suggest that there may be a racial disparity in the prevalence of childhood peanut allergy. one possible explanation for this disparity is that varied feeding practices in minority infants and children may induce a state of tolerance and lead to a lower incidence of peanut allergy. f.i. hsu * , h.j. burstein, m.c. castells, boston, ma. introduction: trastuzumab is a humanized igg1 kappa monoclonal antibody specific for human epidermal growth factor receptor 2 protein, her2, used in the treatment of her2/neu positive breast cancer. we present the first report of desensitization to trastuzumab in a patient with an ige-mediated reaction to trastuzumab and documented igg-anti-igg1 human antibodies. meth-ods: a 37 year old woman with metastatic invasive ductal breast cancer (er/pr positive, her-2 strongly positive), unresponsive to conventional therapy, presented with an anaphylactic reaction to trastuzumab and was evaluated for rapid desensitization by skin testing and serum specific igg antibodies. the patient had previously received trastuzumab. results: the anaphylactic reaction to trastuzumab consisted of diffuse erythema, urticaria, respiratory distress and laryngeal edema. premedication with steroids, h1 and h2 blockade, and slow infusion did not prevent a subsequent reaction. skin prick testing with trastuzumab (21mg/ml) was positive with 2 negative controls, confirming an ige-mediated mechanism. igg anti-human igg1 antibodies (haha) to trastuzumab were confirmed by elisa. the patient was desensitized to trastuzumab 2 mg/kg with an intravenous protocol that started at 0.5 mcg/h, and increased in rate every 15 minutes until a final rate of 30 mg/h, for a total infusion time of 6 to 8 hours. premedication included diphenhydramine, prednisone, famotidine, and montelukast. desensitization was confirmed by negative skin prick and intradermal tests (2 mg/ml and 21 mg/ml), with positive histamine control. the patient tolerated a total of 10 weekly doses of trastuzumab 2 mg/kg. intradermal skin testing prior to her 5th and 10th courses showed reactivity, indicating resensitization. serum levels of tratuzumab were undetectable at 1 week after desensitization. conclusion: allergic reactions to trastuzumab are rare but can include anaphylaxis. in patients with documented haha and/or ige-mediated reactions to trastuzumab and clinical symptoms of type i/mast cell mediator-related symptoms, desensitization can allow continued administration of this treatment by providing tolerance. the clinical effectiveness of desensitizations in patients with ige and haha antibodies remains to be defined. in contrast to reports in the medical literature, details of the medical aspects were limited. there were 2 attacks on infants bringing the total to 3 reported infant attacks to date. two of the 3 infants suffered long term morbidity and 1 died. like those reported in the medical literature, the majority of adults were in long term care facilities, although 2 were in hospitals. overall, 6 of the 20 individuals stung died within one week of stings. no significant medical consequences of stings were reported in 6 of 10 of the newspaper reports as opposed to 2 of 10 reports in the medical literature. conclusion: our data suggest that increasing numbers of fire ant attacks are occurring in medical facilities, where chronically ill, frequently immobile patients come in contact with foraging ants. unattended infants in private homes in fire ant endemic areas also appear at risk. the factors that determine why individuals are stung and the severity of injury after attacks remain uncertain. the presence of fire ants inside health care facilities and homes is a harbinger for fire ant attacks of disabled or infant occupants. we hypothesize that morbidity is determined by the number of stings, the condition of the patient and the type of treatment administered. purpose: to determine if gender confers a risk for positive penicillin (pcn) skin test. method: rates of positive pcn skin tests, according to gender, were determined in patients with a history of pcn allergy undergoing an allergy pre-operative evaluation from june 2002 to june 2004. during this period, 19, 429 patients were seen in the pre-operative evaluation clinic in which 1921 had a history of pcn allergy and comprise our study population. a univariate logistic regression analysis was employed to calculate the odds ratio (or) and the 95% confidence interval (ci) for gender differences in the rates of positive pcn skin test and a multivariate logistic regression analysis was used to adjust for age and history of multiple drug allergies. p-value of 0.05 or less was considered statistically significant. results: of the 1921 patients, 1759 underwent skin testing for pcn, 157 patients did not, and 5 charts were not available for review. the mean age of the study group was 60 years. sixtyfour (3.6%) patients had a positive skin test to pcn. of these, 53 (83%) were females and 11 (17%) were males (or 3.6, 95% ci 1.9-7.2, p = 0.0001). of those with a negative/equivocal pcn skin test, 960 (57%) were females versus 720 (43%) males. in a multivariate logistic regression analysis adjusted for age and history of multiple drug allergies, female gender again was more likely to have a positive pcn skin test (or 4.7, 95% ci 2.3-10.5 p < 0.0001). 157 patients did not undergo pcn skin testing, 62 (40%) were male and 95 (60%) were female. conclusion: this is the first report showing that a greater risk for a positive skin test to pcn exists in association with female gender. age and a history of multiple drug allergies are unlikely to be confounding factors to the observed gender risk. further studies are needed to identify other possible confounding factors and/or mechanisms that can explain this risk. a. fiocchi 1* , p.a. restani 1 , s. cucchiara 2 , g. lombardi 3 , g. magazzu' 4 , g.l. marseglia 5 , k. pittschieler 6 , s. tripodi 2 , r. troncone 7 , a. vierucci 8 , 1. milan, italy; 2. roma, italy; 3. pescara, italy; 4. messina, italy; 5. pavia, italy; 6. bolzano, italy; 7. napoli, italy; 8. firenze, italy. background: cow milk substitutes for children allergic to cow milk proteins (cmp) include soy-based formula and cow s milk hydrolysates. neither can rule out a sensitisation risk. objective: prospective assessment of clinical tolerance to a rice-based hydrolysate formula by children allergic to cow milk proteins (cmp) who consume rice openly. patients and methods: ninety-seven children aged 4 to 136 months with immediate reactions to cow milk confirmed during dbpcfc were assessed for clinical tolerance to cow milk by spt with whole milk, -lactalbumin (ala), -lactoglobulin (blg), -and -casein ( -cas, -cas) (sigma chemical, st. louis, mo). whole milk, ala, blg and cas specific ige determinations were performed using cap test (pharmacia, uppsala, sweden) . similarly, sensitisation to rice and hrf were investigated by spt and cap test. patients sera were investigated by immunoblotting for cmp, rice and hrf (heinz-plada, milan, italy). dbpcfc was carried our with 24 g rhf powder masked in neocate tm (equivalent to 180 ml reconstituted formula). results: spt: all patients were positive to cow s milk and/or cmp fractions (>3 mm wheal diameter). ige determinations gave positive results with cow milk and/or cmp fractions (72/84 patients tested), rice (16/81) and with hrf (2/85). immunoblots (n=87) were positive for -cas (n=46), -cas (n=34), ala (n=39), blg (n=34) and bovine serum albumin (n=52). similarly, although patients sera largely recognized rice (78/87), only one weakly reacted with rhf. challenge with rhf was negative in all cases. conclusions: we conclude that, despite their frequent sensitisation to rice, children with cma tolerate both rice and rhf clinically. hydrolyzed rice formulas may thus represent an alternative protein source for children with cma. r.c. cartwright * , w.k. dolen, augusta, ga. introduction: conventional treatment of human seminal fluid allergy includes abstinence, barrier protection, or subcutaneous immunotherapy with fractionated seminal fluid. treatment using local intravaginal desensitization with unfractionated seminal fluid has recently been described, but experience with this desensitization method is still limited and little has been reported as to its long-term results. methods: a 30-year-old woman with a history of allergic rhinitis and asthma experienced anaphylaxis following her first unprotected intercourse since the birth of her first child. ige-mediated sensitization was demonstrated through the use of specific ige testing (pharmacia cap system) and skin prick testing using undiluted seminal fluid obtained from the patient's husband. after approval from the human assurance committee, the patient underwent rush intravaginal desensitization with steadily increasing concentrations of seminal fluid, beginning with a 1:10, 000 v/v concen-tration. results: her specific ige level to human seminal fluid was 0.26 ku/l. skin prick testing was positive with a wheal of 10 mm diameter with pseudopods and a flare of 25 mm diameter. desensitization was successful and the patient tolerated local application of whole semen without significant reaction. following desensitization, the patient reported that she and her husband engaged in unprotected intercourse without local or systemic symptoms. over the last year since the desensitization, she has not experienced further anaphylaxis, but she has developed local symptoms if her exposure to seminal fluid was delayed past 5 days. the longest time period between exposures has been 2 weeks. she became pregnant 5 months ago and has not had any pregnancy complications. conclusions: local intravaginal desensitization was a safe and effective treatment for human seminal fluid allergy in this patient. a delay in seminal fluid exposure greater than 5 days was associated with the return of symptoms emphasizing the need for frequent seminal fluid exposure to maintain desensitization. l. terracciano, t. sarratud, a. fiocchi * , p. restani, s. guerci, milan, italy. background kiwifruit allergy in children has been seldom reported and the reactions observed are usually mild. anaphylaxis has not been described. we document the case of an infant who developed anaphylacic symptoms within minutes of his mother eating two kiwifruits and initiating breastfeeding. case history in his fourth month, the boy was admitted into an emergency department with dysphonia, breathing difficulties, generalised urticaria and angioedema of the lips and face. this episode was treated as an anaphylactic reaction with epinephrine, chlorpheniramine and hydrocortisone sodium succinate administered via a percutaneous catheter and symptomatic control was achieved within 30 minutes. after 15 days a second anaphylactic episode of similar severity occurred under the same circumstances. neither episode required critical care. the boy presented two months later for clinical evaluation in our paediatric allergy unit. skin prick tests (spt) were positive only with egg white and yolk while negative to cow s milk (and protein fractions), beef, chicken, pork, codfish, rice, wheat, soybean, maize, potato, carrot, tomato, bean, pea, celery, peanut, dermatophagoides pteronyssinus and d. farinae, grass and banana. spt with kiwifruit was specifically ordered because exquisite contact was suspected, and induced a positive wheal (>3 mm diameter). positive specific ige determinations (cap-feia from pharmacia, sweden) with kiwifruit (0.71 ku/l), cat dander (1.97 ku/l) and egg white (1.97 ku/l) were returned but determinations with other inhalant and food allergens were all below the cut-off point of 0.35 ku/l and total ige levels were 155 ku/l. strict avoidance of kiwifruit by the breastfeeding mother proved effective and nothing untoward happened in the intervening year. currently aged 2.5 years, the boy is free from food-related symptoms. prick-byprick tests with native allergens and spt carried out with commercial extracts of allergens associated in the literature with kiwifruit allergy were all negative. comment there are no reports of immediate reactions to kiwifruit under two years. in this case, severe reactions via breastmilk in an infant monosensitised to kiwifruit indicate that nursing may represent a hidden source of exposure. in older children monosensitisation without prior sensitisation to pollen has been described as the major risk associated with severity of symptoms. m. sikora * , j.w. sleasman, n. tangsinmankong, st. petersburg, fl. introduction: treacher-collins syndrome (tcs) is an autosomal dominant disorder with an abnormality of craniofacial development during early embryogenesis. there is a known relationship between new bone formation and development of lymphocytes and cytokines. the association of tcs and humoral immunodeficiency has not yet been reported. we present a novel case of a 12 year-old caucasian female patient with tcs and common variable immunodeficiency. methods: our patient presented with midface hypoplasia, micrognathia, microtia, conductive hearing loss and cleft palate with a history of recurrent upper and lower respiratory infections. patient had a 10-year history of chronic sinusitis, recurrent otitis media and pneumoniae which resulted in bronchiectasis. haemophilus influenza and staphylococcus aureus were persistently isolated from bronchial fluids. laboratory work-up for immunodeficiency was initiated. results: immunoglobulin analysis revealed low igg 450 (528-2190 mg/dl); low iga 42 (44-441mg/dl); igm 65 (48-226mg/dl); igg 1 354 (165-1440 mg/dl); low igg 2 59 (71-460 mg/dl); igg 3 85 (28-125 mg/dl); and low igg 4 <8.1 (2-143 mg/dl). patient had no detectable response to protein-derived vaccines (diphtheria and tetanus) and to polysaccharide-derived vaccines (pneumococcal) at baseline and at 4-6 weeks after immunization. t and b lymphocyte enumeration, ch50, ah50, and mannose-binding lectin were all within normal limits. laboratory findings were consistent with the diagnosis of common variable immunodeficiency. patient began receiving monthly doses of 550 mg/kg/dose of intravenous immunoglobulin resulting in clinical improvement. our patient no longer requires antibiotic therapy for her respiratory infections; pulmonary function has improved and bronchiectasis resolved 6 months after initiation of ivig. conclusion: our finding shows that tcs can be associated with common variable immunodeficiency which suggests a link between skeletal dysplasia and immunodeficiency. a.s. hartel * , j.w. sleasman, n. tangsinmankong, st. petersburg, fl. introduction: streptococcus pneumoniae is the most common cause of invasive bacterial infection in humans. however, incidence of s. pneumoniae infections in healthy adolescents is low (5/100, 000 per year). mannose-binding lectin (mbl) is a c-type lectin which plays a central role in the innate immune response by activating the classical complement pathway and acting as an opsonin by binding c1q receptors. several studies have demonstrated an association between invasive bacterial infections, including s. pneumoniae and a homozygous mutation of the mbl gene. however, this association has not previously been described in patients with the heterozygous mutation. methods: a 13-year-old caucasian female presented with a second episode of meningitis over a 4-year span. streptococcus pneumoniae was isolated from peripheral blood cultures on both occasions. lumbar puncture revealed wbc 22, 600; 6% bands; 83% pmns; glucose 3 mg/dl, protein 329 mg/dl; these results consistent with bacterial meningitis. extensive evaluation for predisposing causes revealed benign arnold-chiari type1 malformation. further immunological evaluation was initiated. results: evaluation revealed igg 867 mg/dl (normal 528-2190); iga 67 (44-441); igm 181 (48-226), and normal igg subclasses. antibody responses to diphtheria and tetanus vaccines were adequate. antibodies response to pneumococcal vaccine given 4 years prior were protective to all 10 common serotype tests (>1.4 mcg/ml). lymphocyte subset analysis was within normal range. howell-jolly bodies were not detected from peripheral blood smear. evaluation for secondary immunodeficiency was negative, including hiv antibody by elisa. complement analysis showed ch50 88 u/ml (65-95); ah50 71% (66-129%), and markedly low mbl of 74 ng/ml (>1000). genetic analysis of her mbl revealed heterozygous mutation in codon 54 and mutations in two promoter regions (homozygous mutation on h/l variants and heterozygous mutation on p/q variants). conclusion: heterozygous mutation of mbl codon when associated with mutation of promoter regions can result in severe impairment of mbl protein production, and may lead to increased susceptibility to invasive bacterial infections and meningitis. rationale: patients with similar symptoms may have allergic, non-allergic, or mixed rhinitis triggers and can differentially respond to distinct medications. we assessed st in our clinic patient population to characterize factors that influence appropriate diagnosis and treatment of rhinitis type. methods: we used a validated commercial questionnaire and chart review of 230 patients seen in an academic allergy clinic, to assess the number of allergic vs. irritant st and demographic and historical factors (including pharmacotherapy) associated with differences in symptoms. results: the population (n=189: 138 female, 51 male) consisted of individuals with a mixed rhinitis history. women had higher st scores than men, including: total scores [10.44+/-0.51 vs. 7.20+/-0.65, p=0.0001 (unpaired t-test)]: allergen scores (4.56+/-0.30 vs. 3.51+/-0.37, p=0.0055); and irritant scores (5.58+/-0.29 vs. 3.69+/-0.41, p=0.0003). further, patients treated with both azelastine (az) and intranasal steroids (ins) had lower st scores than patients treated with either alone (total st: az 10.06+/-0.94, ins 10.3+/-0.97, both 8.0+/-0.88, p=0.0348; allergen st: az 4.69+/-0.54, ins 5.05+/-0.37, both 3.11+/-0.50, p=0.0416; irritant st: no significant difference). conclusions: female patients have significantly higher symptom scores; total, allergic and irritant. rhinitis monotherapy (ins or az) is minimally effective in reducing st but is more effective when used in combination. these data demonstrate rhinitis population heterogeneity and address differential responsiveness to similar medications. increased response to combined drug therapy support the heterogeneous pathophysiology of mixed rhinitis features and may relate to a combination of multiple aeroallergen and air pollution exposure in the houston area. introduction: interaction between eye & nose warrants attention with regard to the propagation and treatment of allergic reactions. the role of topical therapy for rhinitis and conjunctivitis is becoming more widely considered and questions of therapeutic route have been raised. purpose: to elucidate the anatomic and pharmacokinetic interactions of conjunctival & nasal mucosa leading to more rational selection of routes of medication administration. methods:our studies have investigated the effect of ocularly instilled allergen inducing signs and symptoms of rhinoconjunctivitis. 1 study compared effects of allergen administered via conjunctival allergen challenge (cac) or nasal allergen challenge (nac) and analyzed tear & nasal secretions for ecp & tryptase. studies have also used the ability of the cac model to induce rhinitis signs & symptoms to evaluate the relative effects of medication routes: 1) ocular v. nasal spray v. systemic; 2) ocular + nasal spray v. systemic + nasal spray; 3) ocular v. placebo. results: the nac/cac study revealed that, following cac (n=34), significant ocular and nasal signs & symptoms were noted; following nac (n=39), only nasal symptoms were clinically significant. nasal symptom scores between cac & nac differed significantly at 1 timepoint, representing lag in allergen & mediator movement from eye to nose. measurable levels of ecp & tryptase were found in tears and nasal secretions for cac, but only in nasal secretions (with exception of 1 subject) for nac. in cac studies: 1) ocular therapy exhibited greater efficacy in ocular itching relief (n=73;p<0.05) and was not significantly different from nasal or systemic therapy in nasal symptom relief. 2) eyedrop+nasal spray combination exhibited significantly greater prevention of overall rhinoconjunctivitis signs and symptoms than nasal+systemic therapy (n=80). 3) ocular therapy offered greater protection from nasal signs & symptoms compared to placebo (n=32;p<0.05). conclusion: nac and cac results support the unidirectional flow from eye to nose, the ability of cac to yield nasal symptoms, and the efficacy of topical therapy. tearing, due to inflammation of the inferior turbinate would be the only ocular symptom resulting from nasal challenge. these results offer insight to the nature of the connection between ocular and nasal mucosa and the efficacy of varied medication administration routes for management of rhinoconjunctivitis symptoms. introduction: asthma disease management programs frequently target high utilizers because they are responsible for a large amount of asthma costs. once identified, such "frequent fliers" usually are offered interventions including case management. programs using this approach usually demonstrate reductions in utilization. though the interventions may cause this decline, it could also be due to regression to the mean (rtm) which is a tendency for outliers to become more like the mean over time. in this study we measured rtm in a medicaid hmo asthma population to determine whether targeted case management is effective independent of this phenomenon. we hypothesized that directed case management provides additional utilization reduction beyond rtm. methods: a weighted asthma utilization score was determined quarterly for members of an hmo with asthma from 2000 to 2004. rtm was measured by determining how many patients were persistent high utilizers quarterly for 1 year after baseline. to determine the effect of utilization-directed case management, the number of frequent fliers at baseline for each quarter also was determined. results: a total of 296 asthma frequent fliers were identified on january 1, 2001. by september 1, 2001 only 15 of these individuals continued to be frequent fliers. similar decreases in utilization were seen for frequent fliers identified at the beginning of each quarter of 2001. the mean decrease in the number of frequent fliers is shown in the table. this represents a substantial regression to the mean. the total number of high utilizers at baseline decreased by 27% after implementation of utilization-directed case management in 2002 independent of regression to the mean. this also represented a decrease from 1.6% of health plan members with asthma to 0.6% by the start of 2004 suggesting that the decline is not a result of diminishing health plan membership. the benefit appears to be the result of early intervention with members before they become frequent fliers. conclusions: utilization-directed case management can reduce overall asthma utilization by preventing members from becoming high utilizers at an early stage. programs that claim to intervene with plan members who already are high utilizers are likely to be taking advantage of regression to the mean. studies indicate a high incidence of asthma(as) among school-aged children. with the prevalence increasing, significant numbers remain unidentified. they experience morbidity, including school absenteeism, which may be preventable, in part, by adherence to national asthma guidelines. we implemented a pilot study to detect as, as control and initiation of appropriate health care among 7th grade students in a suburban population. the study was coordinated with the middle school staff and the local county health department. the screen parameters included: student questionnaires, peak flows, exercise with peak flow assessment (frast)2, and spirometry as indicated. environmental tobacco smoke (ets) was recorded. results: 196 students screened. 131 no as history and negative screen (d). 31 as history and negative screen (e). 5 as history and positive screen (a). 23 no as history with suggestive written screen and negative screen on exercise (b). 6 no as history and positive screen (c). ets in groups a, b, c: 40%, 32%, 60%. ets in groups d, e: 23%, 16%. individual student results were mailed home with medical follow-up recommended for a positive screen. parents of the 34 children who failed the questionnaire or exercise screen (groups a, b, c) were phoned at a 6-12 wk interval. no student in-group a or b had medical follow-up. 2(33%) students in group c had medical follow-up. conclusion: this as screen of 7th grade students identified 6(3%) as having significant, undetected as. 5(14%) with known as had uncontrolled as at the time of screen. 23(11.7%) students with strong suspicion of as based on questionnaire had an acceptable exercise screen. only 2 of the 34 children with a screen suggestive of as or uncontrolled as had medical follow-up. ets was increased in the homes of students with a positive screen and remains a serious health issue. school screening for as has merit, but mail and phone follow-up was insufficient to intervene or initiate acceptable as treatment. references 1. redline s. et. al. development and validation of school-based asthma and allergy screening instruments for parents and students. ann allergy asthma immunol. 2003; 90: 516-528 2. tsanakas.j.n., et al. free running asthma screening test. arch diseases in childhood.1988; 63:261-265 3. american college of allergy, asthma, and clinical immunology screening test ages (8-14) acaai.org. introduction. some laboratory evidence suggests that desloratadine is effective in inhibiting of inflammatory mediators, which play an important role not only in allergic but also in virally induced inflammation. the purpose of this study was to assess its efficacy in acute bronchiolitis developed in young children suffering from concomitant atopic dermatitis (ad). meth-ods. participants were 34 young boys and gilrs aged 18-36 who suffered from acute bronchiolitis as established by wheezing, rhinitis and fever. all patients also had concomitant ad as established by hanifin and rafka criteria. patients were allocated to receive syrup formulation of desloratadine (erius, schering plough) 1, 25 mg/day for 5 days (active group n=17) or no desloratadine treatment (control group n=17) using quota allocation system. we calculated physical global symptom score (combination of cough, wheezing, chest retractions, nasal flaring, blocked nose, runny nose, sore throat -0-5 scale) and respiratory distress assessment instrument (rdai) to examine the patient at baseline and on day 5th after therapy was initiated, day of normalization of body temperature, respiratory rate, heart beat rate, and use of albuterol. results. both group of patients were comparable on age, gender, family history of asthma, time of onset of the acute respiratory illness, extent of medication taken prior to entering the study, global symptom score and rdai index. all children were evenly treated with oxygen, oral theophylline (10 mg/kg/day) and adequately rehydrated. on day 5th global symptom score of patients receiving desloratadine was 2, 51â±0, 51 vs 3, 42â±0, 62 in control group (p=0.035). on day 5th it was also significant difference between active and control groups on rdai index (4, 44â±1, 24 vs 7, 23â±2, 30; p=0.046) especially for significant drop in wheezing score in active group. day when respiratory/heart rate normalized, temperature returned to normal, use of albuterol did not differ significantly in these groups. conclusions. our preliminary study is the first to show that desloratadine is an effective agent in viral lower respiratory tract infections of young children suffering from ad. it encourages further gcp trials to explore action of desloratadine in infantile bronchiolitis and concomitant ad. h.j. su * , w.t. lin, p.j. tsai, c.y. huang, p.c. wu, tainan, taiwan. increasing prevalence of childhood asthma has been observed across the world, and found to be associated with, partly, indoor pollution, including bioaerosol exposure. meanwhile, adequate ventilation is shown to be effective in diluting most indoor air pollutants, while only limited data are available addressing directly how the ventilation rate is implicated with childhood respiratory symptoms. this study aimed to examine the concentration distribution of selected indoor air pollutants, including bioaerosols, in domestic environment, and further to assess the effects of ventilation rate, characterized by a co2 trace gas concentration decay method, on concentration variations of the above-mentioned air pollutants. study subjects were chosen from a prior city-wide questionnaire survey based on positive response to inquiry for physician-diagnosed asthmatic status and wheezing symptoms in the past 12 months. environmental assessments, including ventilation and air quality measurements, were conducted twice, 1 in early winter and the other on early summer. respiratory health diary and pefr (peak expiratory flow rate) were recorded for 1 week concurrent with the sampling activity. increasing ventilation rate is statistically associated with decreasing indoor concentrations of co2 and tvocs. after adjustment for sex, age, and selected housing characteristics, the or between tvocs concentrations and reporting cough of study children is 9.47, and 12.84 between co2 and nasal congestion. the or between indoor bacterial concentration and the morning pefr less 80% is 10.98 in the similar multivariate logistic regression for data collected from winter study. in summer, the only significant relationship is between ventilation rate and the morning pefr less 80% of study children, or= 0.17, in a multivariate logistic regression. this study has identified less reporting of childhood respiratory symptoms, especially for coughing and the morning pefr less 80% are associated with increasing ventilation rate, and higher levels of indoor air pollution appear to be present with greater frequency of the above symptoms. this study suggest quantitatively that proper management of ventilation efficiency may be beneficial for the control of childhood respiratory illnesses. *adjusted for: sex, age, environmental tobacco exposure, use of incense and air conditioner **:p<0.05 ns:no statistical significance with whole model test background: moderate-to-severe allergic asthma can have a substantial impact on a patient's asthma-related quality of life (arql). in addition to asthma symptoms, allergic rhinitis, rhinosinusitis and other related comorbidities are often apparent in patients with more severe disease making it difficult to treat. despite guideline-consistent care, many patients still experience variability in asthma control signaling an unmet need within this population. omalizumab (xolairâ®) has recently demonstrated clinical efficacy and safety in treating asthma. objective: the aim of this paper is to summarize the arql outcomes associated with omalizumab therapy in moderate-to-severe allergic asthma. methods: we performed a systematic review of arql data from the clinical study reports and published clinical trials on omalizumab. arql was measured by the juniper-asthma quality of life questionnaire (aqlq). results: statistically significant results for arql endpoints consistently favored omalizumab over placebo. the magnitude of the changes in arql were consistently aligned with clinical endpoints. moderate to large effect sizes in the omalizumab groups were maintained throughout the 28-week clinical trial program and during the 24-week double-blind extension phase. however, the placebo groups also experienced within-group improvements and moderate effect sizes. a meta-analysis indicated a 1.6 to 2.0 fold increase in large (>1.0 point) improvements in overall aqlq scores in the omalizumab-treated group compared with placebo during the stabilization and steroid-reduction phases of the clinical trials. conclusions: the consistently positive impact of omalizumab on arql outcomes during the clinical trial program provides evidence of its value as an adjunct therapy in patients with moderate-to-severe allergic asthma. significant differences and large effect sizes were observed despite the fact that the control group received active, guideline-consistent treatment producing a substantial placebo effect. improvements were observed in overall, symptom, activity, emotional and environmental dimensions of the aqlq indicating that omalizumab produced benefits in arql in patients with moderate-to-severe allergic asthma. background: omalizumab, a monoclonal anti-ige antibody, significantly improves asthma-related quality of life (arql) for patients with moderatesevere allergic asthma who express symptoms despite moderate-high inhaled corticosteroids (ics) doses. mean scores can mask underlying variability in arql outcomes. this investigation examined variability in outcomes to elucidate the specific impact of omalizumab treatment. methods: aqlq data (n=948) from two randomized, double-blind, placebo-controlled clinical trials were pooled to assess underlying variability in the mean scores and to identify key drivers of arql treatment-effect differences (juniper-asthma quality of life questionnaire (aqlq)) between omalizumab and placebo (active control) patients. results: correlations between aqlq and other clinical outcomes were low to moderate at best (r=0.14 to r=0.60). aqlq assessment captures patient benefit that supplements clinical outcome measures. across all component items of the aqlq patients receiving omalizumab improved more than patients receiving placebo (active control) (p<0.05). omalizumab patients reported the greatest improvement for reducing waking with symptoms in the morning (symptoms domain: 2.06 vs. 1.50; p<0.001), limitations in all activities done (activities domain: 1.18 vs. 0.68; p<0.001), the fear of not having medication available (emotions domain: 0.99 vs. 0.60; p<0.01), and symptoms from being exposed to dust (environment domain: 1.31 vs. 0.88; p<0.001), compared to placebo (active control) patients. conclusion: arql assessment provides complementary and non-overlapping information on clinical benefit that is distinct from other clinical outcome measures. examination of underlying variability in aqlq mean scores and item-level response extend previously published results on omalizumab treatment effect by showing that aggregate arql improvements for omalizumab patients are strongly influenced by symptom and activity improvement. a. brimer 1 , k. malhi, c. adams, c. dinakar, kansas city, mo. introduction: the desire to belong to a group is a very powerful motivator and is exceptionally strong in the adolescent population. asthma is a disease that makes people feel different. this perception may impinge on patient adherence with medication regimens. we hypothesize that belonging to a club where every member has asthma may encourage identification of the adolescent asthmatic with their peers, and mitigate the perception of being different. objectives: (1) to investigate the factors that make the asthmatic adolescent feel different (2) to explore the hypothesis that group activities, such as an asthma club, would help adolescent asthmatics feel less different. methods: as part of an ongoing survey, children with asthma between the ages of 8-18 years were offered an anonymous questionnaire in the primary care and adolescent clinics at our hospital. the questionnaire included both multiple-choice and open-ended questions designed to explore the feelings of the respondents. the responses were numerically tallied and reported as percentages. results: at the present time, 31 surveys out of a proposed 100 have been completed. one third of the youth with asthma answering the survey had negative feelings regarding their asthma. nearly forty percent of the respondents reported that their diagnosis made them feel different from their healthy peers. forty-five percent responded that they have felt restricted or excluded from school activities, athletics, and clubs due to their asthma. over one-third of them feel uncomfortable taking their inhaler in front of their friends. most respondents (93.6%) indicated that they enjoy group activities. the majority of respondents (89.7%) rated playing sports as their favorite group activity. conclusion: almost forty percent of asthmatic youth surveyed indicated that having asthma made them feel different and resulted in restriction/exclusion from school activities, athletics, and clubs. an overwhelming majority expressed a preference for participation in group activities, particularly recreational sports. this social preference towards group activities may be incorporated into an intervention, such as an asthma club, to help asthmatic youth adjust to the disease and its treatment regimen. introduction: airway hyperresponsiveness (ahr) is an exaggerated narrowing of the airways in response to stimuli, such as allergens, histamine, and cold air. ahr is a characteristic feature of asthma linked to chronic airway inflammation. phosphodiesterase 4 (pde4) is an enzyme found in key inflammatory cells involved in the pathophysiology of asthma. inhibitors of pde4 prevent the breakdown of cyclic adenosine monophosphate, a natural modulator of inflammation. roflumilast is an investigational, oral, once-daily pde4 inhibitor, which has shown anti-inflammatory activity in vitro and in vivo. this study examined the effect of a single dose of roflumilast on changes in ahr following allergen-induced asthmatic reactions in patients with mild asthma. methods: this double-blind, randomized, crossover study consisted of 2 treatment periods separated by a 2-to 5-week washout period. a total of 13 patients (forced expiratory volume in one second [fev 1 ] 70% predicted) who were hyperresponsive to histamine (provocative concentration causing a 20% drop in fev 1 [pc 20 fev 1 ] 16 mg/ml) were randomized to receive a single dose of oral roflumilast 1000î¼g or placebo on day 1 of each treatment period followed by an allergen challenge 60 min after medication. histamine provocation was performed before and 24 h after intake of study drug. results: there was no change in fev 1 60 min after roflumilast administration, suggesting the absence of direct or acute bronchodilation. allergen challenge elicited early and late asthmatic reactions that were attenuated by a single dose of roflumilast 1000î¼g. the histamine pc 20 fev 1 in patients treated with roflumilast decreased to a lesser extent than in those patients treated with placebo. the change in pc 20 fev 1 from baseline after challenge was 2.51 â± 2.95 mg/ml (mean â± sd) with placebo and 1.23 â± 2.75 mg/ml with roflumilast. the magnitude of the change in pc 20 fev 1 was statistically significantly different between the placebo and roflumilast treatment groups (p=0.002). thus, roflumilast decreased the development of ahr by approximately 1.1 doubling-dilutions. conclusions: a single dose of oral roflumilast 1000î¼g attenuated allergen-induced ahr. these data provide further evidence that roflumilast may provide anti-inflammatory activity in vivo and may be an effective treatment for patients with asthma. introduction for the past 7 years we have been tracking pediatric asthma admissions and evaluations at the huntington memorial hospital. during the fall and winter months (oct-march) from 1996 to 2002, we noted a 1.6 x increase in the number of asthma admissions and evaluations compared with the spring and summer (april -september; 4, 993 patient encoun-annals of allergy, asthma & immunology ters in 7 years). we have analyzed potential causes for this increase. diesel particulate was estimated in 1998-9, and a 2.5-fold increase in the fall versus spring was found in burbank, a city adjacent to pasadena. pollutant particles from the combustion of fossil fuels may act as immuno-adjuvants to allergen exposure as has been demonstrated experimentally in mice and in human nasal exposure studies. methods computerized analysis of asthma admissions and evaluations were calculated according to established codes for acute and chronic reactive airways disease. infectious diseases in patients were analyzed by standard asthma questionnaire. also, pollen and mold counts, as well as diesel particulates and meteorological conditions were studied. results similar numbers of viral infections occurred in the fall of 2001 and spring of 2002. among the most prevalent pollens and molds are chinese elm pollen (sept -oct) weed pollens (july -dec), and a newly recognized aureobasidium mold (nov -march). pollen grains can fragment and release respirablesized debris that are loaded with allergens (taylor et al 2002 (taylor et al , 2004 . the conidia of aureobasidium are also of respirable size and were identified by sequence analysis. fine particulate air pollution (pm2.5), containing diesel particles, is increased in the fall and winter in southern california. con-clusions the incidence of asthma outbreaks may vary with air pollution levels in the immediate environment. pollen fragments and particles from fossil fuel combustion can deposit in similar regions of the lower airways. rainfall increases in the fall and winter and this coincides with increased molds and aureobasidium. aureobasidium was recently discovered in high concentrations in pasadena, is known to be allergenic and could be a factor in increased asthma. a mixture of pollens and molds and fine combustion particles may be relevant to this increased incidence of asthma in the fall and winter months in pasadena. background we have previously noted that tree and ragweed pollen grains can be airborne for most if not all daily periods during their respective seasons (aaaai, 2003) , (acaai, 2003) . because grass levels are lower than those of trees & weeds (aaaai / nab), we chose a longer daily interval to examine (six hours) that we had for trees (one hour) and ragweed (three hours). methods twenty-four hour microscope slide samples were collected using a burkard 7 day air sampler from 05/01/04 to 06/30/04. the slides were examined @ 100 x along a single longitudinal traverse. the presence or absence of grass pollen was noted per six-hour segment (six successive fields). results the presence of airborne grass pollen during the 4 daily segments was sparse the first two weeks of may. it gradually increased during the next 10 days, and then was detected during most of the daily segments through to the end of june. # ammophila arenaria (aa) is a highly resilient grass with habitat in europe, north america, australia, new zealand, south africa and the mediterranean, used predominantly for dune stabilization. patients with atopic diseases including allergic reactions to pollen are transferred to coastal regions in order to minimize pollen exposure. in spite of the presence of aa pollens, patients experience allergy relief at the coast. our study examines the contradiction between the presence of strong grass allergens and the absence of allergic symptoms in atopic patients, and whether allergic cross-reactions among different types of grass pollen include aa pollen. 9 adult patients presenting symptoms of grass pollen allergy underwent prick testing and rast testing to grass pollen mix and extracted aa pollen. 4 subjects showed positive results in prick and rast testing to aa extracts and were subsequently tested via rhinomanometry for reactions to aa using prick test solutions. 2 subjects showed positive reactions to prick tests for aa extract and grass pollen mix, but did not show specific antibodies. all other sera showed elevated specific ige levels, with specific reactions on 8 protein bands of aa. in sera incubated with grass pollen extract, almost all specific bands previously detected with aa were now inhibited. 3 patients with high levels of total and specific ige to aa showed weak bands after inhibition, demonstrating the allergenicity of aa. comparing data from coastal and mainland weather stations in june and july from 1961 to 1990, coastal wind speeds average 6.6 to 6.9 m/s while inland wind speeds average only 3.6 to 3.7 m/s. high wind speeds likely dilute pollen concentrations. based on findings of an inverse relationship between wind speed and pollen concentration in the dispersion of ragweed pollen, we hypothesize that concentrations of aa pollens may be similarly influenced. no sensitized patient reported allergic symptoms in coastal areas inhabited by aa plants, indicating that under natural conditions, either the plant modifies its pollen allergenicity or that environmental conditions including salt aerosols, wind patterns, topography or light exposure cause the modification. as such patterns are likely to become more dramatic as the effects of global climate change transform the natural environment, these findings may also become relevant for other grass allergy types. asthma is the most common chronic inflammatory disorders of the airways with increased prevalence in the past decade. it is characterized by airway obstruction, airway inflammation and airway hyperresponsiveness (ahr) to non-specific stimuli. in this study, we examined the effect of a novel class of molecule, ocid1001, in inhibiting antigen-induced early and late allergic response (ear and lar), ahr, and airway eosinophilia in mouse and guinea pig models of asthma. pulmonary functions were measured in conscious unrestrained animals by whole-body plethysmography. animals were sensitized with ovalbumin (ova; 20mg, intraperitoneally) with 2mg alum followed by treatment with ocid1001 (120mg/kg, i.p. twice daily for 10 days). after the last dose, animals were challenged with ovalbumin. pulmonary functions were recorded for ear and lar and 24 hrs later for ahr. this was followed by bronchoalveolar lavage, blood and lung tissue collection. treatment with ocid1001 (120mg/kg) significantly attenuated lar in ova-sensitized and challenged mice or guinea pigs with no effect on ear. ahr to methacholine in mice and to histamine in guinea pigs were prevented by treatment with ocid1001. ocid1001 attenuated the rise in total number of inflammatory cells in the lung and almost ablated the rise in bal eosinophilia in the lung due to antigen sensitization and challenge. effect of ocid1001 on pulmonary functions and airway inflammation in ova-sensitized and challenged mice were comparable to that of dexamethasone in both models of asthma. these data suggest that ocid1001prevents the underlying pathophysiological changes in allergic airway inflammation and therefore could prove beneficial in the treatment of bronchial asthma. ma; 2. madison, wi; 3. portland, or; 4. milwaukee, wi; 5. normal, il; 6. denver, co; 7. los angeles, ca; 8. fremont, ca. introduction. daclizumab (zenapaxâ®), a humanized monoclonal antibody directed against the il-2 receptor chain (cd25), is approved for prevention of renal allograft rejection and is under evaluation for treatment of asthma. daclizumab inhibits activation of human t lymphocytes by blocking il2induced proliferation, and by reducing production of th2-and th1-associated cytokines. we recently reported that daclizumab improved pulmonary function in a phase ii trial of patients with moderate to severe chronic persistent asthma (jaci, 2004, 113 (2):s286). we now report additional data from this trial on the possible role of daclizumab as an anti-inflammatory agent that affects asthma outcomes. methods. 116 non-smoking asthmatics age 18-70 with baseline fev1 50-80% predicted despite use of 1200 mcg daily inhaled triamcinolone (taa) or equivalent were enrolled in a randomized, multi-center, double-blind, placebo-controlled trial. patients were randomized (3:1) to i.v. daclizumab (2 mg/kg followed by 1 mg/kg every 2 weeks) or placebo added to stable dose taa. starting at week 12, patients underwent 25% reduction of taa every 2 weeks while continuing study drug to week 20. results. patients on daclizumab demonstrated a prolonged time to exacerbation requiring systemic steroid rescue compared to placebo patients (p=0.024). exacerbation rates were reduced in the daclizumab group compared to the placebo group for the 20-week steroid-stable and steroid-taper phases (11.6% vs. 28.6%, p=0.09). patients on daclizumab demonstrated decreased peripheral eosinophil counts from baseline to week 20 (-30â±20 /mm 3 vs. placebo +60â±30 /mm 3 , p=0.004). daclizumab-treated patients with elevated baseline serum eosinophil cationic protein (secp) had a significant reduction in secp from baseline to day 56 compared to placebo patients (p<0.01). peripheral eosinophils decreased significantly in daclizumab patients who had no asthma exacerbations compared to an increase in daclizumab-treated patients with at least one exacerbation (p=0.032). conclusions. daclizumab reduces time to and frequency of exacerbation in treated asthmatics. the mechanisms of this effect remain to be fully elucidated, but initial findings suggest that associated reductions in circulating eosinophil and eosinophil products may play a role in these therapeutic effects. hae is a genetic deficiency causing a decrease in c1 esterase inhibitor levels. it is a rare condition (approximate prevalence 1:10000 to 1:50000 individuals). it is manifest by acute attacks of swelling which can involve the larynx (a potentially life threatening condition), the gi tract (causing a syndrome similar to an acute abdominal catastrophe) or the skin and soft tissue of the patient including the limbs, face and external genitalia. there is no approved therapy for acute attacks in the usa. pathogenesis of this potentially fatal condition is thought due to excessive activity of plasma kallikrein. dx-88 is a specific and highly active (ki 40 pm) recombinant inhibitor of human plasma kallikrein undergoing evaluation in hae and cardiopulmonary bypass. it is an animal free product. a double blind, randomised (5:1 drug to placebo) placebo controlled dose ascending study of dx-88 in acute attacks of hae was run in the usa and the european union. four dose groups of 12 patients were to be included in the study. the doses were 5, 10, 20 and 40 mg/m2. the primary outcome variables were proportion of patients achieving a significant clinical response within 4 hours of administration of therapy, and safety. secondary endpoints included site response, dose response, and median time to significant response by site and dose group. dx-88 met its primary endpoint; 72% of dx-88 patients had a significant improvement within 4 hours, (placebo response rate 25%, difference 47% p= 0.0169). patients receiving dx-88 responded in a median time of 70 minutes. there was no difference in proportions of cases that responded within 4 hours between the three anatomical sites. time to significant response did not significantly differ between dose groups and anatomical sites. the safety profile was comparable for patients treated with dx-88 and placebo, in terms of saes and aes. in conclusion, dx-88 in this double blind study was shown to be statistically superior by 47% to placebo and to be at least as safe as placebo. the drug is effective at treating any hae site, including the larynx. dx-88 represents an important advance in the management of hae. ar is among the most common chronic childhood disorders, and is most effectively treated with intranasally inhaled glucocorticosteroids (ics). recent evidence suggests that intranasal ics therapy may suppress hpa axis function and decrease growth velocity. this study reports 1-year follow-up data on 24 children (12 female, 9 african american), aged 6 to 14 years (mean 10.4 years) at entry, enrolled in a long-term growth trial of intranasal taa for treatment of ar. primary measures included height velocity, bone mineral density (bmd), serum osteocalcin and salivary cortisol levels. all subjects followed their expected age-appropriate growth velocities. average growth velocities were 5.6 and 5.8 cm/year for girls and boys aged < 12 years, respectively, and 5.5 and 7.7 cm/year for girls and boys aged > 12 years, respectively. mean (+ std) bmd was 1.27 + 0.12 and 1.22 + 0.14 gm/cm2, mean serum osteocalcin levels were 89.1 + 25.5 and 114.5 + 32.7 ng/ml, and mean salivary cortisol levels were 16.7 + 8.0 and 11.5 + 6.5 nm/l at entry and 1-year follow-up, respectively. these results demonstrate no significant effect of one year of intranasal treatment with taa on growth velocity or hpa function in children with ar. 13 patients 6 males, 7 females ranging in age from 66 years to 12 years, received (o) in doses ranging from 2 to 17 injections over 4 to 34 weeks. patients were evaluated with symptoms scores, pulmonary function (pft), blood eosinophil count (bec), medication use, and allergy skin test. st were initially performed by prick and if negative, by intradermal (id) (1/1000 w/v) and if further negative by id (1/500 w/v). skin tests were performed immediately before and 20 minutes after the administration of o. there was no change in pft or bec. however there were significant reductions in symptom scores, including nocturnal asthma (<.0001), exercise tolerance (<.0001), sense of well being(<.0001). in addition, parenthetically there was a reduction in nasal symptoms (<.0001). there were also significant declines in medication use especially for albuterol (<.0001). st declined in all patients evaluated and dramatically in many. for several individual allergens st went from prick positive to id (1/500 w/v) negative. moreover st declined in all instances further, 20 minutes after the administration of o except for 2 patients. in addition to asthma one of the patients had allergic bronchopulmonary aspergillosis and another had allergic fungal sinusitis. three of the patients tested positive on prick test to mouse antigen and in each instance this became negative after administration of o with all 3 patients tolerating o without problem. we conclude: (1.) administration of o is associated with an improvement in symptoms and decreased use of medications (2.) in addition there is a prominent decline in st which is more marked 20 minutes after administration of o compared to immediately prior to administration the explanation of this finding is not apparent. (3.) o appears to be safe to administer to patients even if they demonstrate specific ige to mouse antigen by st a.p. baptist * , t.s. tang, j.l. baldwin, ann arbor, mi. introduction: academic medical institutions are under pressure to shorten or eliminate resident elective rotations due to federal work-hour restrictions. it is unknown if this will affect knowledge and referral patterns for resident and faculty physicians. the objective of this study was to examine the factors associated with resident and faculty perceived knowledge and referral patterns towards allergy/immunology (a/i). methods: a questionnaire was sent to 375 primary care physicians at one academic center. it addressed past history of a/i referrals, referral intentions for conditions that may be seen by allergists, and perceived a/i knowledge. independent variables included history of an a/i rotation, gender, department, years in training/practice, and history of referral to an allergist. results: 228 (61%) completed surveys were returned. using logistic regression with forward selection, we found in the resident physician cohort those with advanced years in training or history of an a/i rotation were more likely to have increased past history of referral to an allergist (or = 4.09, or = 3.81), increased referral intention for chronic sinusitis to an allergist (or = 3.51, or = 5.18), and increased perceived a/i knowledge (or = 2. . for the faculty physician cohort, those with a history of an a/i rotation were more likely to have an increased perceived knowledge about a/i (or = 5.64-6.18). in addition, pediatric faculty physicians were more likely to refer asthma (or = 5.62) and chronic eczema (or = 17.09) to an allergist than faculty from other departments. finally, faculty physicians with a past history of referral to an allergist were more likely to have refer asthma (or = 10.64) and allergic rhinitis (or = 9.78) to an allergist. conclusion: the factors associated with resident and faculty physician perceived knowledge, referral history, and referral intentions towards a/i differ. for residents, senior training level and a history of an a/i rotation appear most important. for faculty, history of an a/i rotation, pediatric department, and past history of referral to an allergist appear most important. given that a history of an a/i rotation may increase perceived knowledge and referral patterns towards a/i, eliminating a/i rotations in medical institutions may have important consequences for patients and the field of a/i. because recent anecdotal reports suggest that hbv may be an effective treatment for patients with multiple sclerosis (ms), there has been a movement of patients to zealous lay practitioners to receive multiple and repeated bee stings. since this practice has real risk of possible fatal allergic reactions as well as emotional and economic costs, properly conducted studies of safety and efficacy are needed. the purpose of the present phase i pilot study was to evaluate the safety of hbv extract in patients with pfms. a total of 9 evaluable bee venom non-allergic patients with pfms (21-55 years) were enrolled and were randomly divided into 4 groups, each receiving an increasing allergen dose immunization schedule for one year. hyperreactivity to hbv was evaluated by questionnaire, px and hematologic, metabolic and immunologic tests including skin tests. any possible beneficial responses to therapy were evaluated by questionnaire, functional neurologic tests (fnt) and changes in measurement of somatosensory-evoked potentials (seps) prior to and at the completion of the study. no serious adverse allergic reactions were observed in any of the 9 subjects even at the highest doses of bee venom therapy. although 4 of 9 subjects had worsening of neurologic symptoms during the course of bee venom therapy, requiring termination, this response could not be ascribed to side effects of the hbv or to a spontaneous worsening of the neurologic disease independent of treatment since there was no correlation of these events with the bee venom injections. of the remaining 5, 3 felt that the therapy was beneficial.there were no changes either in fnt or seps measured during the study. the present report represents the first controlled study evaluating the safety of hbv as a possible adjunctive treatment for multiple sclerosis. while this preliminary safety study suggests that administration of repeated injections of hbv in a step-up dosage regimen in appropriately selected non-hbv allergic patients with ms had no serious adverse allergic reactions, because of the small number of subjects studied, it does not permit conclusions regarding efficacy and therefore provides little evidence to support the use of hbv in the treatment of ms. much larger carefully conducted multi-center studies would be required to establish efficacy. i. finegold * , new york, ny. rush immunotherapy (rit) has benefits for inducing immunologic desensitization in shorter periods of time than conventional immunotherapy. however, there is an increased risk of systemic reactions utilizing accelerated schedules. in the past radiocontrast media reactions have been significantly reduced using a standardized protocol. a modification of this protocol was used prior to rit. the oral premedication consisted of 50 mgm prednisone 12 hours, 7 hours and 1 hour prior to rit, fexofenadine 180 mgm at 7 hours and again 1 hour prior to the procedure, and ranitidine 300 mgm, 7 hours prior to rit. patients tolerated the premedications well. a signed consent was obtained prior to rit. patients were desensitized in an office setting with appropriate therapy for anaphylaxis available without an indwelling intravenous line. injections generally began with 1/100 dilution of the anticipated maintenance solu-tions and were doubled every 20-30 minutes for about 2-3 hours and then the patients were observed for 1 hour or more prior to discharge. in this manner patients were desensitized in 2-3 half day sessions. the patient was injected again in 1 week, 2 weeks and then 4 weeks. doses were increased if they were not at a full maintenance dose. if reactions occurred this process was appropriately decreased. utilizing this technique 46 patients were treated. the average age was 35.5 years old (14-56 years of age) 72 % were males.72% of patients had allergic rhinitis, 25% asthma, 3% insect allergy. patients with complicated medical illnesses were excluded. nine patients had systemic reactions requiring an injection of epinephrine. among the symptoms experienced were wheezing, nasal congestion and flushing. no patient required a second injection of epinephrine, intravenous fluids, or hospitalization. the patient reaction rate was 21 % of patients treated or 9 in 1073 injections or 1% of all injections given during the rush protocol. these results are typical of the increased rate of reactions to rit. however, these systemics were mostly very mild and responded to therapy and in only one case was there a delayed 4 hour reaction. thus premedication while not preventing systemic reactions seemed to modify them to make rit in an office setting a practical and effective therapy. we have previously shown that oligonucleotides consisting a novel 3'-3'linked structure and synthetic immunostimulatory motif cpr (r is a synthetic purine moiety), referred to as second-generation immunomodulatory oligonucleotides (imos), induce potent th1 immune responses and prevent ovainduced allergic asthma in mouse models. in the present study, we examined local and systemic immune responses of imos following intranasal (i.n.) administration to naive mice. these studies showed that imos produce higher levels of serum and local il-12 compared with il-6. we next examined the ability of s.c. and i.n. administrated imos to reverse ova-induced th2 immune responses in a murine model of asthma. treatment of ova-sensitized and challenged mice with imos by either route of administration suppressed il-5 and il-13 levels with an increase in ifn-gamma secretion in spleen cell cultures and lung homogenates. imos decreased levels of serum ige and igg1 and induced higher levels of total and ova-specific igg2a titers in serum and balf. while both routes of imo delivery showed similar efficacy on serum and balf immunoglobulin levels, s.c. delivery resulted in stronger systemic effects on the spleen cell cytokine production and the i.n. route of administration produced stronger local effects on the lung cytokines. imos also decreased eosinophils in balf and suppressed inflammatory cell infiltration and goblet cell hyperplasia in lungs. these effects in lung were superior with i.n. administration of imo than did with s.c. administration. further studies to understand the effect of low multiple doses against a single higher dose of i.n. administered imos in naive mice suggest that low multiple doses induce strong th1 responses locally while the single higher dose produces higher systemic responses. these findings suggest that second-generation imos containing cpr dinucleotides potently reverse ova-induced th2 immune responses with strong th1 type cytokine induction in ova-sensitized and challenged mice and i.n. delivery is superior to s.c. delivery in reversing ovainduced airway inflammation and mucosal secretion. showed ait was medically inappropriate, lacked documentation of necessity for initiation or continuation and/or had strong contraindications in 12/18 (67%) of the reviewed records. method: we audited a convenience sample of our own records for documentation of necessity for (continuing) ait, using a checklist based on the oig report which included the following 6 criteria: an appropriate diagnosis; specific justification; exclusion of strong contraindications; signed, informed consent; a written physician order, and at least annual re-evaluation for continuing ait. results: the first 50 charts in our alphabetized file of 80 total ait charts were reviewed. the patients (21 m, 29 f) ranged in age from 9-63 yr (mean, 40 yr). the mean duration of ait was 2.3 yr (range, 0.25-12 yr). indications for ait included allergic rhinitis alone (68%) or with asthma (26%) or chronic sinusitis (2%), asthma alone (2%) and venom anaphylaxis (2%). all had initial documentation of necessity. seven charts (14%) had no written order to initiate ait. nine (18%) lacked a signed consent form. no strong contraindication was found. (peak flow documentation showed the asthma cases were well-controlled. three episodes of ait-induced anaphylaxis requiring epinephrine had occurred, but ait was subsequently resumed and well-tolerated.) seventeen (34%) charts had no documentation of re-evaluation during the preceding 6-12 months, including 3 with no documented re-evaluation during the previous 24 months or more, of ait. discontinuation of ait was "considered" for 3 patients after 1.5, 7, and 10 yr of ait, respectively, but all were still receiving maintenance doses. the estimated time for completing this review was 15-20 min per chart. inter-pretation: an internal chart review for adherence to ait practice parameters using a checklist such as ours can quickly and easily assess documentation for medicare reimbursement and patient safety. objective(s): immunotherapy is an accepted mode of treatment for children suffering from allergic rhinitis and allergic asthma. this study demonstrates that rapid allergen vaccination (rav) can be as safe as conventional allergen vaccination (cav) in children. rav may also improve patient adherence. study design: 148 pediatric patients, 1-18 years of age, diagnosed with allergic rhinitis and/or mild to severe asthma underwent rav over a 2 1/2 hour period in an office-based setting. all patients were premedicated with prednisone and h1 antagonists for 3 days prior to the procedure. patients were monitored for reactions during the procedure and continued on a cav schedule. adherence was reviewed subsequently. results: a total of 148 pediatric patients underwent rav utilizing a 2 1/2 hour protocol. of the 148 patients, 88 of them were male (59.5%) and 60 of them were female (40.5%). 143 (96.6%) of the patients had allergic rhinitis, 118 (79.7%) had asthma, and 23 (15.5%) had chronic sinusitis. during the procedure, 8 patients (5.4%) experienced systemic reaction, and none experienced true anaphylaxis. seven of the eight patients who suffered a systemic reaction were patients with asthma on inhaled corticosteroids, three of the eight patients were male (37.5%) and five of the eight were female (62.5%). every systemic reaction occurred within 15 minutes of the injection. treatment usually included one or a combination of the following: nebulized breathing treatment with albuterol, two sprays in each nostril of azelastine, and diphenydramine taken orally or intramuscularly. every patient that was treated was discharged within two hours, and no one required treatment with subcutaneous epinephrine, treatment for recurrent symptoms or hospitalization. all of the patients continued with a conventional allergen immunotherapy regimen following the rapid protocol to reach their maintenance dose. typically, 6 months of build-up period was saved. patients reached efficacious dosages almost immediately. adherence rates were 95.3%, 90.5%, and 79.7% at 3, 6, and 12 months respectively. conclusions: effective doses of allergen vaccine can be safely reached using a 2 1/2 hour protocol annals of allergy, asthma & immunology for children. advantages of rav over cav include improved adherence with almost immediate clinical efficacy, and decreased costs. introduction: studies involving allergen immunotherapy (ait) have furthered our understanding of cat allergen, proteases, and dust mite allergen. the impact of these data has not been assessed. objective: to evaluate ait prescribing trends over 12 years (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) (2001) (2002) (2003) focusing on new prescriptions before and after published data regarding specific prescribing recommendations. methods: a retrospective review of 38, 400 ait prescriptions from a centralized allergy and extract laboratory database was performed with respect to published literature on findings and recommendations regarding the ubiquitous nature of cat allergen, effective dosing of cat antigen, combining protease containing extracts with those susceptible to degradation, dust mite antigen dosing, and the use of house dust versus dust mite antigen. results: 1) in 1993, cat allergen was included in 10% of new allergy immunotherapy prescriptions reviewed; in 2003, it was included in 45% of new prescriptions, a statistically significant increase (p<0.00001). 2) over the past 11 years, the mean quantity of cat antigen included in new prescriptions has been unchanged at 1ml/prescription. only 5% of new prescriptions were written at the manufacturer recommended maintenance dose of 4ml, significantly less than those written below this level (p <0.00001). 3) there was no significant change in the percentage of extracts combining antigens with proteases with antigens susceptible to degradation. in 1992, 64% of prescriptions containing alternaria and/or cockroach antigen were mixed with one or more antigens susceptible to degradation; in 2003, 56% of these extracts were still being combined. 4) the mean volume of dust mite mix contained in these prescriptions was between 2-2.99 ml/10ml. 5) prescriptions containing dust mite rose from 20% in 1992 to 65% in 2003. the use of house dust was unchanged over the same period at 1.5% of prescriptions. conclusions: although the percentage of cat containing extracts has increased significantly, dosing of cat allergen has remained unchanged despite published literature recommending higher volumes. protease-containing allergen prescribing patterns have not significantly changed from [1996] [1997] [1998] [1999] [2000] [2001] [2002] [2003] young stage of life is a crucial period for aeroallergen sensitization, considering the immaturity of the neonatal immune system which may lead to t-cell anergy or a deviation towards th2-type response in mice. the aim of this work was to evaluate the influence of oligodeoxynucleotides containing cpg motif (cpg-odn) on ovalbumin (ova) and blomia tropicalis (bt) immunization in early life compared to adult stage. three days old a/sn mice were immunized with ova in al(oh)3 and boosted on 10th and 30th day after immunization (dai) and bled on 37th dai. groups of mice received 4mg of cpg-odn or control-odn associated with ova on immunization and boost. some animals from the three groups (ova, ova+cpg, ova+co) were killed at 20 days old and the spleen was collected and prepared to culture. eight to 10 weeks old female a/sn mice were immunized with ova in al(oh)3, boosted on 14th dai and bled on 21th dai. groups of mice received 50mg of cpg-odn or control-odn associated with ova on immunization. animals from the three groups were challenged 3 months after immunization and bled 7 days later. similar protocols were performed using blomia tropicalis (bt) extract in the place of ova. neonate and adult co-administration of cpg-odn with ova or bt were able to significantly decrease specific ige antibody levels and increase igg2a production. moreover, cpg-odn decreased specific igg1 levels in the bt immunization. the co-administration of control-odn in neonates decreased anti-ova igg1 production. after ova-challenge 3 months later of adult immunization, a similar response was detected in the group that received cpg-odn associated with ova, which showed a decreased anti-ova ige and igg1 and enhanced igg2a levels. analysis of cell division of neonate lymphocytes by flow cytometry showed a decreased proliferation in ova+cpg mice group under ova stimulation. this effect was seen either in b cells and t cells. the results showed that immunization with both allergens, ova and bt, associated with cpg-odn decreased the type i hypersensitivity response. the pattern of antibody production suggests th1-type response induced by cpg-odn, and the establishment of memory th1 response. this findings may imply that the use of cpg-odn in early life seems to be beneficial as an strategy to modulate or to prevent the development of allergic diseases. n. horne * , a. capetandes, m. frieri, east meadow, ny. introduction: it has been shown that dust mite allergens can affect the functioning of airway epithelial cells (winton et. al. br j pharm 124:1048 , 1998 . previous experiments showed ca549 aggregate in the presence of dermatophagoides pteronyssinus (dp) (capetandes et. al. am j clin path, 121:25, 2004) . it is hypothesized that epithelial damage is associated with airway remodeling characterized by fibroblast dysregulation. to evaluate the response of fibroblasts to damaged airway epithelial cells, the bioactivity of serum-free conditioned media from dp-treated ca549 cells (dpcm) was assayed with nhlf. methods: all experiments used insulin-transferrin-selenium supplemented dmem (its). dpcm (generated with ca549 treated with 300 au/ml dp; alk-abello) was added to 50% confluent nhlf for 24 hours at 37oc and 5% co2. its from cultured ca549 without dp (its cm) was added to 50% confluent nhlf (control). cell morphology and density were evaluated by microscopy and mtt assay, respectively. data were analyzed by anova followed by student-neuman-keuls (snk) at p<0.05 with power analysis. results: 50% confluent nhlf treated with dpcm showed decreased cell density (figure 1) , and increased aggregation relative to its cm or its alone. nhlf in its alone or with direct addition of 300 au/ml dp to its (dp its) showed no or weak aggregation. aggregated nhlf showed 100% viability and grew to confluence when subcultured to serum-supplemented media. conclusion: nhlf aggregation was greater, and cell density was lower with dpcm than with its, its cm, and dp its. this suggests that dp-treated ca549 cells release an unidentified factor or factors that contribute to nhlf aggregation and possible apoptosis. identification of these factors would increase the understanding of the fibroblast response to epithelial cell exposure to dp which may be involved in airway remodeling, a feature of chronic severe asthma. j.t. zimmermann * , y.c. huang, m. frieri, east meadow, ny. introduction: budesonide has been demonstrated to inhibit il-8, tgf and gm-csf in ragweed and dust-mite (dm) stimulated human alveolar epithelial cells (j allergy clin immunol 209:3a, 2002; ann allergy asthma immunology 90: p79, 2003) . rantes production and expression in dm and il-1 -stimulated a549 cells has recently been shown to be inhibited by budesonide (allergy asthma proc, in press 2004). histamine is known to influence immune response by regulating cytokine synthesis (allergy 47:024-1992) . in this study we examined the effect of budesonide in the presence of histamine on il-8 production and expression by a549 cells. methods: a549 pulmonary epithelial cells were cultured in dmem for 24 hours in 5% co2 in the presence of 1:20 of 10, 000 au/ml dm, 10 -6 m histamine and 10 -7 m budesonide. il-8 production was measured by a sensitive elisa and il-8 mrna was measured by qualitative rt-pcr using standardized primers for il-8 with a gapdh control. results: a549 cells were stimulated by dm (65-101 pg/ml) (p<0.01). budesonide alone decreased il-8 levels to 38 pg/ml (p<0.05), and in combination with histamine further decreased il-8 levels to 23 pg/ml (p<0.001). relative intensity of il-8 mrna expression was reduced 12-fold in dm-stimulated cells and 2-fold in control cells by budesonide. conclusion: budesonide in combination with histamine showed greater inhibition of il-8 production by a549 cells than budesonide alone possibly by increasing cell membrane permeability. c.r. oliveira * , a.e. fusaro, j.r. victor, e.a. futata, c.a. brito, a.j. duarte, m.n. sato, sã£o paulo, brazil. antigen-driven bystander suppression induced by oral tolerance could be an interesting approach in the allergy field, considering the high incidence of new allergens sensitization in atopic individuals. to address the influence of non-related allergen exposure on the type i hypersensitivity response to the mite blomia tropicalis (bt) or ovalbumin (ova) in mice and to verify oral tolerance effect in the bt/ova co-immunization model. groups of mice were immunized with bt extract and two weeks later submitted to ova-immunization, or first immunized with ova or co-injected with bt and ova. ova feeding was performed five days prior co-immunization. ige abs were estimated by means of passive cutaneous anaphylaxis reaction and specific ab and cytokines secretion by elisa. mice sensitized with bt and then exposed to ova developed an enhanced ige response to itself and to ova, but such response has not been observed when ova-immunization was prior to btimmunization. co-injection of bt and ova led to a dominant ige response toward ova over bt and vice-versa for the igg1 response. ova feeding prior co-immunization decreased ige, igg1 and igg2a ab levels against ova in parallel to a bystander suppression, which avoided the outcome of bt-sensitization. these mice showed increased ifn-?secretion levels induced by antigen-specific stimulus. furthermore, effectiveness of oral tolerance was also related with ova amounts employed in the co-immunization since ova feeding prior co-immunization with low amounts of ova led to inhibition of ige ab response to both allergens, whereas inhibition of specific and non-related antigen igg ab response was broken. the results evidenced that, depending on allergenic potential, new allergen exposure may exert an adjuvant effect on the primary sensitized allergen. the bystander effect to non-related allergen by oral tolerance should be an interesting mechanism to control new allerrationale. cd4 + cd25 + regulatory t cells from patients with atopic asthma undergo apoptosis when stimulated by specific allergen. antihistamines are used to control allergic inflammatory diseases, but their influence on treg cells is currently unknown. the present study investigates the influence of desloratadine (d) on apoptosis of cd4 + cd25 + regulatory t cells in atopic patients having dust mite induced allergic disease, including allergic asthma. methods. patients (n=6) with positive skin prick tests to house dust mite allergens and a clinical history of allergic upper and/or lower respiratory symptoms were treated with d 5mg (schering-plough, usa) once daily for 10 days. no patients used systemic corticosteroids, while theophylline and other medications were stopped at least 72 hours before blood collection. blood was sampled before and after treatment with d. the control group was comprised of 6 individuals without allergic respiratory symptoms and with negative skin prick-tests. peripheral blood mononuclear cells (pbmc) were isolated over a ficoll density gradient and stimulated by specific allergen (dermatophagoides farinae) and in a control series by phorbol myristate acetate (pma). pbmc were labeled with anti-cd4, cd25, cd95, and bcl-2 monoclonal antibodies. the annex-inv-propidium iodide (anv-pi) test was done. lymphocyte subpopulations and apoptosis were analyzed by flow cytometry. results. after treatment with d, atopic patients had no significant differences in the number of cd4 + cd25 + cells. during co-culturing of pbmc from patients treated with d with specific allergen a significant increase in cd4 + cd25 + cells was observed. simultaneously, treatment with d led to a significant increase in expression of the antiapoptotic protein bcl-2 in cd4 + cells. this data paralleled the decrease of cd95 expression on cd4 + cells. there was also a decrease in treg cells in the late stages of apoptosis (anv + pi + cells) in d treated patients. conclusions. the antihistamine preparation desloratadine prevented allergen-specific apoptosis of cd4 + cd25 + t regulatory cells in patients with atopic asthma. the type 1 histamine receptor may be involved in the regulation of apoptosis and/or survival of cd4 + cd25 + t cells. a.g. palma-carlos * , m.l. palma-carlos, lisboa, portugal. introduction: solar urticaria porphyrin corresponds to sun sensitivity to a 4000 a wavelengths and is due to disturbances of posphorin metabolism. photosensitivity can cause urticaria, erythema, polymorphic solar eruption and in more severe cases vesicles and bullae. photosensitivity was confirmed by light test. methods: protoporhyrin in rbc, uro and coproporphyrins in urines, copro and protoporhyrins in faeces and porphyrin precursors have been studied un all the cases of solar urticaria seen in the last few years. results: in 10 patients, 8 female, 2 males, a diagnosis of porphyria has been confirmed by laboratory methods. clinically 4 patients presented solar urticaria and 6 solar erythema or polymorphic solar eruption. 7 patients, 8 female, 2 males (21-54) presented also neuro visceral symptoms: abdominal pains (7) vomiting (4) asthenia (7) constipation (3) muscle pains and paresia (3) depression (2) anesthesic reactions (2). in 2 cases the symptoms were associated with anticonceptional drugs. the conjunction of clinical history with laboratory data has allowed to confirm the diagnosis of 2 cases of protoporphyria erytheropoietica, one triggered by anticonceptionals, 6 cases of coporporhyria hereditaria and 2 cases of porphyria variegata. this group comprises one case of erythropoietic protoporphyria induced by estrogens not previously reported. conclusions: research of porphyrins must be done in all the patients with solar urticaria and erythema. the incidence of sun sensitivity in mixed hepatic porphyriaalso presenting neuro-visceral symptoms which can be drug dependent suggests that porphyria study must be mandatory in suspected cases. a.r. narayan 1* , j. kaplan 1 , v. sirvan 1 , a. chandrasekaran 2 , c. goodwin 2 , l. goodwin 2 , l. guida 3 , m. frieri 1 , 1. east meadow, ny; 2. manhasset, ny; 3. bayshore, ny. rationale: our division has reported that nitric oxide (no) from tracheal epithelium can mediate induction of il-8 (american journal of respiratory critical care medicine 151:642a, 1995) . increased levels of il-8, ltb-4, and no in mononuclear cells (mnc) from cystic fibrosis (cf) patients were noted.(pediatric asthma allergy immunology 10: 101-7 1996) . no in mnc from cf was increased by stimulation with aspergillus fumigatus (asp) and rhdnase (j. clin allergy immunol 105:320p 2000). tnf-is produced from bronchial epithelial cells (bec) in the presence of mnc of normal controls (nc). rantes, a chemokine that facilitates leukocyte migration, is associated with airway inflammation in cf, and asp sensitization in cf patients could amplify pro-inflammatory cytokines such as il-8, tnf-, and rantes. methods: we studied the mrna and protein expression of tnf-, il-8 and rantes in a 65 year-old cf patient and a nc. 1x10 6 mncs from the patient and nc were stimulated with 21î¼g/ml of asp with bec at 10x10 5 and 10î¼g/ml rhdnase. mrna expression was studied by real time pcr (taqman chemistry abi prism 7700) and protein levels by elisa. results: tnf-production in supernatants of mnc with bec from nc increased from 8 pg/ml to 64 pg/ml with rhdnase. whereas in cf patients the tnf-mrna expression was greatly enhanced over nc but declined in the presence of rhdnase (fold difference: 8.37-7.70). there was no difference in expression levels of nc (fold difference: 4.0-3.9) with rhdnase treatment. il-8 expression in mnc with bec of patients increased 2.4 fold compared to nc (1.5 fold). rhd-nase decreased asp stimulated levels to 1.72 fold in patients compared to nc (2.9 fold). mnc and bec rantes production in patients increased from 49 to 1025 pg/ml and decreased to 570 pg/ml with rhdnase, but increased from 1134 pg/ml to 1775 pg/ml in nc. in contrast, rantes mrna expression in all groups was higher in nc but decreased with rhdnase in both cf and nc (37-26 fold vs. 14-10 fold). conclusion: rhdnase can increase no and decrease pro-inflammatory tnf-and rantes in cf patients stimulated with asp. rhdnase could lead to augmented bactericidal activity and epithelial defense by enhancing no production and decreasing the expression and production of tnf-, il-8 and rantes. this is a case report of two steroid dependent atopic dermatitis patients who both responded to treatment with omalizumab. patient a is a 39 year-old white male who presented with a history of severe atopic dermatitis for 10 years along with concomitant mild persistent asthma and allergic rhinitis. he had previously received monthly triamcinolone injections, methotrexate and doxycycline with limited response. on presentation he had mild improvement on a regimen of alternate day prednisone 30mg, fexofenadine 180mg bid, and zafirlukast 20mg bid. however, attempts at weaning prednisone were unsuccessful. omalizumab was initiated at a dosage of 150mg every four weeks. the patient remains prednisone dependent yet free from atopic dermatitis. patient a's diagnostic work up determined a total ige of 33.1 ku/l. the patient's specific ige tests were positive for grass mix, weed mix, maple, white pine, peanut, strawberry, gluten, soybean, wheat, oat, and dog dander. specific ige tests were negative for cat dander, egg white, milk, goose feathers, chicken feathers, mold mix, dust mix, and fish mix. patient b is a 23 year-old white male who presented with a history of severe full body atopic dermatitis along with mild persistent asthma and allergic rhinitis. he also was receiving triamcinolone injections with limited success. he responded to alternate day prednisone 30mg, desloratidine 5mg bid, and zileuton 600mg bid. attempts at weaning prednisone failed until initiation of omalizumab 375mg every two weeks. his atopic dermatitis is now under control with once daily desloratidine and omalizumab every two weeks. he was successfully weaned off of corticosteroid medication and has begun an immunotherapy regimen. patient b's diagnostic work up determined a total ige level of 1159 ku/l. patient b's specific ige tests were positive for weed mix, tree mix, maple, peanut, strawberry, dust mix, cat dander, dog dander, egg white, milk, oat, wheat, goose feathers, and chicken feathers. specific ige tests were negative for grass mix, white pine, mold mix, gluten, soybean, and fish mix. these two case reports reveal significant response to omalizumab in severe steroid dependent atopic dermatitis. further research is strongly indicated considering the quality of life issues with severe atopic dermatitis and potential side effects to long-term corticosteroid treatment. eosinophilic esophagitis (ee) has been described in children and is characterized by high levels of eosinophils (>20-24 eosinophils/high powered field [hpf]) in the esophageal mucosa. a recent report indicates that the combined prevalence of the eosinophilic gastrointestinal disorders may be higher than that of inflammatory bowel diseases (ibd). the presenting symptoms of ee mimick those of gastroesophageal reflux disease (gerd), and patients of all ages may experience a delay in time from onset of symptoms to diagnosis of ee. there is a paucity of data in the literature regarding the delay in time from symptom onset to diagnosis of ee. we report the data on four children three years of age and under with ee who experienced a significant diagnostic delay. four young children were referred to the pediatric allergy clinic with a diagnosis of ee (table) . three of the patients were male and one was female. the patients were 17-36 months of age at the time of diagnosis, and the diagnostic delay was 15.5-33 months (average delay 23.6 months). the most common presenting symptom was vomiting, and three of the four patients had a history of respiratory obstructive symptoms. all of the patients had received conventional treatment for reflux disease, and one had undergone a nissen fundoplication prior to diagnosis. in all four patients the esophageal biopsy revealed >20 eosinophils/hpf. three out of four patients had a family history of atopy, and two patients had a known history of a food allergy. skin tests to foods were positive in two patients and rast (radioallergoabsorbent) testing to foods was positive in one patient. recent data suggests that the diagnostic delay in ibd is decreasing as much as 50%. it is hypothesized that this may be due in part to an increased index of suspicion by health care providers. there is little data available regarding the diagnostic lag in children with ee. it is currently believed that chronic ee can lead to progressive esophageal scarring and dysfunction. stricture formation has also been described in children less than two years of age. given the reported increased incidence of this allergic gastrointestinal disease over the past decade, more data regarding the diagnostic delay of these conditions may be instrumental improving health care providers' awareness of this disorder. a. kohli-pamnani * , e. cooney, p. huynh, f. lobo, new haven, ct. introduction: cutaneous hypersensitivity reactions to amprenavir, an hiv-1 protease inhibitor, are reported in up to 28% of treated patients, of whom 4% have severe or life-threatening rashes, with treatment discontinuation required in 3% of cases. we report a case of successful desensitization to amprenavir, for recurrent maculopapular exanthem, in an hiv-infected patient with late stage disease and limited antiretroviral (arv) agent options. methods: the patient is a 40 year-old caucasian female with late stage hiv disease (absolute cd4 count 30 cells/mm 3 , hiv rna 200, 000 copies/ml) and multiple arv intolerances, who developed a severe generalized maculopapular eruption sparing mucous membranes six days following initiation of a regimen comprised of amprenavir, lopinavir/ritonavir, zidovudine, and lamivudine. a similar reaction occurred following re-challenge with amprenavir alone (600 mg oral formulation bid via percutaneous endoscopic gastrostomy (peg) tube), despite concurrent administration of oral prednisone 20 mg/day and loratidine 10 mg/day. results: skin prick testing with amprenavir 0.01 mcg/ml was negative, whereas intradermal testing with 0.1 mcg/ml was positive with a 7 mm wheal and 20 mm flare. percutaneous and intradermal testing with normal saline was nonreactive. the positive histamine control (skin prick only) yielded a 5 mm wheal and 20 mm flare. subsequently, incremental doses of 0.025 mg, 0.1 mg, 0.25 mg, 1 mg, 2.5 mg, 7.5 mg, 25 mg, 50 mg, 100 mg, 300 mg, 600 mg, and 1200 mg of amprenavir oral solution were administered via peg tube at 20 to 30 minute intervals (table) . the patient successfully tol-erated amprenavir desensitization and has remained on therapy without recurrence of rash out to 16 months of follow-up. conclusions: desensitization may permit continued use of amprenavir in patients with a history of amprenavirinduced maculopapular eruptions who have limited alternate treatment options. efforts aimed at characterizing the mechanism of amprenavir cutaneous hypersensitivity reactions seem warranted, given the frequency of reactions and the limited number of arv agents available for patients with late stage hiv disease. doses of oral solution were administered by peg tube at twenty to thirty minute intervals. introduction: beta-lactam (bl) allergy is the most common drug allergy. in most cases, ige antibodies are specific to the bl nucleus. however, sidechain-specific ige (scsige) to bl has been described. despite this, skin testing (st) to bl other than penicillin (pcn) is not commonly performed. we report a case of a 31 year-old female with a selective allergy to pip, and describe the utility of st to this agent to confirm scsige. methods: st to prepen (pp) and pcn g was carried out with percutaneous (pc) testing followed by intradermal (id) testing. st was also carried out with ampicillin (amp; 1 mg/ml), pip (60 mg/ml at pc level; 1 mg/ml at id level-a non-irritating concentration), and pip/tazobactam (tbm; 60 mg/ml at pc level; 1 mg/ml at id level) to exclude the possibility of selective allergy to tbm. case report: a 31 year-old white female with crohn's disease was hospitalized for treatment of intra-abdominal abscesses. she had immediate flushing and urticaria during an infusion of pip/tbm approximately 2 years prior. the allergy/immunology service was consulted for pcn st because her primary service preferred to empirically treat with pip/tbm. she had received imipenem approximately 8 months prior without untoward reaction. st to pp and pcn g was performed with negative responses and adequate controls. she subsequently received pip/tbm, but developed flushing and urticaria during her initial infusion, consistent with an ige-mediated reaction. two months later, st to pp and pcn g was repeated. in addition, st to amp, pip, and pip/tbm was performed. she had positive responses to pip and pip/tbm with negative responses to pp, pcn g, and amp, implying selective ige-mediated potential to pip. she tolerated an oral challenge with pcn vk 250 mg immediately following st without untoward reaction. conclusion: we have described a case in which st to pip was useful for diagnosing scsige in our patient, who had 2 prior reactions consistent with ige-mediated pathogenesis. this information will be helpful in identifying antibiotics she can safely receive in the future. this case supports the utility of st to bl in addition to pcn, in evaluation and management of patients with a history of adverse reaction to bl that may reflect presence of scsige. a.r. vaishnav * , b.s. bochner, baltimore, md. we report the case of a 39-year-old caucasian male with a 15-year history of asthma, two episodes of eosinophilic pneumonia and chronic peripheral eosinophilia with baseline eosinophil counts around 1000/î¼l who developed amnesia and elevated cardiac enzymes in february 2004. another physician had added montelukast in january 2004 and because of a good response advair was decreased from 500/50 to 250/50 bid. in february his eosinophil count increased to 3430/î¼l and soon he developed left arm numbness, diplopia as well as left arm and leg weakness. at his local hospital, he was found to have elevated troponins and cpks. cardiac catheterization showed normal coronary arteries and good left ventricular function. soon after discharge, he developed confusion and global amnesia. brain mri showed diffuse uptake consistent with global inflammation and/or vasculitis. upon hearing this story, we told him to take 60 mg of prednisone and urgently come to our hospital for admission. within hours, his mental status and visual symptoms improved. physical examination was unremarkable except for subungual splinter hemorrhages. montelukast was stopped and 1 gm/day solu-medrol iv was started. endomyocardial biopsy 2 days later showed mild hypertrophy and fibrosis without eosinophils. repeat brain mri and mra were normal. chest ct showed multiple patchy infiltrates with a new central cavitary lesion in the right lobe. other labs included a negative anca, ana of 1:40, normal complements and csf. our differential diagnosis included churg-strauss syndrome (css) versus hypereosinophilic syndrome (ihes) with myocardial, neurological and pulmonary involvement. serum tryptase was normal as was fluorescent in situ hybridization for the fip1l1-pdgfr fusion gene. based on this, along with the new pulmonary cavitary lesion on chest ct, the diagnosis of css was made. after 3 days of iv steroids, he was switched to 60 mg/day of prednisone. upon discharge his eosinophil count was 350/î¼l on 60 mg of prednisone. after all procedures were completed, he was also started on aspirin 325 mg daily to prevent thrombotic and thromboembolic complications. he was seen in follow-up in clinic and cytoxan 100 mg daily was started. his prednisone is being tapered. he is tolerating the treatment well and so far has had an excellent clinical and laboratory response. introduction-c1-esterase inhibitor (c1-inh) deficiency is a rare disorder classified into acquired and hereditary forms. both entities are distinguished by recurrent angioedema without pruritus or urticaria. the upper airway, head, neck, extremities and gi tract are typically involved. the inherited form usually presents in the first or second decade accompanied by a family history. the acquired form more commonly presents after the fifth decade. in acquired c1-inh deficiency, serological evaluation reveals low levels of c4, c1-inh, and c1q and a normal c3 level. levels of c1q are normal in the hereditary form. the acquired form may be associated with lymphoproliferative disorders and autoimmune disease. acquired c1-inh deficiency is typically recognized before the underlying malignant condition is diagnosed. clinical regression has been reported in patients whose underlying disorder responds to treatment. methods-a case report of a 57-year old female who developed repeated episodes of facial angioedema requiring hospitalization preceded by one year of vague abdominal pain and cramping. data-laboratory investigation of this patient revealed c4<10mg/dl (16-47 mg/dl), c1q<3.5mg/dl(5.0-8.6 mg/dl), ch50<20u/ml(31-66 u/ml), and c1-inh at 3 mg/dl(6-25 mg/dl) with a 51% activity (>68% normal). c3 was 138 mg/dl(90-180 mg/dl). other laboratory evaluation was notable for a normal cbc with diff, comprehensive metabolic panel, amylase, lipase and spep pattern. ige was elevated at 173 ku/l. hematology was consulted. ct of chest, abdomen, and pelvis were nondiagnostic. peripheral blood flow cytometry revealed a small distinct pop-ulation consistent with a clonal b-cell lymphoproliferative disorder. a repeat test showed skewing towards lamba light chain expression. bone marrow biopsy and aspirate were essentially normal except for erythroid hyperplasia on danazol treatment. the physical examination was without any masses or lymphadenopathy. the patient remained asymptomatic after beginning danazol although elevations in rbc, hgb, hct and absolute lymphocyte count have developed. conclusion-acquired c1-inh deficiency is rare cause of recurrent angioedema that has been reported in small cohorts and case presentations. we report another case report that reinforces the need for physicians to evaluate for concomitant lymphoproliferative disorders. chronic urticaria is a distressing condition usually associated with poor quality of life and poor response to symptomatic therapy. a wide variety of causes and mechanisms have been described and in some patients the cause remains unknown. rare cases have been associated with thyroid antibodies and some responded to thyroxin, even in the absence of overt thyroid disease. case report: a 54-yr-old obese white female presented with a history of persistent urticaria/angioedema for 4 mo. urticaria involved various parts of the body and individual lesions usually lasted < 24 hr. it was often accompanied by facial edema. oral diphenhydramine 25mg qid caused only little improvement. the patient could not suspect any offending factors. review of systems and past medical history were unremarkable, except for hyperthyroidism at age 12 yr that was treated with "medication" for 3 yr. on physical examination there were several urticarial lesions though she has been taking diphenhydramine. the thyroid appeared normal regarding size, shape and texture. various second generation antihistamines and doxepin were of little help. laboratory evaluation revealed total serum ige of 7 iu/ml (normal <200 iu/ml) and ch50 of 73 u/ml (normal 22-60 u/ml), but high tsh of 15.2 iu/ml (normal 0.4-5.0 iu/ml) and low free t4 of 0.58 ng/dl (normal 1.45-3.48 ng/dl). her antithyroglobulin titer was 32 iu/ml (normal <100 iu/ml) but the antimicrosomal titer was highly elevated at 382 iu/ml(normal <20 iu/ml) consistent with hashimoto's thyroiditis. thyroxin therapy was initiated at a dose of 100 mcg/d which resulted in marked improvement within one week and the patient was able to discontinue doxepin and other antihistamines. because of marked drop in tsh to 0.08 iu/ml, the thyroxin dose was reduced to 50 mcg/d. her thyroid function tests became normal within two months. she did not experience any recurrence of urticaria or angioedema during over 6 mo of follow-up so far. conclusion: patients with chronic urticaria/angioedema, especially women, should be screened for thyroid autoantibodies and if positive, thyroxin therapy might bring impressive remission in urticaria. hypersensitivity pneumonitis (hp) results from an abnormal immunologically mediated response to an environmental antigenic trigger. typically patients with hp experience transient fever, hypoxemia, muscle and joint pain, difficulty breathing, fatigue, weight loss, and cough. there are two clinical presentations of hp differentiated by onset and resolution of symptoms. patients experiencing acute hp experience the onset of symptoms 2 to 9 hours following exposure to a particular antigen and resolve in 1 to 3 days without specific treatment. however, patients with chronic hp experience symptoms that persist for months to years when exposed to a recognized cause of hp. a 55 year-old caucasian male was referred to our practice with acute bronchitis. his referral was secondary to a history of allergic rhinitis, chronic asthma, gastro-esophageal reflux disorder, and sinus surgery. this non-smoking male was a machine operator at a local factory. he was doing well until he began working in the presence of a heat induction machine and metal lubricating spray called multan ea20 (hinkle surface technologies), i.d. no.: 238073. multan ea20 is a product containing naphthenic petroleum distillates, amine salts, amine soap, triethanolamine hexyl, hexylene glycol, ethanol, sodium petroleum sulfonate, and triazine. this lubricant is known to irritate the eyes, skin, and respiratory tract. recent studies indicate that thermal decomposition of triazine, which readily occurs during metalworking, results in the production of formaldehyde. formaldehyde is a known carcinogen, as well as respiratory, skin, eye and digestive tract irritant. the patient developed serious respiratory health problems resulting in work absence and eventually hospitalization. while hospitalized he received a high resolution ct scan which showed diffuse ground glass appearance, and multiple attenuation areas of the lung which are consistent with hypersensitivity pneumonitis. the patient was treated with corticosteroids, and antibiotics with eventual normalization of lung parenchyma by chest ct. this represents the first reported case of hypersensitivity pneumonitis resulting from exposure to the metalworking fluid and respiratory irritant multan ea20. a.j. ham pong 1* , f. chan 1 , s.l. bahna 2 , 1. ottawa, canada; 2. shreveport, la. sexual intercourse has been known as the route for semen hypersensitivity reactions to the seminal fluid protein or to a contaminating drug or food. we report a case of anaphylaxis to cephalexin-containing semen by ingestion. history of present illness: a 37-year-old woman developed a systemic reaction after swallowing semen. since the couple frequently practiced fellatio without any reactions, her husband suspected cephalexin that he was taking over 2 days (500 mg qid). her reaction began in less than 10 min and peaked over 50 min; first as itchy oral mucosa followed by wheezing, flushing of the face and upper chest, and nausea. diphenhydramine 50 mg was administered po at 30 min and the reaction subsided over 1 hr. past medical history: she had generalized urticaria to oral penicillin more than 15 yr earlier and had positive penicillin skin test. she also had allergic rhinoconjunctivitis, mild intermittent asthma, and positive skin test to house dust mite, cat and dog epidermals, and pollens of grasses, trees, and ragweed. she also had oral allergy syndrome to certain fresh fruits and tree nuts; hazelnuts caused also diarrhea and colic. neither the patient nor her husband ate any nut-containing food on the days preceding the reaction. family his-tory: allergic rhinoconjunctivitis in the mother, sister and brother. eval-uation: the patient sought allergy evaluation about 2 yr after the reaction. she and her husband gave a consent. her serum ige was 108 iu/ml and skin test positive to penicilloyl polylysine 6x10-5 mol id, but negative to cefazoline 10 mg/ml for prick and 3 mg/ml for id. she had negative prick test to her husband's seminal plasma both before and after his intake of cephalexin 500mg qid for 2 days. using a cephalexin bioassay sensitive down to 6.25 mcg/ml, the medication level in the husband's urine at 120 min post last dose was 2400 mcg/ml and in his serum at 135 min was 12 mcg/ml, but was undetectable in the semen collected at 90 min. conclusion: this is probably the first case report of systemic reaction to ingested semen. the reaction occurred in an atopic, penicillin-sensitive woman and seems to be caused by cephalexin excreted in the semen or through urine contamination (1 drop = 120 mcg). in addition to her avoiding penicillin and cephalosporins, she was advised to avoid her husband's semen while him taking such drugs and for at least 3 days afterwards. background:asthma causes serious morbidity & mortality all over yet most asthma educational evaluations and programs have an urban rather than rural focus.there is lack of data on rural north dakota(nd). this nd survey aimed to study knowledge & awareness of management strategies for asthma like use of metered dose inhalers, spacer devices and peak flow meters. methods:the qualitative survey addressed attitudes and beliefs on asthma & its triggers;knowledge of medication delivery routes & use of hospitals and provider visits.a simple questionnaire was self-administered at 6 rural clinics in small towns in southeastern north dakota.10 questions explored asthma knowledge, extent of family history of asthma & factors aggravating asthma.it was voluntary & the population surveyed included patients, family, teachers, employees at nursing homes, the local hospital & clinics. results:of 297 surveys completed 61% had no asthma in the family.of those with a family history(39%), 59% had 1 person with asthma, 28.6% had 2 & 12.3% had 3 or more.respondents were aged 18-90 years & 81.1% were female.see table. discussion:our survey was rural & comparison with urban areas may help in planning for asthma education & resource allocation.61% denied asthma in their family. similarly, nonurban alaskan natives have a lower incidence of asthma compared to nonnatives.our results show a lack of awareness in our area.grain dust exposure was perceived as an asthma trigger but without evidence, local research is needed.in our study smoking was considered a trigger by 91.5% & this may be real.there was lack of awareness of peak flow meters & their role in asthma care.a study showed that compared to other areas even rural nurses used peak flow meters less often to assess and monitor asthma.this suggests a need for comprehensive asthma educational programs in rural areas that are based on national guidelines.we had only a moderate followup rate at 60%.in comparison, one study had 21% missed scheduled follow-ups. exercise induced asthma was known to only 50% of our group. conclusion:the need for better patient-provider communication has been highlighted by the lack of awareness of proven strategies to combat asthma.the use of a simple survey has revealed many unknown facts about asthma awareness in rural nd.further study to determine cost effective solutions to achieve national targets for asthma management are essential. aim: in most studies of asthma, the emphasis was on changes in large and middle airways. the aims of this study:(1)to observe the morphologic changes in small airways and lung tissue(salt) in guinea pig asthma models(gpam); (2)investigate the role of vcam-1, eotaxin, nf-b and ap-1 in the inflammation of asthma; (3)explore the functional variation of alveolar type 2 cells in asthma; (4)evaluate the effects of inhaled glucocorticoids on the above annals of allergy, asthma & immunology parameters in salt of asthma models. methods: (1)the gpam were established by ovalbumin challenge. five groups were divided: control, asthma day 4 and day 14, intraperitoneal dexamethasone, and budesonide inhalation group. (2)the expression of vcam-1, eotaxin, nf-b and ap-1 was determined by immunohistochemical technology and rt-pcr; the dna binding activity of nf-b and ap-1 by electropharetic mobility shift assay. (3)the balf phospholipide concentration was measured by phosphorus detection. results: (1)significant inflammatiom with infiltration of eosinophils and lymphocytes in salt was observed in asthma groups. (2)the protein levels of vcam-1, eotaxin, nf-b and ap-1 expressed in the salt were significantly elevated in asthma groups than those in control. (3)the mrna expression of vcam-1 and eotaxin of lung tissue homogenate was significantly increased in asthma group. (4)the dna binding activity of nf-b and ap-1 of lung homogenate was significantly increased in asthma group. (5)the balf surfactant represented by phospholipides was significantly decreased in asthma groups. (6)glucocorticoids in different ways of intake provided significant effects on the inflammatiom of salt. conclusion: (1)widespread and significant inflammation with eosinophilic infiltration existed in the salt in gpam, indicating asthma is a disease involving the whole airway and lung system. not only there were structural changes, but also impaired function of alveolar cells. the role of small airway inflammatiom may be of great importance. (2)eotaxin and vcam-1 actively mediated the process of inflammatiom, nf-b and ap-1 played important roles in the regulation of vcam-1 and eotaxin. the up-regulation of the above mediators in gpam was expressed in salt similar to that in central airways. we have recently reported that immunomodulatory oligonucleotides (imos) consisting of a novel structure and synthetic cpr or r'pg (r and r' are synthetic purine moieties) stimulatory motif effectively prevent ovainduced asthma in mouse models. in the present study we examined whether these novel imos (hyb2055 and hyb2087) can reverse established allergic airway inflammation in mice. balb/c mice sensitized and challenged with ovalbumin (ova) were evaluated for airway hyperresponsiveness (ahr) to methacholine. following ova-sensitization, mice were randomized and treated with placebo or 30 mg or 60 mg/dose of hyb2055 or 2087 s.c. during the following 10 days. two days after the final treatment, mice were rechallenged with ova and pulmonary functions were recorded. mice treated with either imo were significantly protected from both early (ear) and late (lar) allergic response, airway hypersensitivity and hyperreactivity to methacholine, bal and peribronchial eosinophilia, bal and serum il-5, and total serum ige as compared to vehicle-treated ova-sensitized and challenged animals. there was a significant increase in immature lung dendritic cells (cd11c+cd45r+) together with increase in serum il-10 levels and significant decrease in lung dc2 type cells (cd11c+ cd11b+cd8a-) as compared to vehicle-treated ovalbumin-sensitized animals in the lungs following treatment with either imo. these data suggest that both imos are effective and potent in attenuating key features of established allergic airway inflammation in bronchial asthma, and this effect could be mediated via decreasing lung dc2 cells and increasing immature dendritic cells. additionally, imos contain a novel 3'-3'-attached structure that provides higher metabolic stability and may permit lower and/or less frequent dosing. hyb2055 was evaluated for its safety and immunopharmacology in a phase 1 clinical trial in healthy human volunteers. introduction -hemoglobinopathies are common in southern europe and mediterranean area the more frequent being thalassemia and sickle cell disease. aside of the major hematological diseases of homozygotic patients minor forms are frequent, thalassemia minor and sickle cell trait. in these cases mycrocytosis with decrease of red cell volume and mean corpuscular volume or abnormal erythrocytes are found and can lead to hemorheologic disturbances in bronchial circulation and bronchial hypereactivity. the rationale of this study is to evaluate the incidence of asthma in hemoglobinopatic patients allergic to house dust mites.methods-from 4 000 patients seen in the last 4 years in an out-patient allergy clinic 44 cases of hemoglobinopathies have been confirmed by red cell count, hemoglobin electrophoresis, assays of hemoglobin a2, f, and s, and sickle cell test.all these patients had allergic disease characterized by clinical history, skin prick test to aeroallergens total and specific ige (rast-cap-feia) and respiratory function evaluation. results -hemoglobinopathies: betathalassemia 39 cases, betadelta thalassemia 2, sickle cell trait 2, hemoglobin c.1. aside of 4 cases of urticaria, all the patients presented respiratory allergy, rhinitis in 12 cases of thalassemia and 1 hemoglobin c, asthma with or without rhinitis in 25 cases of thalassemia and 2 cases of sickle cell trait. therefore asthma was present in 67, 5%. in a group 491 of respiratory allergic patients without hemoglobinopathies, 57% had asthma and 43% only rhinitis. conclusions -the prevalence of asthma is higher in hemoglobinopathies.(p<005 square chi test). hemorheological changes probably greater rigidity of red blood cells and capillary bed can contribute to bronchial hypereactivity. detection of hemoglobinopathies must be done in asthmatic patients with slight anemia or mycrocytosis. we investigated the role of aspirin-exacerbated respiratory disease (aerd) as a risk factor for the development of airway remodeling. patients with aspirin intolerance develop hyperplastic sinusitis with fibrosis and nasal polyposis. we speculated that similar mechanisms could be acting in the lower airway and that these individuals would demonstrate more severe asthma and evidence for airway remodeling. the epidemiology and natural history of asthma: outcomes and treatment regimens (tenor) study is a multicenter observational study of subjects with severe or difficult-to-treat asthma. baseline data were compared between subjects 18 years who reported asthma exacerbation following aspirin ingestion and those who did not. the primary measure of asthma remodeling was the maximally achieved post-bronchodilator spirometry. adult subjects with aerd (n=469) were compared with aspirin tolerant subjects (n=3009). subjects with aspirin intolerance demonstrated evidence for airway remodeling as shown by lower post-bronchodilator predicted fev 1 . in addition, they were more likely to have physician-assessed severe asthma, to have been intubated, and to have required high-dose inhaled corticosteroids or oral corticosteroids in the previous 3 months. we conclude that aspirin intolerance is associated with remodeling of both the upper and lower airways. asthma is a complex and variable disease with two main components, airway inflammation and smooth muscle dysfunction. according to national and international asthma guidelines, subjects with persistent asthma can be classif ied into one of three categories (mild, moderate, or severe) based upon lung function, symptoms, nighttime awakenings, medications and exacerbations. though it is widely believed that there is a high degree of variability in both pediatric and adult subjects with asthma, few studies have compared variability between them. therefore, an analysis of previously conducted asthma studies was undertaken to evaluate pediatric subjects aged 4-11 years (n=276) and adult subjects (n=85) previously receiving short-acting beta 2 -agoinsts alone in seven double-blind, randomized, 12-week trials. the analysis is limited to subjects who were randomized to placebo in these trials. during the study, subjects exhibited marked fluctuations in asthma severity. despite the fact that all subjects met criteria for moderate or severe asthma at baseline, 27%, 18%, 48% and 8% of weeks for pediatric subjects and 9%, 14%, 71%, and 6% of weeks for adults were spent in the intermittent, mild, moderate and severe categories, respectively. a summary of severity classification based upon symptoms and albuterol use is presented below. in addition, based upon pef % predicted, 62% and 52% of weeks were spent in the intermittent/mild category for pediatric and adult subjects, respectively. however, fluctuations in pef occurred frequently, with 46% of pediatric subjects and 30% of adult subjects experiencing 10 changes in severity based on pef over 12 weeks, indicating more variability in pediatric subjects. this analysis clearly demonstrates that asthma is a variable condition and that both pediatric and adult subjects frequently move between severity categories. furthermore, there are marked differences in severity classifications between pediatric and adult subjects. asthma severity, and consequent optimal therapy, cannot adequately be assessed by discrete, point-intime assessments of lung function, frequency of albuterol use, or asthma symptoms, especially in the pediatric age group. studies suggest that there may be an association between single nucleotide polymorphisms (snps) in the beta 2 -adrenergic receptor gene (adrb2) and the response to beta 2 -adrenergic bronchodilators. polymorphisms at codon 16 have been at the center of this debate. therefore, a retrospective analysis of six large, randomized trials was conducted to evaluate clinical responses to salmeterol administered with fluticasone propionate (fsc) 100/50mcg bid for 12 weeks in patients ( 12 yrs) with moderate or severe asthma and differing adrb2 polymorphisms at codon 16. baseline demographics were similar for all genotype subgroups. all measures of asthma improved over baseline and were similar across arg16/gly subgroups at 12 weeks. pairwise comparisons were conducted between genotypes and there were no differences other than fev 1 as noted in the table. findings from this retrospective analysis show that regardless of arg16/gly genotype, clinical response to salmeterol with an ics was similar during chronic dosing. although prospective studies are needed to fully understand the effect of adrb2 polymorphisms on response to therapy with a long-acting beta 2 -agonist, this analysis suggests that therapy with salmeterol and an ics together is appropriate for caucasian patients with differing arg16/gly genotypes. coronary artery disease(cad) and asthma commonly coexist in adults. iv dipyridamole thallium scintigraphy is considered a safe non-invasive technique in the evaluation of cad when patients can't exercise. dipyrdamole is a purine that blocks reuptake of extracellular adenosine increasing serum adenosine levels after iv administration.this results in a transient coronary vasodilation increasing the sensitivity of the thallium study. methylxanthines reverse the effects of endogenous adenosine by competitively antagonizing adenosine at local purinoreceptors. we report a case of a 69 yr.old female with a 30 year history of stable mild persistant asthma treated with daily salmeterol and low-dose fluticasone. she was referred to cardiology for atypical chest pain. within minutes of a standard iv dose of dipyridamole the patient reported chest tightness, cough, and wheezing. all these symptoms, typical of her past asthma flares, were abolished within 5 minutes of an aminophylline infusion and before albuterol was administered.the stress test was completed and was normal. inhaled adenosine induces bronchconstriction and is used as a probe for bronchial hyper-responsiveness. commercial iv adenosine preparations used in treating supraventricular tachycardia are reported to induce bronchospasm in known asthmatics. since serum levels of adenosine are transiently increased following iv dipyridamole, bronchospastic symptoms during dipyridamole stress tests should not be unexpected. an earlier study found an increased incidence of wheezing in 39% of patients with known copd/asthma undergoing dipyridamole stress tests despite pretreatment with beta agonists. the marked decline of theophylline use for chronic asthma in recent years may actually be increasing the incidence of this risk. cardiologists performing thallium stress tests are familiar with the risk of asthma flares after dipyridamole. they use iv aminophylline frequently to reverse several types of clinical dipyridamole reactions, including bronchospasm. on the other hand, we are impressed that allergists are relatively unfamiliar with this association. allergists and asthma specialists as well as asthmatic patients should be aware of risk of acute dipyridamole induced bronchospasm during elective cardiac stress testing. it has been shown that adhesive molecules are involved in inflammatory diseases of the lungs such as bronchial asthma. the purpose of the study was to measure and establish possible difference in serum levels of soluble icam-1 in 42 atopic patients (patients with allergic rhinitis and patients with bronchial asthma) in comparison with 28 patients without atopy (patients with asthma without rhinitis); whether there is a difference in sicam-1 levels between groups of 26 patients with allergic rhinitis and asthma in comparison with group of 16 patients with allergic rhinitis only and also in comparison with 10 healthy controls. results of the study have substantiated statistically significant difference in sicam-1 levels between all groups of patients in comparison to healthy control, but no statistically significant difference in sicam-1 levels between patients with and without atopy (z=-1.738) or between patients with allergic rhinitis and bronchial asthma in comparison with group of patients with allergic rhinitis only (z=0.00). conclusion: icam-1 is an important marker of inflammation in patients with allergic rhinitis as well as in those with bronchial asthma. atopic status does not influence differences in sicam-1 levels. although mean sicam-1 levels were higher in patients with allergic rhinitis and bronchial asthma (312.71 ng/ml) in comparison with mean sicam-1 levels in patients with allergic rhinitis only (279.69 ng/ml), no statistically significant difference was noted in sicam-1 levels between these groups of subjects, i.e. asthma itself did not contribute to statistically significant increase of sicam-1 levels. k. nadarajah * , g.r. green, m. naglak, abington, pa. objective: to study the various clinical outcomes of penicillin skin testing (pst) in a community-based hospital and to determine the percentage of patients who have an antibiotic modification and the choice of antibiotic used following the result of pst. method: this study is a retrospective chart review of all in-patients who were penicillin skin tested during a period of 6.6 years(jan 1997 to july 2003). information was collected on 101 patients using a detailed data collection form. data was summarized using descriptive statistics including frequencies and percentages. results: of the 101 patients penicillin skin tested, 92 had a negative test, five had a positive test and in four patients the test was indeterminate(histamine controls were negative). eighty six percent of the patients had a history of penicillin allergy, 7.9% had a history of cephalosporin allergy and 5.9% had a history of both penicillin and cephalosporin allergies. the duration of antibiotic prior to pst ranged from zero to 18 days. there was a 72.7% (67/92) reduction in the use of vancomycin, a 24.9% (23/92) reduction in the use of floroquinolones and a 7.6% (7/92) reduction in the use of aminoglycosides following pst. aztreonam was used in 19.6% (18/92) of patients before pst and in zero patients after pst. use of penicillin-based drugs was 49% (45/92) after pst and cephalosporin use increased from 4.4% (4/92 (all third generation cephalosporins)) to 47.8% (44/92( second and third generation cephalosporins)). i.e., 97% of patients with a negative pst received a penicillin or a cephalosporin. vancomycin usage was higher among pst positive patients. endocarditis was the diagnosis in 22% of all patients skin tested and staphylococcus aureus (23.8%) and enterococcus (16%) were the most common organisms on culture. there were no serious adverse reactions to the use of penicillins or cephalosporins when used following a negative pst, and there were no adverse reactions to penicillin skin testing. conclusion: in the population studied, pst lowers the usage of vancomycin, floroquinolones and aminoglycosides and increases the use of penicillins. third generation cephalosporin usage was increased by pst in our study. overall, pst results in antibiotic modification that could lower the emergence of multi-drug resistant organisms and vancomycin resistant enterococcus. the aim of the study was to find a new marker which could be easily done to predict about possible allergy development in infants. preventive procedure is always economically better than treatment itself.food allergens are able to stimulate lymphocytes even in prenatal period. immunological maturity of newborns is still in the center of our interest because its dependence on many different factors. the question was if cd30 activity in cord blood and in 1-year-old children correlates with development or not of allergy? the examined group consists of 120 newborns(58, 2% of boys). breastfed were only 87 children until 3-months-old and 62 until they were 6-monthsold. total ige from cord blood and mothers' blood taken at delivery were measured using unicap. immunological detection was done using fluorocytometry(becton nad dako). additionally parents were questionaired( family atopy). our reaults show that positive family atopy history(group a) or elevated level of ige( group b) or symptoms of allergy in first 3 months of life(group c) does not correlate with cd30 antigenicity. in all subgroups cd30 frequency was 1%. our findings show unfortunately that cd30 cannot be a predictive marker for allergy development. rationale: the etiology of eosinophilic esophagitis (ee) is unknown and the relationship to a type i allergic response is unclear. comparison of patients with positive and negative type i allergy testing may further clarify ee and determine what are the most common food allergens. methods: this is a retrospective chart review of medical records from january 2000 to january 2001 of children 1 year of age with biopsy confirmed ee (n = 42). ee was defined as having 15 eosinophils per high power field on esophageal mucosal biopsy. patients were grouped according to positive (n = 26) and negative (n = 16) allergic responses on skin or radioallergosorbent testing (cap rast, pharmacia). skin testing with commercial extracts (hollister-stier laboratories and greer laboratories) was performed in an allergist's office. a wheal of 3mm greater than the negative control on skin testing or ige > 0.35 ku/l on rast was considered positive. we performed fisher exact analysis to determine if associations existed between a type i allergic response and factors such as age, symptoms, peripheral eosinophilia, and personal and family history of atopy (asthma, allergic rhinits, and atopic dermatitis). results: ee patients with a positive type i allergic response were significantly younger than those with a negative response (mean 4.6 yo, median 4.5 yo, range 1 to 10.3 yo versus mean 8.5 yo, median 7.8 yo, range 1 to 21 yo; p = 0.0065). vomiting as a presenting symptom was significantly increased in the allergic population (85%, 44%; p = 0.014) and abdominal pain as a chief complaint was significantly increased in the non-allergic population (31%, 69%; p = 0.026). personal and family history of atopy and peripheral eosinophilia were similar between groups. the most common allergens were cow s milk (54%), peanut (46%), egg (42%), soybean (38%), and wheat (27%). conclusion: patients diagnosed with ee who present at a young age or who present with symptoms of vomiting may have a type i allergic response contributing to the esophageal eosinophilic inflammation. consistent with food allergies in children, milk, peanut, egg, soybean, and wheat were the most common foods found with allergy testing. because the positive predictive accuracy of food annals of allergy, asthma & immunology testing is only about 50%, the challenge remains to develop a specific plan to confirm causative foods such as through oral challenges or elimination trials. rationale: the relationship between specific ige and igg levels in atopic individuals is unknown. increasing antigen exposure is expected to increase igg production, however, the influence on ige levels is unclear. to further clarify this relationship the following studies were conducted. methods: three hundred and sixty tandem determinations of specific ige and igg levels in 65 individuals were collected using the immunocap 100 instrument (pharmacia diagnostics) and commercially available reagents. only subjects who had ige levels > 0.35 ku/l and igg determinations > 2 mg/l to the same specific allergenic species were included in the study. specific ige and igg determinations were to alternaria alternata, aspergillus fumigatus, penicillium notatum, cladosporium herbarium, felis domesticus, canis familaris, dermatophagoides farina, and periplaneta americana. correlation coefficients were calculated using excel (microsoft). results: the review of this data set yielded 55 tandem determinations of specific ige and igg levels in 25 atopic individuals. the most common ige sensitization was to alternaria. sixtyfour percent of individuals had specific ige directed against alternaria. the lowest ige response rate was for cat and roach. only 20% of individuals had an ige response to those specific species. correlation coefficients (cc) were calculated between specific ige and igg levels and were positive for all eight species tested. the highest cc was for dog (n = 6, cc = 0.92) followed by aspergillus (n = 13, cc = 0.71), penicillium (n = 6, cc = 0.69), alternaria (n = 13, cc = 0.62), cladosporium (n = 8, cc = 0.35), cat (n = 5, cc = 0.31), and roach (n = 5, cc = 0.16). the lowest correlation was for dermatophagoides farina (n = 7, cc = 0.03). conclusion: when individuals with measurable specific ige and igg levels are considered, there appears to be a positive correlation between specific ige and igg levels for many allergenic species. factors that influence the correlation are likely to be both genetic and environmental. identifying this link and a clinical application are our next challenge. recently, protein microarray tests are competing with traditional allergenspecific in vitro assays. while the advantages of microarrays in allergy testing are attractive, microarray analysis alone has not been very effective in reducing analysis time and automated microarray equipment typically is much larger than its benchtop counterparts. we have incorporated microarray technology into an automated microfluidic cartridge that provides rapid allergen testing using a compact, low-cost, desktop instrument. the injection molded microfluidic cartridge (fig. a) contains arrays of miniature pumps and valves that direct reagents independently to a solid phase reaction area. standard ige (nibsc) as well as allergens were immobilized within the cartridge to form a protein microarray. a small desktop analyzer actuated the pumps in the cartridge to automatically carry out a chemiluminescence-based elisa reaction. total ige quantitation was performed in a 10 minute reaction. fig.b shows the resultant image of a dilution series of immobilized ige. concentrations ranged from 0.625 to 1000 iu/ml corresponding to 1.9 fg to 3 ng ige per spot. the average cv value for ige quantitation was 12% showing good linearity (r2 = 0.99) and 6 fg sensitivity. this quantitative ige curve is used to eliminate the effects of cartridge variability. specific ige detection was demonstrated using 3 extracts, d. pteronyssinu(dp), a.fumigatus and b. verrucosa(bv). a 2-step, 20 minute reaction elisa technique was employed. fig. c and d show the resultant images for bv and dp positive serum, respectively. the sensitivity of the dp specific ige test was further investigated using a positive class 1 serum sample confirmed by mast. dilution of the class 1 serum with negative control serum could then be detected on the cartridge down to an 8 fold dilution, resulting in a limit of detection in the range of 0.08-0.31 iu/ml for dp specific ige. we have demonstrated total ige and allergen-specific ige detection with total analysis times less than 30 minutes in a convenient, low cost system using a microfluidic-based microarray cartridge. such rapid diagnosis allows physicians to provide treatment while the patient is still in the office. background: accurate allergen skin tests (ast) are the basis of optimal care of the allergic patient. completing these tests on the first visit can expedite the diagnosis and treatment and offer patients(pts.) efficient use of their time and increase satisfaction. appropriate pre-visit preparation is necessary to reduce the variables that affect ast outcomes. both positive and negative skin test controls are necessary to assure the ast are reliable. methods: we conducted a retrospective chart review of 1, 248 sequential pts. skin tested at an allergy practice, in order to examine the success of our pre-visit instructions and to identify other medications that may affect ast. pts. were given verbal and written instructions to discontinue antihistamines and other histamine-1 receptor antagonist medications (h-1a) 5 days before their visit. they then underwent ast only if adequate positive (histamine) and negative (saline/vehicle) controls were obtained. results: only 53(4.2%) of the 1, 248 pts. had inadequate histamine response (ihr). of these 53 pts., 23(1.8%) had used h-1a within the prior 5 days. 18(1.4%) pts. had taken h-1a in the recent past, but stopped them at least 5 days prior to testing. 12(1.0%) pts. had no exposure to h-1a. the use of psychiatric medications in the pts. with an ihr was also examined. of the 18 pts. who discontinued h-1a for more than 5 days, 13(76%) were also taking various medications drugs used in the treatment of psychiatric disorders (ssris, benzodiazepines, atypical antidepressants & antipsychotics) which are not usually associated with h-1a. the group of 12 of the pts. with no prior use of h-1a included 10 (83%) who were also on various psychiatric medications. the high prevalence of psychiatric medication use in these two groups is in contrast to the to 23 pts. with recent use of h-1a in whom 43% were on psychiatric medications. conclusion: pre-visit patient education about discontinuation of h-1a can lead to successful first visit ast in the overwhelming majority of patients (95.7%).failure to stop h-1a at the appropriate time occurred in only 1.8% of the pts. 1.4% of pts. discontinued h-1 a for the recommended 5 day interval, but still had ihr. another 1% of pts. had an ihr yet no obvious use of h-1a. a few pts. taking psychiatric medications not normally associated with h-1a had ihr. further investigation into this issue is warranted. a. blaziene * , a. chomiciene, l. jurgauskiene, n. ciaponiene, vilnius, lithuania. background: sublingual specific immunotherapy (sit) is accepted as an alternative treatment to subcutaneous sit of seasonal allergic rhinitis. the aim of this study was to evaluate changes in allergen-specific ige and basophil degranulation test (bdt) before and after 1 year of sit with a grass pollen mix. methods: 6 patients (3 male and 3 female, aged 25-44 years) having sensitization to grass pollen with seasonal allergic rhinitis were treated with standardized grass pollen extracts. the blood samples were collected before and after 1 year of sit assessing allergen-specific ige using an elisa method and bdt using a direct immunofluorescent method employing monoclonal antibodies. results: the sit was well tolerated by all patients. an increase in total ige after sit was observed in all patients. specific ige concentration was increased in 2 (33.3%) patients, while the bdt result was greater in 3 (50%) patients after 1 year of sit. conclusions: allergen-specific ige and bdt may serve as markers to indicate the clinical efficacy of sit for seasonal allergic rhinitis patients. a.g. palma-carlos * , s.l. silva, m.l. palma-carlos, lisboa, portugal. introduction -the incidence of primary immunodeficiencies in patients attending an out-patient center for clinical allergy and immunology depends on the recruitment and on patients refered. methods -in the last 3 years 3 000 patients have been observed in lisbon clinical allergy center reporting allergic diseases or repeated infections or refered by specialists (ent, gynaecology, internal medicine, pediatrics, or gp.). screening for primary immunodeficiencies has been done by electrophoresis, assay of immunoglobulins and complement, igg subclasses and flux-cytometry for t, b and nk cells. results -102 cases (3, 4%) of primary immunodeficiencies have been diagnosed. humoral: 13 deficits of iga (12, 7% of immunodeficiencies), 7 of igg (6, 8%) 16 of igg subclasses (15, 7%) 11 of common variable immunodeficiency cvi-(10, 8%), 2 of igm (2, 0%). complement: 4 cases of c1 esterase inhibitor deficiency (3, 9%) cellular: 45 cases of mucocutaneous candidiasis (44, 1%) in fertile females, 2 cases of cd4 deficiency (1, 9%). combined: 2 cases of deficiency of the couple cd40/c40 ligand with igg deficiency (1, 9%).conclusions -in the present series chronic mucocutaneous candidiasis is the prevalent primary immunodeficiency, due to the number of patients refered by gynaecologists. aside of this group where a decrease of nk cells was the more common immunologic pattern, humoral immunodeficiencies are frequent, mainly cvi, iga, igg and igg subclasses deficiencies. the search for immunodeficiencies must be done in all patients with repeated infections attending immuno-allergology departments. a case of atypical c2 complement deficiency. c.c. randolph * , waterbury, ct. introduction:c2 complemennt deficiency occurs in 1 in 10, 000 individuals .it results in decreased opsonization and chemotaxis with increased prevalence ofsle and other rheumatic disordersas well as enhanced vulnerability to pyogenic infection.there are two types of c2complement deficiency :type 1(90%associated with sle)with no protein translation and type ii with absence of protein secretion.we present a 15 year old white female otherwise healthy with recurrent urticaria and angioedema with c2 complement deficiency. method:case report:a 15y/o w/f athlete presented with a two month history of recurrent hives and angioedema which she associated with ingestion of halloween candy .one week before evaluation she had hives with coconut as well.her history was othewise unremarkable except for recurrent uti's, annual sinusitis, pneumonia in 1998 as well as migraines.she denied sexual activity.her physical exam was normal.results:an evaluation for autoimmune disease revealed normal esr, ana, dsdna, mono and hepatitis serology as well as lyme titers however her ch50 was low17u/ml(normal 26-58u/ml)and evaluation of complement revealed c4 14mg/dl(normal 16-47mg//dl)and c2 <1.3mg/dl(normal 1.6-3.5mg/dl)with normal c3, c5-c9.her father had nor-malc4 but c2 was 1.4mg/dl (normal 1.6-3.5mg/dl)her sister had c2 of 1.5mg/dl and normal c4 and her mother had normal c2 and c4.her workup included positive prick skin test to ragweed, ash and grass and she was started on rhinocort and clarinex seasonally.she has been followed for one year with resolution of hives and is asymptomatic.her diagnosis had been confirmed by a pediatric rheumatologist.conclusion;we present an atypical case of c2 complement deficiency in an currently asymptomatic individual. background: we diagnosed a 10 month old male with cgd and aspergillus brain abscesses and pulmonary infiltrates. review of the literature suggests he is one of the youngest cases of cgd complicated by cerebral aspergillosis. case report: a ten month old male previously seen for unexplained persistent pulmonary infiltrates since 4 month of age presented to our hospital with lethargy, fevers, and increased irritability. ct scan of the head revealed severe hydrocephalus. multiple brain abscesses were found on surgical exam and cultured for aspergillus fumigatus. he had a history of failure to thrive and hypotonia since birth. family history was significant for parents that were second cousins. there was no family history of recurrent infections or childhood deaths. physical examination was significant for a child with weight and height in the 25% and 75%, respectively with persistent fevers >38.5 c, hypotonia, hepatosplenomegaly, and left lower lung field rales. initial immune workup was normal except for elevated total ige of 215 ku/l. cd4+ (526/m3) and cd8+ (332/m3) t cells were initially low, but later increased to normal levels without intervention. neutrophil oxidase activity assessed by dihydrorotamine 123 (dhr) oxidation was 0% of control. superoxide production assessed by cytochrome c reduction was zero. the patient was treated with interferon ? for presumed cgd. his aspergillus brain abscesses improved with intravenous voriconazole and caspofungun. the responsible organism for his recurrent pulmonary infections was not identified, but improved with antifungal therapy and broad spectrum antibiotics. the dhr test of both parents and siblings were normal. antibody testing showed a complete deficiency of the p67 protein with normal levels of gp91, p22, and p47 proteins. evaluation of the exons of the ncf-2 gene that encodes the p67 protein were normal. conclusion: mutations due to p67 protein deficiency are responsible for 3% of cases of cgd. there has been only one previously reported case of p67 deficiency without ncf-2 exon mutations in which a single point mutation in an intron of the ncf-ii gene was identified. fungal infections may complicate cgd, however cerebral aspergillosis is seldom encountered. this case annals of allergy, asthma & immunology reports a 10 month old with cgd due to a p67 deficiency without exon mutations complicated by cerebral aspergillosis. introduction: lymphoid interstitial pneumonia is an uncommon condition which is considered both as a disease per se or as an inflammatory pulmonary reaction to various external stimuli or systemic diseases; however, at the present time most of the cases remain idiopathic. we present a case of an infant who developed a lymphoid interstitial pneumonia associated to a deficit of interferon-production. methods: we describe a clinical case and review the medical literature. results: we present the case of a five months old male with a history of cough, respiratory distress and four previous hospital admissions regarded as a 'pneumonic' events from two months of age and four siblings dead (two of them with 'abdominal disease' and one of them with candidiasis) during their first year of life. the parents referred no consanguinity. the physical examination showed a malnourished child with signs of bilateral lung consolidation. oxygen supplementation and intravenous antibiotics were started. our patient didn't have neonatal history related to the present compliant. the chest film revealed a diffuse bilateral interstitial pattern which was confirmed by pulmonary ct scan. sweat chloride test, hiv and epstein barr virus serology test were all negative. an initial immunologic evaluation reported slightly increased leukocytic count, hypergammaglobulinemia, lymphocityc flow citometry and nitro blue tetrazolium reduction test in normal parameters. the open lung biopsy showed a thicked pulmonar interstitium with moderate number of lymphocytes with not atypical pattern. our patient was discharged with clinical improvement, ambulatory oxygen supplementation and inhaled fluticasone-salmeterol. in an ambulatory follow-up we evaluated lymphocytic production of cytokines and we found no levels of interferon-. we started weekly administration of oral transfer factor. the patient showed an excellent clinical improvement evidenced by no more oxygen dependence, weight gaining and absence of further hospital admissions. con-clusions: our patient represent a new linkage between lymphoid interstitial pneumonia and primary immunodeficiency characterized by interferonproduction deficit, maybe with a non previously described molecular defect and a probably autosomic recessive inheritance pattern; also we confirmed the transfer factor usefulness to induce gamma interferon endogeous production. objective: marijuana is a schedule class 1 psychoactive control substance more frequently used by the oriental societies( in the event of jubilation) causing altered state of conscience, euphoria, its prolonged use is followed by addiction and dependence.it contains more than 426 chemical entities with over 60 are of the cannabinoid i.e, cannabidiol (cbd), cannabinol (cbn), and delta-9, tetrahydrocannabinol (thc) the later on use has been associated with craving for further use of narcotics just to enhance the euphorient effects .the active ingredients i.e, delta-9-tetrahydrocannabinolthc) and other cannabinoids(thc) are liquid soluble at high concentrations which alters membrane function, resulting in alterations in immune cell response. cannabinoid has immunosuppressant properties causing impaired cell-mediated and humoral immune system activities, cytokine production, leukocyte migration and natural killer-cell(nk) activity resulting in reduction in the host resistance to bacterial and viral infection, (pms)with hiv infection are at higher risk of developing aids, infection by opportunistic bacteria, fungi, or viruses (pms), when compared to non marijuana smokers, have more respiratory ill-ness.cannabinoids also characteristically as being immunomodulators i.e, generally suppressing but occasionally enhance some immunological responses, some have suggested that the immunosuppressive effects of cannabinoids might be useful clinically; for example, in treating multiple sclerosis.as per clinical response cannabinoids had been found exacerbating existing allergies from antigenic complex (eliciting formation of specific antibodies/metabolites as a hapten, combining with a body proteins). methods .in the follow up studies including 18individuals(all males age25-60 years) with(pms).of more than 6 months having serum level of tch >10um, there have been 20 times reduction in the proliferation of t lymphocytes with a proportionate increase in the proliferation of b lymphocytes, reduction in the cytotoxic activity of t lymphocytes, reduction in macrophage activities i.e, phygocytosis rationale: patients with xla are subject to arthritis and cellulitis. these three relatives have had similar courses, suggesting infectious etiology. methods: two brothers and a cousin, from an african-american family known to carry xla, have been diagnosed with xla and chronically treated with ivig. all three have developed arthritis and cellulitis of a lower extremity. the eldest, now 23 years old, had a 5-month waxing and waning arthritis and cellulitis that was refractory to the oral antibiotics attempted. his younger brother had not yet accomplished pubertal changes at the age of 16, and was below 3rd percentiles for weight and height. he also had several months waxing and waning arthritis and cellulitis refractory to oral antibiotics. he and his cousin have had esophogastroduodenoscopies that show gastritis and duodenitis with heavy growth of an organism visualized by specific staining for h. pylori. the cousin has also experienced more recent weight loss and arthritis/cellulitis. results: the younger brother had a blood culture that grew a curved gram-negative rod. a subsequent culture at the state lab grew a similar organism that was urease-negative. the two brothers are at or near completion of a six-month course of ertapenem and gentamicin; they have had resolution of their arthritis and cellulitis. the younger has gained 10.3 kg and experienced his pubertal changes at the age of 17 years. con-clusions: there are prior reports of several different related organisms that can cause arthritis and cellulitis in patients with xla. these include helicobacter, campylobacter, and flexispira species. the urease-negative organism would not be flexispira, but may be a campylobactor species or helicobacter canis. the results from this family suggest that long-term combination iv antibiotics may be indicated for patients with this syndrome. slow virus infections have been reported to affect the central nervous system. parvovirus b19, herpes and cmv are usually not included in the diagnosis of cns diseases nor has been associated with cns manifestation in an immuno-compromised patient. in this abstract, we report on a neurological manifestation that can be linked to ebstein-barr/herpes virus and parvovirus-b19 in an immune deficient patient. a 50 year old female presented to our clinic with a history of chronic fatigue symptoms, daily arthralgias, frequent sinus infections and idiopathic tremors for the past 6 years. the patients neurological evaluation, including mris was found to be within normal limit, despite worsening tremors of her head and arms. a full clinical and labora-tory evaluation was performed which revealed igg subclass, low t-cell numbers and functioning, low response to specific antibodies and positive igm for ebv, parvo and cmv. the patients common immune deficiency coupled with chronic viral infection and worsening tremors led us to try high dose ivig (2g/kg divided over 3 days on cycles of every 3 weeks). within three months of starting ivig, the patient had a large reduction in her tremors and negative igms for parvovirus, herpes and cmv. given our findings, we suggest that ivig may play a role as a neuro-immune modulator, as has been shown in other neuro-immune diseases. we further suggest that the interaction between parvovirus b-19, herpes and cmv as part of the slow viruses, combined with underlying immune disorder may lead to neurological presentation and high dose of ivig can reverse the syndrome. purpose: to date, only two patients older than fifty years of age have been diagnosed with velocardiofacial syndrome (vcfs); this case represents the third such patient. methods: physical and laboratory findings of the patient are presented as a case report. results: we describe a sixty-six-year-old male, recently diagnosed with vcfs, confirmed by fluorescent in-situ hybridization (fish), was referred by his psychiatrist for comprehensive care. he had a history of cleft palate and learning disabilities as a child, with the onset of psychiatric illness in his late teens. although there was no history of cardiac disease, the patient had agenesis of the left renal artery as well as other vascular anomalies, including hypoplasia of the left a1 segement of the anterior cerebral artery. other findings included hypothyroidism, hypoparathyroidism, sensorineural hearing loss, and typical facies. he also suffered from chronic candidiasis. immunologic laboratory studies revealed over a 2:1 ratio of cd8:cd4 t cells with a decreased cd4 percentage, markedly diminished b cell percentage, decreased t cell mitogen responses, and markedly decreased b cell mitogen responses. nevertheless, total serum igg and specific antibody responses remained normal, with a low serum igm. conclusions: this patient meets the criteria for the diagnosis of vcfs; only the third reported case diagnosed over the age of fifty. though his immunologic findings may be consistent with his diagnosis, they may be due in some part to immunologic senescence given his age. background: the classic presentation for patients with xla and mutations in the btk gene includes marked hypogammaglobulinemia, absent b cells, and significant sinopulmonary infections beginning at 4-5 months of age. typically, mds presents with anemia, leukopenia, monocytosis, and thrombocytopenia with recurrent infections, skin rash, and hepatosplenomegaly. many of these subjects demonstrate chromosomal abnormalities including monosomy 7. we describe a case of mds presenting with some features of both conditions. clinical history: we present a 2 year old male with a suspected diagnosis of xla, chronic sinopulmonary disease beginning at 12 mo, diffuse bronchiectasis, and agammaglobulinemia with absent b cells. he had wbc =3750 cells/ul, with 60% monocytes and platelet count of 122, 000 /ul. he had no anemia, hepatosplenomegaly, or skin rash. bone marrow biopsy showed mds with absent plasma cells and monosomy 7 in 95 % of his cells. btk expression and sequence analysis were normal. conclusion: while xla is the most likely primary immune deficiency that would present in a male with the clinical picture described above, this case illustrates the importance of maintaining an expanded differential diagnosis in patients with presumed primary immunodeficiency. j. wang * , l. mayer, c. cunningham-rundles, new york, ny. background: chronic granulomatous disease (cgd) usually results in acute or chronic infections with a defined spectrum of bacteria or fungi. other characteristics include inflammatory disorders, including genitourinary or mucosal inflammation resembling inflammatory bowel disease. gm-csf has been used in the treatment of mucosal inflammation in glycogen storage disease ib and crohn's disease with some success. objective: to explore the use of a novel therapy in the treatment of mucosal inflammation associated with cgd. methods: the patient was treated with daily gm-csf (0.6 mcg/kg/dose subcutaneous injection) along with parenteral antibiotics and total parenteral nutrition. after 4 days on gm-csf, hydrocortisone enemas were added due to continued pain and swelling. results: rectal and abdominal pain significantly improved, blood streaked stools decreased; he tolerated a regular diet and was discharged home 10 days after starting gm-csf. he now has no rectal or abdominal pain and no blood in the stool. conclusions: gm-csf may be a useful therapy for the management of mucosal inflammation in cgd patients. it appears safe and well tolerated and permits avoidance of immune suppressive alternatives. introduction: management of autoimmune cytopenias in patients with cellular immunodeficiency may be very challenging. treatment of these cytopenias with corticosteroids may potentiate the immune dysfunction leading to further infections. methods: we describe a 15 month-old female with a cellular immunodeficiency and autoimmune thrombocytopenia / hemolytic anemia being treated with steroids and ivig without improvement. rituximab, a monoclonal antibody that binds to b-lymphocyte cd20 surface antigens, was initiated. results: this patient presented at 11 months of age with failure to thrive, eczema and recurrent bacterial pneumonias. she was diagnosed with a t lymphocyte immunodeficiency with decreased absolute numbers of cd3 (493), cd4 (365), and cd8 (80) lymphocytes. t cell function was markedly decreased as measured by pha, cona, and pwm. she developed chronic thrombocytopenia with platelets of less than 20, 000 and coombs positive anemia with hemoglobin of 6 g/dl. she was placed on 4mg/kg/day of prednisone with minimal improvement and continued to develop severe pneumonias. rituximab 375 mg/m 2 /week was initiated for 5 doses. her cytopenias improved with an increase in both platelet count (229, 000) and hemoglobin (15.1g/dl). her absolute cd19 count fell from 1319 to 0. she was weaned off steroids permanently. she has also continued on ivig, prophylactic antibiotics, and as needed rituximab pending bone marrow transplant. conclusions: rituximab, a monoclonal anti-cd 20 antibody, may be helpful in treating autoimmune cytopenias in patients with cellular immunodeficiency in which steroids need to be avoided. ivig antibody replacement substitutes for the subsequent humoral antibody depletion due to induced secondary b cell lymphopenia. introduction: the patient is a 3 month old male born at full term. during his prenatal course he was noted to have a pulmonary abnormality in his left lower lobe at approximately 12 weeks of age. serial ultrasounds and fetal mri were consistent with the diagnosis of congenital cystic adenomatoid malformation (ccam). histology from elective resection of the lesion performed at 2 months of age revealed no evidence of ccam. silver stain revealed florid pneumocystis jiroveci (carinii) infection. the patient was completely asymptomatic. the differential diagnosis for this infection in the newborn period includes hiv infection, severe combined immunodeficiency, and x-linked hyper-igm syndrome. the infection has also occurred in newborns with apparently normal immune systems. methods: immunology evaluation was performed to evaluate the patient for the listed diagnoses. a complete blood count was performed. lymphocyte subsets were performed by flow cytometry. quantitative immunoglobulins g,a, m and e were measured by nephelometry. specific antibodies to tetanus and diptheria were determined by elisa. hiv status was ascertained by western blot and dna pcr. dichlorofluorescein assay was performed. fluorescenceactivated cell sorter technique was used to evaluate cd40 ligand. lymphocyte stimulation to mitogens and tetanus were performed. results: the patient had negative hiv1/2 antibodies and a negative hiv dna pcr. the result of the complete blood count was normal with an absolute lymphocyte count of 6, 750. the patient had normal percentages and numbers of cd3, cd4, cd8, cd19, and natural killer cells. lymphocyte stimulation to mitogens and tetanus was normal. dcf assay was normal. facs revealed normal levels of cd40 ligand. at 5 months of age he had protective titers to diptheria and tetanus titers of 0.52 iu/ml (protective >0.6 iu/ml). at 5 months igg, a, m and e were 235 (normal 218-636), <6, 36, and <5 respectively. conclusion: immunologic testing revealed no evidence of severe combined immunodeficiency, hiv infection or x-linked hyper-igm syndrome. the patient remains well clinically with normal growth and development with no subsequent infections. pneumocystis jiroveci pneumonia can be seen in infants with apparently normal immune systems. commercial preparations of igg produced for iv use (ivig), must fulfill regulatory requirements. the method of preparation, however, may produce alterations in the content or function of igg subclasses such as disturbed composition which can be reflected as a lowered clinical effectiveness of the product. we report 2 patients with specific igg3 immunodeficiency, that, when changed to a new ivig preparation, had lessening of clinical effectiveness of the new product but who also experienced recovery after they were changed to a different ivig product. case 1. a 53 y/o male with hx of cervical lymphadenopathy associated with recurrent uri, fatigue, cognitive alterations and hypercholesterolemia. he was dx in 1993 with a specific igg3 immunodeficiency for which he was started on ivig infusions 400mgxkg q/4 w which brought his igg3 levels to normal values 21 mg/dl, (18-95 mg/dl) with good clinical improvement. when he was changed to a different ivig product with lower iga content his initial symptoms returned with decrease of his igg3 to 17 mg/dl (41-129 mg/dl) he was changed to a different ivig product with higher iga content with disappearance of all his previous symptoms. case 2. a 47 y/o female with history of chronic yeast infection, fatigue, joint pain, asthma, ge reflux, depression, hypothyroidism and shunt for hydrocephaly. she was diagnosed with igg1 and igg3 immunodeficiency and started on ivig 400 mg x kg x q/4 w. when changed to another ivig with lower iga content she experienced worsening of her symptoms during the 2 months that she was receiving it. she was changed to a different ivig product with a higher iga content with complete improvement of her symptoms. although the content of iga in product 1 (50-150 ug/ml) was significantly lower than in prod-uct 2 (720ug/ml), the total igg and igg subclass distribution (including igg3) were comparable therefore, the lack of clinical effectiveness of product 1 would appear to be related to qualitative alterations in the product related to methodological preparation possibly in removal of the iga or other physicochemical alterations affecting biologic activity which contributed to a lessened clinical efficacy of the product. we present these cases to alert the allergist-immunologist to these observations when treating patients with igg or igg subclass deficiencies. background: development of atopy has been known to occur in nonatopic recipients of bone marrow transplants ( bmt) from atopic donors. the reverse condition, with atopic recipients losing evidence of specific ige after bmt from non-atopic donors is quite unique. case report: ph is a 37 year old male referred for recurrent nasal congestion. as a teenager, the patient was treated for chronic allergic rhinitis and asthma, atopic dermatitis diagnosed as severe, and multiple food allergy. skin testing done as a teenager showed 3+ reactions to multiple pollen, dog, cat, most seafood, cashew, walnut and pecan. at 16 years of age, he underwent an allogeneic bmt from his non-atopic brother for acute myelogenous leukemia. asthma and atopic dermatitis were observed to clear almost completely and allergic rhinitis improve after the bmt. his blood type changed from 0+ to 0-. skin testing done on his current visit showed unremarkable responses to all pollen, cat, dog, dust mites and foods with good histamine control. discussion: the negative skin test results suggests that his current nasal symptoms are vasomotor in nature. considering the past severity of his symptoms, it appears unlikely that he lost his specific-ige sensitivity spontaneously. transfer of atopy is known to occur in non-atopic recipients of bmt from atopic donors. in a study of 12 patients undergoing allogeneic bmt for hematologic malignancies, nonatopic recipients developed positive skin tests with profiles similar to atopic donors. 1 a possible mechanism is passive transfer of memory b-cells which initiate specific-ige production with a donor pattern. a reverse of this mechanism could occur with the recipient gaining lymphoid precursors with no atopic tendency leading to clearing of atopy. the literature yielded one report of asthma resolving after high-dose chemotherapy and autologous stem cell transplantation the authors suggested that chemotherapy could have resulted in immune system reconstitution, normalization of the t-cell repertoire and resolution of asthma. introduction: primary central nervous system (cns) lymphomas constitute only a small percentage of central nervous system tumors in adults and are seen more frequently in aids patients and immunodeficiency states. they are extremely rare in children, even those with primary immunodeficiency. we present a 4-year-old female with combined immunodeficiency who developed an eber+ (ebv-associated) large b-cell lymphoma that was confined to the cns. methods: the patient is a 4-year-old female that was being evaluated for combined immunodeficiency who presented to our institution with acute fever and seizure activity. results: the patient had a history of recurrent pneumonia, otitis media, sinusitis, and upper respiratory infections. she also exhibited failure to thrive, chronic diarrhea, and sen-sorineural deafness. she was found to have a combined immunodeficiency with severe neutropenia and lymphopenia, low iga, low igm, and poor specific antibody response to protein and polysaccharide antigens. she had no response to a candida delayed hypersensitivity skin test. hiv tests were negative. she was thought to have acute meningoencephalitis causing the fever and seizure activity, however bacterial, viral, and fungal studies were negative. she received multiple anitbacterial, antifungal, and antiviral agents. she died secondary to brainstem compression due to severe cerebral edema. autopsy revealed an eber+ large b-cell lymphoma that involved about 80% of her brain and spinal cord. no tumor cells were found elsewhere. con-clusions: this case represents a rare manifestation of combined immunodeficiency: the development of a primary cns lymphoma. the tumor cells were found to be eber+ (ebv-associated). ebv is known to be associated with lymphoma, especially in aids and immunocompromised patients. only 6.5% of primary tumor sites in severe combined immune deficiency patients involved the cns in the immunodeficiency cancer registry that was instituted in the 1970s. v. litvinova * , g. muzlaev, krasnodar, russian federation. introduction: glyoma is one of the most prevalent diseases among all brain tumors and more than 35% of them are malignant. in the previous investigations it has been shown the immune disorders in patients with glyoma tumor. at the same time it was suggested the possible anti-tumor activity of some proinflammatory cytokines (tnf, il1, il8), which can penetrate via haematoencephalic barrier and induce the lysis of tumor cells. the aim of this investigation was to study the serum and spinal fluid concentrations of one of the key immunoregulatory cytokines -gamma ifn and il18 in patients with glyoma tumor. methods: the concentrations of the gamma ifn and il18 have been studied in serum and spinal fluid of 16 patients with glyoma by eliza method. in control, the same parameters have been studied in 6 patients with brain trauma. results: it has been shown that concentrations of gamma ifn and il18 in serum and spinal fluid was 1.5-2 times higher than in trauma patients (p<0.001). the serum levels of gamma ifn and il18 in glyoma patients were 82.8 and 28.5pg/ml, accordingly. in trauma patients-44.3 and 16.3pg/ml. the concentration in spinal fluid of the studied cytokines was 1.8 time higher than in control patients. conclusion: proinflammatory cytokines gamma ifn and il18 may be involved in pathogenesis of glyoma and can participate as possible anti-tumor factors of immunity in glyoma patients. a. arrey-mensah * , r.u. sorensen, new orleans, la. rationale: immunodeficiencies need to be ruled out in infants that present with failure to thrive. patients with t-cell lymphopenia, hypogammaglobulinemia and pancytopenia may have a primary immunodeficiency such as scid, or a secondary immunodeficiency that may need to be managed differently. methods: evaluation of cellular and antibody-mediated immunity of a 15 month old aaf admitted with failure to thrive and chronic diarrhea. ohistory of duodenal atresia corrected by creating a blind duodenal loop and anastomosis of the stomach to the jejunum at birth. o mass in hypogastrium. results: immunologic evaluation revealed: " lymphopenia ranging 210 to 350cells/ul " anemia: hemoglobin 7.6g/dl, retic 6.8 " ancs ranging 700 to 2100 " thrombocytopenia 54000l to 26500l " cd4+: 80 " cd8+: 50 " cd4/cd8r: 1.5 " cd19: 290 " cd56: 190 " mitogen responses were normal: " pha 46, 397cpm " con-a, 7, 690cpm " pwm, 36, 168cpm immunoglobulins: igg 102mg/dl iga 80mg/dl igm 55mg/dl ige 20 iu/ml total protein was 3.4g/dl, albumin was 1.2g/dl the immunoglobulin-g half-life study was 7 days in our patient: metabolic imbalance: hypokalemia (1.8mmol/l) hyponatremia (127mmol/l) hypocalcemia (4.6mg/dl) blood, stool, urine cultures normal. stool ova, parasite, virus were negative. hiv-pcr (-) radiological evaluation: superior mesenteric vein thrombosis, chronic malrotation and volvulus, dilated duodenal blind loop with possible lymphatic obstruction. the patient improved clinically and all immunological markers normalized after surgical removal of adhesions and obstruction. conclusion: the patient had a secondary immunodeficiency due to lymphangiectasia. lymphangiectasia should be considered in the presence of a lymphopenia with normal lymphocyte function and hypogammaglobulinemia accompanied by hypoproteinemia and hypoalbuminemia. hypogammaglobulinemia and hypoproteinemia were secondary to gastrointestinal losses. the immunological component of 22q11.2 deletion syndrome (also known as digeorge syndrome;dgs), hypoplasia of the thymus, is quite variable among patients and provides the opportunity to determine the relationship between thymic function and t cell receptor (tcr) repertoire diversity. using a novel measure of repertoire diversity based on cdr3 length polymorphism called hamming distance, tcrbv repertoire diversity in dgs was found to differ from control subjects by having an overall skewing of receptor expression. as expected from clinical outcomes, there was also great intra-individual variability in dgs tcr repertoires. the degree of repertoire diversity was directly correlated with thymic output as measured by t cell receptor excision circles (trecs), i.e. greater thymic output resulted in more diverse repertoires (see figure below). this result demonstrates a quantitative relationship between thymic function and repertoire diversity in humans and may reflect the balance between thymic output and peripheral expansion to maintain an adequate tcr repertoire. in addition, it may suggest a basis wherein limited repertoire diversity mediates both immune deficiency and autoimmunity. tcr repertoire diversity in dgs, as measured by hamming distance, correlates with thymic output, as measured by trecs (plotted on a logarithmic scale) a. sabra 1* , s. sabra 1 , h.j. castro 2 , j. malka-rais 2 , j.i. mendez-inocencio 2 , g. santos 1 , j.a. bellanti 2 , 1. rio de janeiro, brazil; 2. washington, dc. a major investigative effort of our laboratory has been directed to the study of non-ige mechanisms and their role in the immunopathogenesis of food allergy (fa). we have previously reported th1 and th2 cytokine alterations associated with several clinical entities that had overlapping disease manifestations affecting the mucosal-associated lymphoid tissues (malt), of the gi tract (galt), skin (salt), nasal (nalt) and bronchial tissues (balt). the objective of the present study was to evaluate specific immunologic alterations in a group of patients with non-ige fa. peripheral blood cd4 and cd8 lymphocyte subset analyses were performed in 10 patients with fa documented by double-blind placebo-control food-challenge (dbpcfc). all patients were treated with an amino-acid based formula (aabf) and then received an open challenge using a panel of commonly offending allergenic food allergens in a normal diet.the clinical picture of all 10 patients with fa were linked to malt-related manifestations; 8 with galt symptoms of diarrhea, vomiting, abdominal pain and ftt, 4 with balt symptoms of asthma, 4 with salt symptoms of eczema, 3 with nalt symptoms of rhinitis and 2 with edema, ascites and anaphylaxis. all subjects had normal serum ige and eosinophil levels, negative ige food rast tests, normal cd4 (mean 1562 + 368) and very low cd8 (174 + 42) levels in peripheral blood. abnormal cd4/cd8 ratios >3.5 were observed in all patients. age-and gender-matched controls revealed cd4/cd8 ratios ranging from 1.5 to 2.5. both patients with anaphylaxis had cd4/cd8 ratios >6. all patients responded well to aabf. open challenge to common offending foods from a regular diet (milk, soy, wheat, egg, nuts, beef and chicken), revealed multiple food allergies. after two years of follow-up on an aabf regimen, the 10 patients remain well but allergic to multiple foods. very low cd8 levels remain as the unique immunological alteration in all 10 patients.these studies suggest that abnormalities of very low cd8 distribution may play a pathogenetic role in non-ige mediated fa. since cd8 lymphocytes play a role in immunologic tolerance (it), it is tempting to speculate that the very low cd8 levels may signal the failure of development of it in our patients predisposing them to the development of allergies to multiple food components. background: mixed connective tissue disease (mctd) is a disease taht have caused controversy, while some authorities consider it a distinct rheumatic disease, others believe that it's an early stage of a fully defined autoimmune disease. the distinctive feature is the presence of the u1 small nuclear rnp autoantibodies. clinical features involve raynaud's is phenomenon, swollen hands, sclerodactyly, esophageal hypomotility, polyarthritis, and myositis, allof them can be present in others well deined rheumatic diseases. only aew cases have been described in the pediatric population. objetive: to determine the frecuency of mixed connective tissue disease in mexican.children in a tertiary level institution according to kasakawa's criteria, alarcon-segovia's criteria and sharp's criteria and establish if a diagnosis of a well defined autoimmune entity was made during the follow up. methods:medical charts were assessed with the diagnosis of mctd between 1988 and 2003 in our hospital. results: between 1988 and 2004, 9 , 919 cases of autoinmune diseases were treated; 310 with systemic lupus erythematosus(sle), 6544 with rheumatoid arthritis(ra), 1, 128 with scleroderma and 1, 937 with dermatomyositis. we found only four cases, 3 of them did not complete the kasakawa's criteria but the diagnosis was probable according to alarcon-segovia and sharp's criteria. one of them developed sle after one year of follow up. the case that fulfilled the diagnosis criteria of mctd; raynaud's phenomenon, rnp antibody positive, arthritis, lymphadenopathy, restrictive pulmonary disease, sclerodactily and muscle weakness developed a full blown sle at 10 years follow up. discussion: the disease is extremely rare in children. we conclude that at least in pediatric age the disease may not exist by it's own, but it's an early stage of a defined autoimmune disease, and the terminology "un differentiated connective tissue disease" is more appropriate to define this cases. a. baysan * , h.y. song, s. gupta, l. yel, irvine, ca. hereditary angioedema (hae) is an autosomal dominant disease characterized by episodic angioedema of the skin or mucosa of the respiratory and the gastrointestinal systems. hae is caused by a quantitative (type i) and/or functional (type ii) deficiency of plasma protein c1 inhibitor, an early component of the classical complement pathway. attacks of hae may be lifethreatening and even cause death when the airway is involved. here, we report a 67 year-old female patient with hae type ii, who has seven affected family members, two of whom died of laryngeal angioedema. the patient had a history of recurrent swelling of the eyelids, lips, tongue and extremities, and respiratory distress since five years of age. she was hospitalized on several occasions one of which required intubation and assisted ventilation. laboratory studies, between the attacks, revealed normal serum ch50 and complement c3 levels. complement c4 level was decreased to 5 mg/dl (n:16-47 mg/dl). c1 esterase function was impaired, 46% (n: greater than 68%) in contrast to normal quantitative c1 esterase. the patient was on long-term danazol treatment for ten years and experienced side effects, most notably hirsutism. currently, there are limited efficacious and safe treatment options for hae. the treatment of choice for acute attacks and prophylaxis appears to be the c1 inhibitor concentrate, which is not yet licensed in the us. the present patient emphasizes the need to establish the correct diagnosis and an appropriate management plan in recurrent angioedema. j. hajsam * , l. ponomarjev, krasnodar, russian federation. background: the previous investigations indicate on the positive effects of ncir in different chronic inflammatory and infectious diseases. nevertheless, the mechanisms of the clinical efficacy of ncir remain still unknown. the aim of this investigation is the study of the immune disorders in patients with chronic tonsillitis and the immunomodulatory effects of the complex treatment in combination with ncir. methods: 55 children with chronic tonsillitis in the age from 7 to 14 years old were under the observation. the t cell receptors (cd3+, cd4+, cd8+, cd16+, cd25+, hla-dr+) have been studied using flow cytometry method. the cytokines (il6, gamma ifn and il18) have been investigated by eliza method. the treatment include traditional methods in combination with ncir. control group (without tonsillitis) consists of 56 children of the same age. results: it has been shown that in chronic tonsillitis was dcrease of the number of cd3+, cd25+ and hla-dr+ cells. the decrease of cd3+ cells was mainly due to decrease of cd4+ cells. at the same time it has been shown the increase in number of cd8+ cells. in chronic tonsillitis have been determined the increase in serum proinflammatory cytokine il6 level in 3.6 times (p<0.001). at the same time the levels of gamma ifn and il18 were lower than in control up to 3-4 times. the studied treatment method including ncir resulted in increase in the number of cd4+ and cd25+ cells. the level of il6 decreased from 95 pg/ml to 28.4 pg/ml. at the same time the serum concentration of gamma ifn and il18 increased up to 2.4 and 1.9 times, accordingly. conclusion: in chronic tonsillitis it has been shown the immune disorders in t cell's subpopulations and cytokine production. the efficacy of ncir mainly depends on the normalisation in t cellular subpopulations and increase in the concentration of gamma ifn and il18. introduction: viral hepatitis is characterized by suppression of cd4+th1cell function related to disease severity. the aim of our research was the determination of total ige concentration and anti-c1q-autoantibodies levels in patients with viral hepatitis c (vhc) and mixed viral hepatitis (vhb+c) and the investigation of their correlation with t cell parameters. methods: 31 patients with vhc and 11 patients with vhb+c confirmed by pcr were examined. evaluation of serum total ige level was performed by elisa kits produced by "vector-best", russia. immunophenotyping of peripheral blood mononuclear cells (pbmc) was done by cytometry with monoclonal antibodies to cd3, cd4, cd8, cd11b, cd16, cd20, cd25, cd95 and hla-dr-antigens. results: the level of serum total ige in patients with vhc and vhb+c was significantly increased in all groups studied, especially in acute hepatitis c (526.8â±129.4 mu/ml, p<0.05) compared with the control group. analysis of pbmc subpopulations in patients with vhc and vhb+c was done related to the total ige level: group i -0-200 mu/ml; and group ii ->200 mu/ml. in patients with viral hepatitis and high total ige level, the content of cd3+t-lymphocytes, cd4+t-cells and cd4/cd8 ratio were significantly decreased compared with the control group (p<0.05). more notable changes were found in patients with acute vhc and vhb+c. the increase in cd20+-cell content was seen in groups with both low and high levels of total ige. the content of cd16+-cells in patients with high levels of total ige was also increased (p<0.05). conclusion: patients with vhc and vhb+c had significantly greater levels of total ige compared with the control group (p<0.05). the increase in total ige levels in patients with viral hepatitis is associated with imbalances of t-lymphocyte subpopulations, including a decrease in cd4+t-cells, and an increase in b-and nk-cells. title: occupational airway allergy among health care workers (hcw) with latex allergy. introduction: for the last years the frequency of latex allergy has increased. health care workers (hcw) is the risk group of this diseases. latex allergy symptoms occure in different organs -including skin, conjunctive, nose and bronchi. study aim:the aim of this study was to estimate the incidence of airway allergy in group of hcw with latex allergy. materials and methods: the investigations were carried out in a group of 252 hcw, aged 21-67 (average age 36, 3). there were two hundred and eight women and forty four men in the group. investigation consisted of questionaire examinations, skin prick tests (latex), patch tests (rubber additives), sige (latex) and spirometry. results: seventy eight (31%) hcw reported undesirable effects after the contact with latex products. fourty (15, 9%) hcw reported symptoms of airway (nose and bronchi). latex allergy (spt and/or sige and anamnesis positive) was diagnosed in 49 (19, 4%) cases. the symptoms concerned with: skin, nose and conjunctive (12 cases, 25%); skin and conjunctive (2 cases, 4%); nose and conjunctive (2 cases, 4%); nose and skin (5 cases, 10%); bronchi, skin, nose, and conjunctive (2 cases, 4%) and only skin in 26 cases (53%). conclusions: the incidence of occupational airway allergy in group of health care workers with latex allergy is high (43% of all cases). latex allergy symptoms usually affect skin, but sometimes it includes also other organs -conjunctive, nose and seldom with bronchi. the incidence of anaphylaxis is increasing. the food allergy and anaphylaxis network wishes to expand the use of injected epinephrine by first responders to allergic emergencies. in indiana, there are 7, 500 first responders, 14, 900 basic emts, 1, 350 advanced emts, and 2, 500 paramedics. the use of injected epinephrine was only permitted by paramedics and advanced emts (17% of all responders). in 2002 a bill was introduced to expand the use of injected epinephrine by ems personnel in the event of an allergic emergency. it was sponsored by the indiana allergy asthma and immunology society and the emergency medical services commission of indiana. on july 1st 2003 senate bill no. 213 took effect permitting all first responders to administer, without restrictions, injected epinephrine. once the legislation passed it became the responsibility of the medical director (md) of each ambulance service in the state to implement the change. in an attempt to assess the impact of this legislation we surveyed each of the mds in the state 9-12 months after the passage of the bill. mds were notified of the legislation by memo and public meetings. in addition each md received a copy of the legislation. of the 266 mds, 56 (25%) responded to the survey. results: 1. unaware of the legislation: 14 (25%) 2. aware of legislation but no implementation: 9 (16%) 3. aware of legislation with implementation restricted to basic emts: 29 (52%) 4. aware of legislation and implementation at all levels: 4 (7%) conclusions: twenty-five percent of mds were unaware of legislation. among those that implemented changes the majority (52%) permitted use by basic emts only. allergists, lay organizations, and ems commissioners need to assure implementation of legislation with all mds within the state. a. khadavi 1* , b. silverman 2 , a. schneider 2 , 1. great neck, ny; 2. brooklyn, ny. rabbit anaphylaxis is extremely rare, with one documented case upon inhalation only. we describe a patient with severe anaphylaxis upon consumption of a rabbit. a 6-year-old female with a 3-year history of asthma and allergic rhinitis was presented for evaluation. the patient complained of worsening asthma and rhinitis symptoms in the home and upon exposure to outdoor pollen. further history revealed the family had a rabbit as a pet. laboratory testing showed her total ige was 865 ku/l, rast results were normal for tree, ragweed and molds (<0.35 kiu/l). positive results were found for ragweed, dust, cockroach, cat, dog, mouse, peanut and rabbit epithelium (8.43 kiu/l, class iv). among other environmental control measures, the family was advised to eliminate the rabbit from the home environment, as it could be a potential trigger for their daughters allergy symptoms. two days later, the patient presented to the emergency room with wheezing, coughing and angioedema of the hands and face. she was treated with albuterol, diphenhydramine and oral steroids. the parents said they followed all of our instructions and did not know why anaphylaxis occurred. further questioning revealed that the family consumed the pet rabbit on the same night preceding the anaphylactic reaction. this was the first time the daughter ate rabbit. the parents assumed that only exposure to the live rabbit would worsen her allergy and asthma symptoms, never expecting an allergic reaction via ingestion. they were advised not to feed their daughter rabbit again and were given a prescription for self-injectable epinephrine. this demonstrates either complete identity, partial similarity or cross reactivity between inhaled and food allergens, as has been noted previously with certain other foods such as garlic and crustacean proteins. physicians need to advise food allergic patients that an allergic reaction can develop upon inhalation of the food, as seen with peanuts. but also respiratory sensitization to an allergen can lead to allergic symptoms upon its ingestion. t. nsouli 1* , j. scheiner 2 , j. malka-rais 2 , j.a. bellanti 2 , 1. burke, va; 2. washington, dc. the safety of selective cyclooxygenase-2 (cox-ii) inhibitors in patients with known nsaid-induced allergic reactions has not been definitely established and is still open to debate. in the present report, we describe two patients with hypersensitivity reactions to naproxen, the first characterized by a systemic anaphylactic reaction and the second by localized urticaria following ingestion of the drug. the first case was a 56 y/o wf with a history of osteoarthritis who, 15 minutes after the ingestion of 375 mg of naproxen, developed generalized pruritus, urticaria, laryngeal edema and hypotension. she was treated in the er with epinephrine, diphenhydramine and iv corticosteroids. epicutaneous and intradermal skin testing to celecoxib revealed negative results similar to a control. an oral challenge with celecoxib was well tolerated by the patient without any adverse responses. the second case was a 57 y/o wf with a known history of chronic urticaria and osteoarthritis requiring regular use of naproxen. a complete allergic and immunologic workup was negative. upon discontinuation of the drug there was resolution of the urticaria. an oral challenge with celecoxib was well tolerated by the patient without adverse sequelae. these two case reports exemplify two extremes in the spectrum of adverse allergic reactions to naproxen, a non-selective cox-i and cox-ii inhibitor, one systemic, the second localized and suggest that the pathogenesis of these symptoms was most likely pseudo-allergic in nature and not immunologically-mediated. the dissimilar chemical structures of naproxen and celecoxib together with their differing mechanisms of action suggest that the absence of allergic reactions to challenge with celecoxib, a cox-ii inhibitor, may be related to a lack of cross-reactivity between the two drugs. although these findings suggest that oral celecoxib could be a possible safe alternative in patients with naproxen-induced drug reactions, it would be prudent to first conduct careful challenges with the drug in a well-equipped medical setting where clinical acceptability and tolerability could be safely assessed. introduction: most fixed and removable dentures are made from casting alloys. many orthodontic appliances are also fabricated from metallic biomaterials. it has been documented in vitro and in vivo, that metallic restorations release metal ions mainly due to corrosion. those metallic ions may be distributed systemically and locally and could pay a significant role in the induction of oral or/and systemic immunoinflammatory conditions. this study determines the frequency of sensitization to metal salts and clinical characteristics in the group of patients with complaints related to adverse effects of dental alloys. methods: 31 patients (29 women and 2 men) aged 35-71 years with symptoms assumed to adverse effects of dental alloys were studied. all patients were studied with base metal salts, including cu 2+ , co 2+ , cr 6+ , mg 2+ , mn 2+ , ni 2+ , ti 3+ , zn 2+ using patch tests. all patch tests substances were 3% salts in petrolatum. the patch tests were conducted in accordance with recommendations of the icdrg. occlusion time was 2 days, and patch tests were read when removing the patches (finn chambers on scanpor, epitest ltd oy, tulusa, finland) and 2 to 4 days later. the total number, percentage of irritant and allergic patch test reactions were calculated. results: in 25 of 31 patients (80%) sensitivity to base metals used in dental restorations was noted. symptoms included burning mouth (45%), metal taste (19%), electrical sensations (11%), dry mouth (9%), and taste irritation (12%), but 16/31 patients (54%) had no symptoms. local gingivitis (19.3%), anomalies of the tongue (12%), stomatitis (12%) and lichenoid reactions (6%) were often seen. the most frequent patch test reactions were caused by ni (45%), cr (41%) and co (19%) . conclusion: this study demonstrated higher frequency of hypersensitivity reactions to ni, cr and co in this group of patients often having symptoms such as burning mouth, metallic taste, electrical sensation, local gingivitis, and anomalies of the tongue. w.y. mak * , s. kearney, b. silverman, a. schneider, brooklyn, ny. the process of intravenous drug desensitization often involves simple but tedious calculations. miscalculations may arise due to human error. for patients who are truly allergic to the drug in question, such errors can be life threatening, if not fatal. we propose the use of a spreadsheet to minimize such calculation errors. spreadsheets, such as microsoft excel, ibm lotus 1-2-3, and corel quattro pro, are used extensively in finance for tedious and repetitive calculations. this property of a spreadsheet makes it an ideal tool to assist with any drug desensitization protocol. we chose microsoft excel for its availability at our institution. a general template was initially created with equations in specific cells which were based on the protocols listed in patterson's allergic diseases, 6th edition and middleton's allergy: principles and practice, 5th edition. by inputting specific numbers, such as the amount of drug and volume of diluent into key cells of the spreadsheet, the program will automatically calculate the protocol for the given intravenous drug. an example of our pipericillin protocol is listed below. we find that the use of a spreadsheet not only minimizes calculation errors and hence reduces the likelihood of avoidable reactions; but also decreases our preparation time for the desen-sitization protocol. we recommend its use for all allergists performing drug desensitizations. states 25 years ago, the infestation of homes across the northeast, southeast and midwestern states with these insects during the fall and winter months has become increasingly common. in the last 5 years, several investigators have published case reports of patients with allergic rhinitis, conjunctivitis and asthma symptoms associated with suspected inhalational exposure to high levels of proteins from these beetles. we report a series of 5 patients who presented with a spectrum of various allergy complaints ranging from symptoms of allergic rhinitis, asthma, urticaria, angioedema and acute anaphylaxis (with documented elevated serum tryptase) on exposure to high numbers of multi-colored asian ladybeetles(malb.) methods: we performed western blotting with the patients' serum and a whole-body ladybeetle extract made from confirmed h. axyridis obtained from one of the infested homes in that region. results: blots with the patients' serum revealed ige binding to 3 different proteins with molecular weights approximately 8, 28 and 78 kd. the serum from two patients bound a 28 kd protein possibly similar to the 30 kd protein previously identified by yarbrough et al. jaci 1999; 104; 704-5 . ige from four patients bound to an 8 kd protein not previously reported. lastly, serum from two patients revealed ige binding to a 78 kd protein possibly similar to the heavier proteins mentioned in an abstract by magnan et al. jaci 2002; 109; 580 . conclusion: we present five patients with specific ige to malb and allergic symptoms on exposure to high levels of malb. we conclude that malb are likely a significant source of several different allergenic proteins and that malb are increasingly becoming a significant cause of a wide variety of hypersensitivity reactions across the united states. as multiple exposed subjects and several entomologists report that these beetles bite humans, we speculate that a wide range of ige-mediated symptoms including urticaria, angioedema and anaphylaxis can occur by exposure to proteins by inhalation, direct contact and possibly by inoculation of these proteins into the skin by the bite or scratch of this beetle. a case report and literature review. c.s. taylor 1* , s. ramesh 2 , 1. getzville, ny; 2. buffalo, ny. introduction: lentils belong to the legume family and are the staple ingredient of the ethnic indian diet. lentils have been shown to cause allergic reactions and even anaphylaxis. however, little research has been done to distinguish the types of lentils used commonly in the indian diet and their various hypersensitivities. some of these lentils include the black gram (phaseolus mungo), mung bean and split chick peas (bengal gram). case report: we report a 19-month-old indian boy who presented with severe atopic dermatitis since the age of four months. his dermatitis was exacerbated by the ingestion of peas and beans and resolved with the avoidance of such. at nine months of age, the child was introduced to boiled mung beans and subsequently developed lip swelling within a few minutes. a similar reaction occured with split chick peas. physical exam at consultation revealed severe eczema. skin tests using commercial extract revealed 5+ response to peanut (he had never eaten peanuts), soybean, pea and egg. subsequent skin tests at the follow up visit to prepared reagents revealed much greater than 5+ response to mung bean, chick pea, split chick peas, and black gram. the patient developed a systemic response during testing which required epinephrine. discussion: legume allergy (other than peanut, soy and peas) is rare in the unites states but has been reported in asia and the mediterranean area. it has been reported in one case series that patients with lentil allergy react to more than one lentil. there is a five percent cross reactivity between peanut and other legumes such as soy and peas. however, the extent of cross reactivity between peanut and the other legume sub-groups (ie. lentils) is not well documented. there also appears to confusion in the labeling of the various lentils used in ethnic diets. conclusion: this case has been presented to make allergists aware that there are many differnt types of lentils that can cause hypersenstivity reactions and the importance of considering ethnicity and dietary habits in evaulating for food allergy. background: epinephrine is the drug of choice for the treatment of anaphylaxis however it is frequently underutilized. one possible reason is the fear of adverse cardiac effects. the most common side effects of epinephrine are palpitations, tachycardia, sweating, nausea, vomiting, respiratory difficulty, pallor, dizziness, weakness, tremor, headache, nervousness, anxiety and arrhythmias. a previous study showed that administration of epinephrine, in a small number of healthy adults did not cause any significant cardiac adverse events and vitals sign changes were not clinically significant. the purpose of this retrospective analysis is to determine the safety profile of epinephrine in a large number of patients that were administered epinephrine for treatment of anaphylaxis that occurred in a physician's office. methods: all patients in an allergy office, that were administered epinephrine for acute anaphylaxis between 1999-2004 were selected for this retrospective analysis. a chart review for adverse events and vital was conducted. vital signs and side effects had been monitored every 5 to 10 minutes for minimum of 30 to 90 minutes after the administration of epinephrine. results: 105 patients between the ages of 8yrs to 55yrs received 128 injections of epinephrine. after an injections of epinephrine 60% of the patients had a pulse between 50-90, 27% between 72-100, and 13% between 102-110. systolic blood pressure determined 81% of patients to be between 80-140, with 10%, between 142-160, and 7% between 162-170, and 2% between 172-180. concurrently, diastolic blood pressure was found to have 94% between 50-90, 3% between 92-100 and 3% betweem 102-110. the most common reported side effects were tremor, headache and pallor. any rise in blood pressure and heart rate after epinephrine was transient and returned to normal within 90 minutes of observation. there were no serious side effects. all patients responded to the epinephrine and were able to go home. conclusions: this retrospective analysis revealed that the administra-tion of epinephrine is safe and effective for the treatment of acute anaphylaxis in an outpatient setting. the use of epinephrine for treatment of anaphylaxis is life-saving and its use to treat non-cardiac or elderly patients who have anaphylactic reactions should be encouraged. purpose: a clinical pathway was established to decrease the use of vancomycin in surgical patients with self-reported penicillin (pcn) allergy. methods: in 2001, our institution developed a preoperative evaluation (poe) clinic for elective surgical patients. in june 2002, on-site, same-day allergy consultation and penicillin skin testing was made available for preoperative patients with self-reported pcn allergy. we reviewed the antibiotic recommendations, the actual administration of vancomycin, and compliance by the surgeons with our recommendations from july 1, 2002-september 16, 2003. results: during this time, 11, 819 patients were seen for their preoperative medical exam at the poe clinic, and 1204 were evaluated for pcn allergy. of these, 1120 patients met irb standards to participate in the study. the mean age of the patients was 60 years. the top three surgical specialties represented in the poe clinic were orthopedic (28.4%), urology (22%), and neurosurgery (15%). of the 1120 patients, 1031 underwent skin testing for pcn allergy. eighty-five percent (85%) or 951 of these patients with a history of pcn allergy were recommended to use -lactams such as cefazolin, and 164 (15%) were recommended to avoid -lactams. forty-three (43) or 4% had one or more positive skin tests to pcn. of the 1120 patients, 957 patients actually received pre-operative antibiotics. of these 957 patients, 718 (75%) of those received cefazolin, 60 (6%) received clindamycin, 33 (3%) received ciprofloxacin, 25 (2%) received levofloxacin. some patients received more than one antibiotic for prophylaxis. only149 (16%) patients received vancomycin. conclusions: establishment of a clinical pathway in a preoperative clinic that includes allergy testing and consultation reduced vancomycin use to only 16% in surgical patients with a history of penicillin allergy. h. yarmohammadi * , a. nowak-wegrzyn, new york, ny. introduction: anticonvulsant hypersensitivity syndrome is a potentially fatal drug reaction with cutaneous and systemic reactions to the arene oxideproducing anticonvulsants. in most cases, the hallmark features of fever, rash, and lymphadenopathy are accompanied by multi organ-system abnormalities. fatal outcomes are most often associated with liver failure. recognition of the syndrome, which may have variable presentations, is the key to prompt discontinuation of the drug, close monitoring, and management. case 1: a 16y/o male received dilantin for seizure prophylaxis following craniopharyngioma resection. fourteen days later he was readmitted for fever and csf leak from surgical site. he was started on ceftriaxone and vancomycin empirically; an lp and pan culture was done. he continued to have low grade fever and, on the 6th day of admission, developed a maculopapular rash on trunk. on day 8th lfts increased and cbc showed eosinophilia. antibiotics were stopped but lfts continued to rise. on day 10, dilantin was stopped and lfts normalized in 2 days, fever stopped and rash disappeared. case 2: a 17 y/o girl was admitted to the hospital with generalized rash, facial edema and fever (39 degrees c). she developed a pruritic maculopapular erythematous rash over her trunk and face 2 weeks prior to admission. she then developed high fever. three months prior to this visit she had been started on phenytoin (300mg/kg) for control of grand mal seizure. physical exam revealed cervical and axillary lymphadenopathy. she had elevated wbc (13, 400), eosinophilia (20 %), and elevated lfts. phenytoin was stopped upon admission but 24 hours later she continued to have fever, elevated lfts and devel-oped erythema in her mouth. treatment with ivig and prednisone was initiated and resolution of symptoms was seen within 2-3 days after therapy. conclusions: the timely recognition of anticonvulsant hypersensitivity syndrome is important, because accurate diagnosis prevents potentially fatal re-exposure and influences subsequent anticonvulsant treatment options. ivig and prednisone should be considered in situations where prompt improvement of the lfts or clinical symptoms is not observed. the recently published results of a telephone survey about the prevalence of seafood allergy in the us indicate that seafood allergy is a significant health concern. aim of the present study was to retrospectively review our data on the topic. we have interviewed 7391 subiects attending our allergy outpatients about any suspected food allergy. over 95% were 14 years or older. any reaction to food was reported by 33% of the patients, more frequently by women. of these 2419 patients, 125 reported reactions to seafood (5%) with an overall prevalence of seafood reactions of 1.7%: 50 to fish (0.7%), 58 to shellfish (including mollusks) (0.8%) and 17 to both (0.2%). in the case of the reactions to fish it is quite possible that shellfish is also included, as the patients were often unable to tell the role of finfish from shellfish apart. this is most probably due to the fact that seafood dishes or a complete seafood meal in italy generally include both shell and finfish. in only less than half cases there was a convincing relationship between the ingestion of seafood and the reaction. the reactions reported were: gastrointestinal (17), non life-threatening angioedema (15), mild oral allergy syndrome (13), acute urticaria (9), asthma (3), rhinoconjunctivitis (2). the gastrointestinal reactions might not all be true (ige-mediated) allergic reactions, but also toxic. in conclusion, even in a selected population like that attending an allergy clinic and using a broad definition of adverse reaction, seafood allergy appears to be a rare phenomenon and of limited clinical impact, the prevalence of moderate to severe reactions (angioedema and asthma) in the whole selected population being 0.2%. clopidogrel (plavix) is an antithrombotic agent currently used to prevent thrombotic cardiovascular events by inhibiting adenosine diphosphate (adp)dependent platelet activation. clinically, it has been used in patients with aspirin intolerance or who developed neutropenia from ticlopidine. there have been reported cases of clopidogrel causing rash and urticaria. often these patients are told they are allergic to clopidogrel and should not take it again, despite the fact that no workup was ever performed to elucidate whether the reaction was indeed immunologic in nature. a review of the literature revealed no reported attempts at desensitizing a patient to clopidogrel after a presumed immunologic drug reaction. we present the case of a 49 year-old female who initially took clopidogrel (75 mg. p.o. daily) for transient ischemic attacks. after tolerating the medicine for five days, it was replaced with an aspirin/warfarin combination, which she took for the next five days. reintroduction of clopidogrel a week later was uneventful, until she developed a pruritic, maculopapular rash on the 5th, through 7th days of restarting therapy. at that time, she was not taking any other medications, and had no cardiopulmonary or gastrointestinal complaints. she had discontinued the clopidogrel and was asymptomatic during our consultation. skin testing was done using clopidogrel prepared at concentrations of 1 mg/ml and 1/10 mg/ml. at the same time, control skin testing on three non-atopic subjects was performed and produced no reaction to either epicutaneous or intradermal testing. by contrast, the patient had a positive skin reaction at both concentrations on intradermal testing. the patient was hospitalized for an oral desensitization where clopidogrel dilutions were prepared by the hospital pharmacy. the patient tolerated an initial dose of 0.02 mg. serial three-fold increases in concentration were given every 15 minutes, until a total cumulative dose of 77 mg. was reached. the patient tolerated the entire procedure and suffered no adverse reactions upon continuation of the treatment. this demonstrates the utility of oral desensitization to clopidogrel in patients with a positive skin test who require this medication. lamotrigine is a non-aromatic anticonvulsant with desirable pharmacological profile. the most common idiosyncratic reaction in children is rash (10-20%). severe cutaneous adverse reactions and systemic hypersensitivity reactions are uncommonly reported. method: case presentation an 11-yearold caucasian female was prescribed lamotrigine in escalating dose for her first generalized seizure. a week later she developed a pink rash on her cheeks gradually progressing to her trunk, hands and feet. three days later she was seen in the er and treated for possible streptococcal-pharyngitis with fever and rash. oral penicillin-v treatment was initiated. the rash continued to spread all over her body with mild pruritis and sores on lips and mouth. few blisters were noted in left ear, hands and feet. later lamotrigine was discontinued. oral steroids were prescribed. she continued to develope new blisters, rash and hemorrhagic plaques and dysuria. she was later transferred to our institute. the physical examination was significant for afebrile girl without pallor and icterus. bilateral conjunctivitis without keratitis evident. tender cervical lymphadenopathy was palpable. multiple ulcers on lips and gingiva were seen. several targetoid lesions on trunk and extremity were noted along with few hemorrhagic plaques on extremities. superficial sloughing of distal fingers and toes was noted. nikolskys sign was not demonstrable. the systemic examination was unremarkable. laboratory tests: hemoglobin 14.2g/dl, wbc-normal range without eosinophilia. normal pt/aptt and inr. liver function tests showed elevated sgpt-1380iu/ml and sgot-225iu/ml with normal bilirubin. urine analysis was normal. serology for cmv, ebv, hsv and hepatitis a and b was negative. skin biopsy showed full thickness epidermal necrosis and sub epidermal clefts. aggressive supportive therapy was initiated. corticosteroids were continued for five more days. prior to being discharged from hospital the rash had dried and most lesions faded. the blisters and oral ulcers had healed. the liver enzymes had decreased. conclusions: we report an occurrence of stevens-johnson syndrome with lamotrigine in a young child. in the literature severe reactions are associated with higher doses or rapid escalation of the dose, and concomitant use of valproate. early recognition and withdrawal of medication is necessary to improve the outcome. introduction: in patients with a history of penicillin (pcn) allergy and negative pcn skin tests to major and minor determinants, 97-99% of patients will tolerate pcn administration without risk of an immediate reaction. in fact, middletons allergy principle & practice reported that no life-threatening false-negative reactions have been reported when pcn was administered after a negative pcn skin test. we describe a case in which a patient with a history of pcn allergy and negative pcn skin tests to the major and minor determinants experienced life-threatening anaphylactic shock when administered piperacillin/tazobactam. case history: a 38-year-old woman with crohns disease was admitted for treatment of an enterocutaneous fistula. three months before admission, the patient reported a severe reaction to either piperacillin/tazobactam or intravenous (iv) lorazepam needing respiratory support in the intensive care unit. in order to delineate this problem, an allergy consultation was obtained. serum ige antibodies to pcn, measured by a commercial cap system radioallergosorbent test (rast) fluoroenzymeimmunoassay (feia; pharmacia and upjohn, uppsala, sweden), and pcn skin tests to major and minor determinants were negative. a skin test (prick and intradermal) to piperacillin/tazobactam at 4.5mg/ml was also negative. five minutes into receiving 3.375 grams of piperacillin/tazobactam iv, the patient reported feeling lightheaded, flushed, nauseated, and diaphoretic. the blood pressure decreased to 80/50 from a baseline of 110/60, heart rate 150/minute and appeared toxic. no wheezing or rash was noted on physical examination. patient was treated with iv epinephrine, diphenhydramine, and dexamethasone and recovered without sequela. serum tryptase, drawn 1 hour after the beginning of the reaction, was elevated at 56.3 ng/ml but decreased to 17.6 ng/ml 12 hours later. complement levels were normal. conclusion: despite a very high negative predictive value of a negative pcn skin test to the major and minor determinants and reports that no life-threatening false-negative reactions have been reported when pcn is administered after a negative pcn skin test, physicians need to be very cautious in administering piperacillin/tazobactam and other b-lactams in patients with a history of severe reactions such as anaphylaxis to past pcn administrations. a. majmundar * , d.a. khan, dallas, tx. introduction: a variety of adverse drug reactions have been reported after therapy with allopurinol. successful protocols for desensitization to allopurinol have been developed. we report a case of a patient who was successfully desensitized to allopurinol only to develop dress after four months of allopurinol therapy. methods: a 57 year old man was referred to our department with a remote history of rash and fever resulting in hospitalization after initiation of allopurinol. due to severe gouty arthritis unresponsive to colchicine and requirement of chronic steroids, it was recommended to attempt allopurinol desensitization. based on the history of his prior reaction, a slow desensitization protocol was performed beginning with allopurinol 10î¼g and increasing the dose weekly to 25î¼g, 50î¼g, 100î¼g, 200î¼g, 500î¼g, 1mg, 5mg, 10mg, 25mg, 50mg, and 100mg. the patient tolerated the entire desensitization protocol without adverse reaction and was initiated on daily allopurinol at 200 mg per day. results: four months after desensitization and daily allopurinol use, the patient developed fevers and an acute maculopapular eruption on his back and abdomen without mucosal involvement. laboratories demonstrated eosinophilia of 936 cells/mm 3 , elevated ast of 101, alt of 102, and ggt of 163 u/l. he was treated with prednisone 80mg a day which was tapered weekly over 5 weeks with successful resolution of his symptoms, eosinophilia and transaminitis. conclusion: while desensitization to allopurinol can be safely accomplished, allergists need to be cognizant of the potential for delayed serious drug reactions such as dress. wiskott aldrich syndrome is an immunodeficiency characterized by eczema, pyogen infections, and mixed immunodeficiency.we describe a male seven-month old, perinatals antecedents without importance who had an ulcer in site of application of bcg. non-blood relatives, healthy parents. at twomonths-old, he initiated with continuous fever, not quantified, treated with multiples antibiotics without resolution, he was hospitalized, plaquetopenia and anemia were diagnosed, he received a red globules and plateles transfusion, one week after he presented a disseminated dermatosis characterized by erythema and desquamation, at four-month-age presented right axillary adenomegaly, hepatoesplenomegaly and recurrent bilateral media otitis for what was hospitalized in our institute. he was malnutrition, bad general condition, febrile, with disseminated dermatosis affecting the head, trunk and extremities characterized by erythema and desquamation, in addition he had left ankle cellulitis, right axillary adenomegaly, hepatoespenomegaly. during his hospitalization he presented left hand cellulitis, hairy skin abscess, oral candidiasis, required surgical treatment by econdary compartimental syndrome because cellulitis of left ankle. persistent hemogram reported thrombocytopenia with normal platelet volume, blood cultives were positive for grampositive bacterias, isoaglutinines, were normal. immunoglobulines were elevated for the age range, he received antimicrobial and antifungic treatment. but he died. in the autopsy timic alymphoplasia was reported, cortical lymphoid depopulation in lymphatic ganglia and spleen, disease by disseminated cytomegalic inclusion, multifocal pulmonary pneumocystosis, bcgitis, disease graft versus guest. . with the previous features we concluded in a compatible mixed immunodeficiency with wiskott-aldrich syndrome with particular characteristics that make this case interesting. the patient course with cellular immune deficiencie with thrombocytopenia and eczema, even when he didn't have platelet sizing diminished, we consider that the patient had a severe of wiskott s aldrich syndrome and at the moment we are awaiting result of genetic study uasp gene. background : hypersensitivity to mosquito bites (hmb) is a disorder characterized by necrotic skin reaction and systemic generalized symptoms subsequent to mosquito bites. it has been suggested that hmb is associated with chronic epstein-barr virus (ebv) infection and natural killer cell leukemia/lymphoma. we describe here a korean child who had hmb associated with chronic ebv infection and natural killer cell lymphocytosis. case : a 5-year-old male was admitted with well-demarcated necrotic skin lesions and severe swelling on right ear lobe developed after mosquito bites. he had suffered several similar symptoms since last summer, which complicated as deep scars on skin. hepatosplenomegaly or peripheral lymphadenopathy was not detected. laboratory tests showed wbc 7, 280/mm3 (neutrophil 39%, lymphocyte 56%), total eosinophil count 156/mm3, ige by prist above 1, 000 iu/m. immunoglobulin levels were normal. specific ige for aedes communis by cap was negative. lymphocyte subset analysis demonstrated increased nk cells (cd16+cd56, 43%) and decreased cd3 and cd4 cells. igm for anti-nuclear antigen (ebna), igm for viral capsid antigen (vca) and igm for anti-early antigen (ea) dr to ebv were negative. but the levels of anti-vca igg (> 200 u/ml), anti-ea dr igg (> 150 u/ml) and anti-ebna igg (62 u/ml) were increased. type a eb virus was demonstrated in blood mononuclear cells by dna pcr method, and eber in situ hybridization was negative in necrotic tissues. immunostaining with nk-cell marker (cd56) revealed many immunoreactive cells with the perivascular inflammatory infiltrates in tissue. skin patch tests for mosquito allergen (aedes togoi and culex pipiens) showed positive response to c. pipiens. introduction: scimitar syndrome is a congenital anomaly resulting in anomalous pulmonary venous return from the right lung to the inferior vena cava. recurrent respiratory infections have been associated with scimitar syndrome. methods: we report on a 16 year-old adolescent female who presented to immunology clinic with recurrent pneumonias. results: the patient presented with numerous recurrent pneumonias, multiple er visits, and hospitalizations. she complained of intermittent chest pain, cough, fatigue and exercise intolerance. the patient had a large secundum atrial septal defect surgically corrected at 5 years of age. a cardiac echo obtained at 7 years of age revealed rvh, but was normal at 9 years of age. she was a known atopic asthmatic. previous immunologic workup was normal with iga 183 (33-202), igg 1290 (633-1280) and igm 97 . at presentation to our clinic pulmonary functions were fvc of 79% and fev1 of 78%. review of previous chest radiographs showed chronic changes with an opacity partially obscuring the right hemidiaphragm. a high resolution chest ct-scan showed a large irregular venous structure extending through the right chest joining the inferior vena cava above the liver consistent with scimitar syndrome. the patient was referred to pediatric cardiology who recommended surgical correction. conclusion: scimitar syndrome may present as recurrent pneumonias and chronic lung disease. a high resolution chest ct scan may be useful in delineating this disorder. background: laryngomalacia is the most common cause of stridor in infants but only rare reports exist of clinically relevant laryngomalacia in adults. objective: to present a case of laryngomalacia in an adult with significant respiratory symptoms initially attributed to asthma. methods: an 18 year-old female with a history of allergic rhinitis and gastroesophageal reflux disease presented to the allergy clinic for further recommendations regarding a prior diagnosis of asthma poorly controlled on inhaled fluticasone, montelukast and albuterol. the patient was clinically diagnosed with asthma at age 13 due exercise related symptoms. the symptoms progressed and intermittent trials of various inhaled steroids provided minimal relief. on evaluation, the patient described constant wheezing which occurred only on inhalation and originated from the throat. symptoms did not respond to albuterol use three to four times a day, rhinitis control and long-term, high-dose, antireflux therapy. baseline spirometry was normal. histamine bronchoprovacation and fiberoptic laryngoscopy were performed for further evaluation. results: histamine challenge was positive with a 33% decrease in fev1 with 1 mg/ml histamine. however, laryngoscopy revealed redundant airway tissue most notable over the right arytenoid cartilage, consistent with laryngomalacia, which prolapsed into the laryngeal vestibule significantly obstructing the airway on inspiration only. the patient was referred to otolaryngology and surgical excision using a carbon dioxide laser was performed with subsequent improvement in symptoms and decreased asthma medication use. conclusions: we report an unusual case of laryngomalacia in an adult presenting as asthma, which was successfully treated with laser surgical excision. laryngoscopy of the patient revealing redundant airway tissue most notable over the right arytenoid. c. so 1* , s. kuhl 2 , 1. davis, ca; 2. mather, ca. c. so, s. kuhl u.c. davis medical center, sacramento, ca & sacramento va hospital, mather, ca background: wheezing is an uncommon manifestation of phrenic nerve dysfunction. objective: we offer a description of wheezing attributable to phrenic nerve dysfunction to remind clinicians that dyspnea and wheezing can be caused by cor pulmonale which can be caused by phrenic nerve dysfunction. methods: a 71-year old male non-smoker presented with chronic dyspnea and occasional wheezing for the last decade. the patient had a remote history of pericardial stripping for presumed tuberculous pericarditis. he also had a non-productive cough and orthopnea. dyspnea was exacerbated by putting his hands over his head and bending over. he had been treated with inhaled corticosteroids and bronchodilators without relief. results: repeated chest x-rays showed a chronically elevated right hemidiaphragm. pulmonary function tests showed a restrictive pattern with: fev 1 1.2 (40%), fvc 1.59 (36%), tlc 3.23 (49%), dlco/va 4.54 (125%) and no bronchodilator response. left heart catheterization was normal while right heart catheterization showed elevated pulmonary artery pressures (56/20) and he was subsequently diagnosed with cor pulmonale. cardiopulmonary exercise testing showed an increase in minute ventilation which was achieved predominantly by an increase in respiratory rate rather than to an increase in tidal volume suggesting restrictive or interstitial lung disease. chest ct showed left ventricular enlargement and no evidence of interstitial lung disease. a fluoroscopic sniff test was performed and showed paradoxical movement of both diaphragms. he was diagnosed as having diaphragmatic dysfunction as a result of phrenic nerve injury from prior pericardial stripping. conclusions: wheezing and chronic dyspnea can be related to phrenic nerve dysfunction. a review and discussion of various causes of phrenic nerve dysfunction, including autoimmune causes, is offered. patients with a history of prior cardiothoracic surgery who present with recalcitrant dyspnea and wheezing may benefit from evaluation for phrenic nerve dysfunction. background: sudden sensorineural hearing loss (ssnhl) is defined by a loss of at least 30 db in 3 contiguous frequencies over a time course of 72 hours or fewer. etiologies of ssnhl include viral infections, ototoxic drugs, autoimmune diseases, trauma, neoplasms, and vascular occlusion, but viral labyrinthitis is the most common cause. in cases of sudden hearing loss, herpes infections can be reported in approximately 70% of cases caused by viral infections. typically, sensorineural hearing loss is not recurrent. we report a case of recurrent ssnhl is which oral herpes lesion preceded the onset of symptoms on three consecutive episodes. case report: a 55-year-old male with a history of hypertension, hypothyroidism and chronic tinnitus of the left ear (since a gunshot wound 18 years prior) presented to clinic with a complaint of recurrent episodes of sensorineural hearing loss. the first episode of bilateral hearing loss occurred 14 months prior. an otolarnolgologist treated with a steroid taper and valacyclovir and the hearing loss resolved after one day of therapy. since the initial presentation, the patient reports three subsequent episodes of ssnhl, with two of the episodes responding to prednisone and valacyclovir and one episode responding to steroids alone. oral herpetic lesions preceded at least three of the episodes one day prior to the hearing loss. laboratory data was significant for an elevation of varicella-zoster igg, and of hsv igg. hsv igm was not performed. rpr was non-reactive and ana was negative. a mri of the head was normal. audiogram demonstrated 30db increase and speech discrimination improved from 80% to 100%. the rest of the laboratory data was unremarkable. the patient has been maintained on daily valacyclovir therapy and has had no further episodes of hearing loss. conclusion: our patient experienced hearing loss with concomitant evidence of hsv-1 stomatitis. this suggests a cause and effect relationship. we found that the antiviral therapy was effective for treatment of the ssnhl in this patient as demonstrated by the absence of further symptoms while on antiviral prophylaxis and conclude the most likely etiology of the recurrent hearing loss was secondary to the recurrent herpes simplex infections. abstract the illness was described for the first time in 1937 in the chinese literature by kimm, and szeto, the definitive histological description was published by kimura in 1948, this illness is endemic in asia, but rare, about 200 cases had been reported. kimura disease is extremely sporadic in the rest of the world. the etiology of this disease is ignored but it is believed that there is an aberrant immune reaction to an unknown antigenic stimulus, however epstein barr's virus, human herpes virus 8 and candida albicans had been involved in certain cases. the mast cells had been implicated in its pathogenesis and a th2 cytokine pattern with the production of interleukin 4, 5 and rantes which regulate the synthesis of ige and orchestrate the eosinophilic infiltration. on the other hand it is suggested that the eosinophils had undergone an accelerated apoptosis in this illness. case report. it is a 7 year-old boy with a 6 months evolution with the presence of bilateral subcutaneous nodules of 4x5 cm in parotid and submaxillary glands, presenting hypereosinophilia (8172 total eosinophils ) and high ige ( 9187 total ige), with normal renal function and negative mycotic and parasitic tests.the histopathologic findings revealed the presence of eosinophilic infiltrates with capillary proliferation and fibrosis. discussion. for the clinical characteristics of the nodules together with the hypereosinophilia, extremely high ige and the characteristic histological lesions the diagnosis is kimura disease. the usual clinical presentation consists on several indolent subcutaneous nodules that grow very slowly in volume, located in the neck and head, accompanied by satel-annals of allergy, asthma & immunology lites adenophaties, and with increment in the salivary glands, there is renal affectation in half of the patients, and the laboratory detects hypereosinophilia and elevation of the total ige. the histological lesions, shows hyperplastic lymphoid tissue with proliferative germinal centers, with infiltration of eosinophils in their interfollicular and perivascular zones sometimes forming an eosinophil abscess and proliferation of poscapillary venules. at the moment he have been treated with prednisone (1mgkdia), with great improvement in the clinical evolution. this is the first case reported in the literature in mexico. introduction: the incidence of cow's milk protein allergy (cmpa) is approximately 2-3% and presents primarily during the first year of life. manifestations of cmpa in the neonatal period include gastroenteritis, colic, lethargy, metabolic acidosis, and hematochezia or melena and appear to be non-ige mediated. ige mediated reactions in the neonatal period, such as urticaria or angioedema, are unusual. case: a 13-day-old african-american male presented with a 3 day history of rash, swelling, and erythema overlying multiple joints. there was no history of fever, diarrhea, or eczema. he had been on no medications prior to admission. besides mother with a history of childhood asthma, there was no family history of atopy or food allergy. he had been fed cow's milk-base formula (similac â® ) since birth exclusively. physical examination revealed a diffuse erythematous, raised, macular-papular rash, with areas of duskiness and exfoliation. there was angioedema overlying the joints and periorbital areas (figure 1). laboratory evaluation included cbc with diff, hgb electrophoresis, lumbar puncture, urinalysis, c 1 q (qualitative and quantitative), c 2 , c 3 , c 4 , and cultures of the blood, csf, and urine which were within normal. percutaneous allergy skin testing for cow's milk allergy was performed revealing a 3 + reaction to cow's milk extract (greer, lenoir, nc) with positive histamine and negative saline controls. rast testing showed 8.23 ku/l for -lactoglobulin and 5.10 ku/l for cow's milk. he was placed on an elemental formula. skin lesions and swelling resolved completely within 36 hours. at 2 week follow-up the patient was thriving without complaint. conclusion: early sensitization to cow's milk protein in the neonatal period may occur, resulting in ige mediated urticaria and angioedema. the rashes may be misdiagnosed as erythema multiforme or anaphylactoid purpura, since hemorrhagic lesions and cockade pattern are common. physicians should be aware that these reactions may occur so that early recognition and management may be initiated. neonate with periorbital angioedema and exfoliating, urticarial rash. rationale: two patients, presenting with invasive fungal cns infections, were found to have nk cell dysfunction and hypogammaglobulinemia. methods: case reports results: patient #1: a 47 year old caucasian male presented with headache, double vision, periorbital swelling, and bilateral sinus disease on ct scan. biopsies showed invasive rhinocerebral mucormycosis. he continued to deteriorate in spite of iv and intrathecal amphotericin b, hyperbaric oxygen, many debridement procedures, and a left orbital exenteration. immune evaluation revealed low igg, low igm and a barely detectable nk cell killing activity. neutrophil respiratory burst was normal. he continued to worsen despite ivig replacement. he had intolerable side effects to ifn-a. gm-csf (500 mcg qod) was initiated, in order to boost nk cell activity. this resulted in stabilization of his infection. he was discharged on oral anti-fungal therapy (posaconazole), ivig, and gm-csf. sixteen months later, he continues to remain stable clinically and radiographically on ivig and gm-csf. patient #2: a 62-year-old caucasian male presented with headache, mental status changes, and ataxia. a head ct scan showed a left mass effect and edema. he underwent surgical debridement for ventriculitis and zygomycetes (the same family as mucormycosis) was found. he was started on iv amphotericin b and oral posaconazole. his immune evaluation revealed low igg and igm and low nk cell activity. neutrophil respiratory burst was normal. he was started on ivig and gm-csf after which his nk cell function improved significantly. he remains clinically stable on ivig and gm-csf with persistent radiographic evidence of enlarged ventricles. conclusion: hypogammaglobulinemia is usually not associated with invasive cns fungal infections, suggesting that nk cell dysfunction was likely responsible for the clinical courses of these patients. nk cell deficiency has been reported to be associated with recurrent mucosal candidiasis, suggesting an important role for these cells in the control of some fungi. the spectrum of the clinical presentations of nk cell deficiency is not known since it is not normally included in immune system evaluations. these patients illustrate the importance of including functional nk cell assessment in any evaluation of immune function. introduction: to report a case of successful systemic hydrocortisone desensitization, since allergic reactions and systemic desensitization to corticosteroids have rarely been documented. method: we present a patient with multiple medical problems who has a history of both radiocontrast induced anaphylactoid reaction and corticosteroid allergy. this patient had to undergo cardiac catheterization and corticosteroid desensitization was performed prior to the procedure. results: skin testing to radiocontrast is not considered helpful, therefore patients with suspected reactions to radiocontrast are generally premedicated with corticosteroids and antihistamines to decrease the risk and severity of a reaction. 1, 2 since this patient experienced an allergic reaction to a corticosteroid previously, she was skin tested to two different corticosteroids. the least reactive skin test revealed a 3+ positive immediate reaction to hydrocortisone. cardiac catheterization with contrast was considered absolutely necessary in this case and corticosteroid desensitization was performed. the half-life of hydrocortisone is the shortest among the tested corticosteroids (80-118 minutes), so a protocol was developed with short intervals of escalating doses. each dose was diluted yielding a total volume of 75ml to avoid fluid overload because patient has renal failure. during desensitization, patient developed pruritus and erythema between the 3 rd and 4 th dose that resolved immediately with 50mg diphenhydramine. after desensitization, the patient continued to be on hydrocortisone 200mg intravenously every four hours. one hour prior to the procedure, the patient was premedicated with hydrocortisone and diphenhydramine and was administered radiocontrast without any adverse reactions. conclusion: we successfully desensitized our patient to a corticosteroid and premedicated her with hydrocortisone and diphenhydramine before administering radiocontrast. this case illustrates that intravenous desensitization may be a suitable approach to therapy in corticosteroid allergic patients who require systemic corticosteroids administration. autoimmune neutropenia is defined as a decrease in the absolute number of peripheral neutrophils caused by an immunologically-mediated mechanism. autoantibodies directed to neutrophils can lead to the peripheral destruction of neutrophils and/or inhibit myelopoesis in the bone marrow. although recurrent aphthous stomatitis is often the heralding sign of neutropenia, the diagnosis of ain requires the demonstration of specific antineutrophil antibody which acts by promoting the immune destruction and clearance of neutrophils by mononuclear phagocytes. the present case report describes the rare clinical association of ras in an adult. a 66 yr-old black male presented with a 3 year history of recurrent and repeated painful multiple oral ulcers. initially the oral ulcers occurred on a monthly basis then over time the ulcerations on the oral mucosa and tongue began to appear weekly and later continuously. past medical history revealed no drug allergies but a positive history of hypertension. physical exam revealed an otherwise healthy male with no lymphoadenopathy or splenomegaly. laboratory workup revealed : hiv negative, viral culture for h. simplex negative, mild increase in cd8, cyroglobulins negative, anti dsdna negative anti-smith and rnp negative, wbc count 3300/ml, neutrophils 29% (anc 957), lymphocytes 54%, monocytes 11%, and platelets: 243, 000. bone marrow biopsy revealed a normal production of neutrophils. a direct neutrophil antibody assay: revealed an elevated value of 6, 576 (n= <4, 000). although following initiation of prednisone (60 mg) an immediate increase in anc was seen, the levels fell as the dosage was tapered. the figure below shows the time course and dose-response relationship of anc and prednisone dosage. this case report illustrates the importance of recognition of the relationship of ras and neutropenia, an association that can masquerade as other clinical entities. background: dyspnea, wheezing, and decreased fev1 are suggestive of asthma. it is essential for the clinician to consider a broad differential diag-nosis as the outcome could be catastrophic if the correct diagnosis is missed. case presentation: we present a case of a 48 y.o. filipino female who was referred to our clinic for the evaluation of cough, shortness of breath, and wheezy respiration associated with changes in voice quality, nasal and palatal pruritus, and postnasal drainage. her initial evaluation revealed mold spore hypersensitivity by prick puncture testing and spirometry with an obstructive pattern with fvc-3.05 l (99%) and fev1-1.25 l (50%) predicted and a 15% reversibility post nebulized albuterol. an initial diagnosis of allergic rhinitis with adult onset asthma was made and she was started on salmeterol, budesonide, montelukast, and pirbuterol. her symptoms persisted and rabeprazole was added to treat possible laryngopharyngeal reflux. repeat spirometry revealed fev1-0.84 l prompting treatment with systemic corticosteroids again with no improvement. fiberoptic laryngoscopy was within normal limits. a high resolution computed tomography was obtained and showed a mass in the left side of the trachea which was obstructing 60% of the airway. bronchoscopy revealed a tumor 4-5 cm below the vocal cords with the appearance of adenoid cystic carcinoma which was confirmed by pathology. the tumor was resected by removal of 7 cm trachea with re-anastomosis, followed by a 6 week course of radiation therapy. all medications were discontinued. her symptoms of wheezing, dyspnea, and cough completely resolved. repeat spirometry was within normal limits and she remained asymptomatic. surveillance bronchoscopies have been negative for any recurrence. discussion: adenoid cystic carcinoma (acc) is an uncommon form of malignant neoplasm that occurs within the salivary glands. tracheobronchial acc typically presents with symptoms of cough, dyspnea, and hoarseness. due to its slow growth, acc has a relatively indolent course. in a recent study of a cohort of 160 acc patients, survival was 89% at 5 years but only 40% at 15 years. standard therapy is surgical resection often followed by radiotherapy. conclusion: in patients who fail conventional therapies for asthma it is important to entertain other diagnosis and have a systematic approach to establish the correct diagnosis. ipex is an extremely rare, hereditary condition characterized by immune dysfunction, polyendocrinopathy, enteropathy and x-linked recessive inheritance that leads to death without prompt diagnosis. patients usually present by 4 months with severe diarrhea, failure to thrive, and early onset iddm. most children die by one year without a bone marrow transplant. immunologic evaluation is typically normal except for elevated ige, eosinophilia, and autoantibodies. we report a case of ipex in an infant who presented at birth and died at 79 days of multi-organ system failure. this male infant was born at 30 weeks due to chorioamnionitis and prom. at birth, copious green fluid appeared from his rectum and ng tube which evolved into a secretory diarrhea. workup for fistula was negative. at 2 weeks, the patient developed ascites and explorative laparotomy revealed an inflamed appendix. after the laparotomy, the patient had no further stool output and never tolerated enteric feeds. he remained intubated and had problems with apnea and coagulapathy. pathology of the appendix showed an excess of lymphocytes. immune system investigation showed elevated ige (5320) and igg (979). serum anti-enterocyte igg antibody was positive in the patient and negative in his mother. based on this data, ipex was suspected which autopsy seemed to confirm. autopsies are scarce in patients with ipex. the findings revealed many organs affected by fibrosis but lymphocyte infiltration of only the pancreas and gi tract. the pancreas revealed almost complete loss of the exocrine structure, with invasion of fibrosis and chronic inflammatory cells. the mucosa of the gi tract from the stomach to rectum showed columnar epithelium taken over by fibrosis, capillaries and chronic inflammation. these inflammatory cells were cd3+ lymphocytes and plasma cells on immunochemistry. the lymphoreticular system was consistent with lymphoid paucity in the thymus, lymph nodes and spleen. preliminary data suggests this patient has a splice mutation of the foxp3 gene. ipex is an extremely rare disease, often difficult to diagnose while a patient is alive. infants will present in early infancy with diarrhea and endocrinopathies. without prompt diagnosis, death is inevitable. as a result, one must be aware of atypical presentations and considered in patients with total villous atrophy and one other clinical feature such as iddm or autoimmunity. introduction: digeorge syndrome (dgs) is characterized by thymic hypoplasia, parathyroid hypoplasia, and conotruncal cardiac defects, but has a wide variety of clinical manifestations. there is also an increased risk for autoimmune phenomena in later life due to thymic hypoplasia. case report: a 13 year-old aa girl with tetralogy of fallot (repair at age 2), developmental delay, asthma, recurrent sinopulmonary infections/skin abscesses, gerd, arthralgias and seizure disorder (due to hypoxic encephalopathy during cardiac surgery) presented to allergy/immunology clinic for immune workup. there was no history of documented hypocalcemia. at age 10, she developed persistent annular patches on her left leg. a skin biopsy appeared consistent with sarcoid dermatitis. there was no other evidence of sarcoidosis except for slightly elevated ace level. given lack of systemic involvement, the skin lesions were not treated, but resolved spontaneously. at age 12, she developed swelling of the right mandible, and a bone biopsy revealed garre's osteomyelitis (sterile hyperproliferative osteomyelitis), likely triggered by dental caries, with elevated esr (40) and polyclonal hypergammaglobulinemia (igg 2640), but normal crp. immune workup revealed a decrease in cd4 and cd8 cells (cd4/cd8 ratio 2.44), slightly elevated b cells, high-normal range nk cells, normal range t cell cytokine production in response to mitogens and il-12, but excessive production of proinflammatory cytokines in responses to lps. in conjunction with facial dysmorphism, dgs was suspected, and fish analysis revealed 22q11.2 microdeletion. a repeat workup did not reveal evidence of systemic sarcoidosis, and autoantibody screening was negative including lupus anticoagulant. she was treated with a cox-2 inhibitor, secondary to gerd and mild thrombocytopenia, and her joint symptoms resolved with a concurrent decline in esr (to 30) and igg level (to 2390) after 2 months. conclusion: recurrent infections with fragmented care and resultant chronic inflammation (hence overstimulation of the immune system) may have led this dgs patient to develop atypical autoimmune phenomena and other unusual clinical manifestations. this case illustrates the importance of recognizing the phenotypic features of dgs early in life, and of providing close monitoring and coordinated care. rationale: we report a case of a patient with celiac disease who continues to have symptoms of fevers, nausea, vomiting, night sweats and fatigue despite being on a gluten free diet whose symptoms have been responsive to antihistamines. methods: case report. results: in 1998, this 41 year-old white male suffered from mononucleosis and episodes of prostatitis. he began suffering from fatigue and fevers and was followed at a chronic fatigue syndrome center in 1999. in november 2000, patient was placed on famvir alleviating his sore throat. he was later placed on interferon gamma which was discontinued due to increased fevers, nausea and vomiting. after stopping medication, symptoms abated for sometime. in 2002, patient's father was diagnosed with celiac sprue. in april of 2003, the patient developed a pruritic rash on his right arm. biopsy revealed subepidermal vesicles with pmn's at the tips of dermal papillae. in may of 2003, he developed oral ulcers as well as joint pains. patient underwent endoscopy with biopsies revealing intraepithelial lymphocytosis in the duodenum. patient has been on a strict gluten free diet since october 2003. he reports that some symptoms have improved: skin lesions, itchy eyes, and oral ulcers. however, he has begun to suffer from constipation and continues to intermittently have night sweats, fevers, nausea and vomiting. in february of 2004, he had pruritus that was not alleviated by hydroxyzine. a regimen of benadryl and pepcid was started to aid with the pruritus. the patient reported in the improvement of his symptoms of pruritis, sweats, and emesis. conclusions: diagnosis: celiac disease(cd) patient with persistent nausea, vomiting, sporadic fevers, and fatigue despite maintaining a strict gluten free diet has shown improvement of symptoms with antihistamines. patient has history of chronic infections: prostatitis and chronic ebv. patient also reported alleviation of symptoms after interferon therapy suggesting some autoimmune component to his current illness. cd prevalence in the united states is much higher than once thought 0.5-1% of the u.s. celiac disease has been associated with increased risk of lymphoma and malabsorption leading to neurological diseases. this is a rare case of cd associated pruritus responding to antihistamines. rationale: eosinophilic cystitis is a relatively rare condition in children and adults with a varied course. it usually responds to short-term nsaid and steroid therapy. we report a man with a severe case who responded to prolonged oral steroids. case report: a 54 year old caucasian man with a prior esophageal cancer s/p esophagectomy, diabetes, hypertension, allergic rhinitis and chronic obstructive pulmonary disease presented with suprapubic pain, urinary frequency, dysuria, and hematuria. urinalysis showed numerous red blood cells and bacteria but no malignant cells or eosinophils. he was treated with antibiotics with resolution of symptoms. several weeks later he experienced severe suprapubic pain and hematuria resulting in a symptomatic drop in his hemoglobin. he underwent a cystoscopy and biopsy that revealed a chronic cystitis with an inflammatory infiltrate containing numerous eosinophils. he was unresponsive to treatment with nsaid and intravesicular dmso and was then referred to our service. we started prednisone 20 mg/day but the dysuria and hematuria persisted. prednisone was doubled plus a third generation quinolone was added. three weeks later the hematuria and dysuria resolved and he was asymptomatic. the antibiotic was stopped and prednisone was gradually tapered over several weeks. whenever his steroid dose dropped below 20 mg/day he experienced an exacerbation of his symptoms. over the last three years this dose of prednisone has kept his symptoms abated and his renal function stable. conclusion: eosinophilic cystitis is an uncommon diagnosis of unknown etiology. we describe a patient with debilitating suprapubic pain and symptomatic anemia from the hematuria associated with eosinophilic cystitis. for over three years since we first saw him, continued therapy with 20 mg of prednisone/day has prevented exacerbations. this case is unique in the severity of the hematuria experienced and the prolonged relatively low steroid dose needed to suppress exacerbations. we propose that in eosinophilic cystitis patients with severe hematuria who may otherwise be candidates for a cystectomy, a trial of prolonged oral prednisone may be beneficial. rationale: allergic reactions to insulin occurred more frequently in the past, with porcine and bovine preparations. in contrast, allergic reactions to human insulin preparations are now reported in <1% of patients treated with insulin. insulin allergy may be manifested as an immediate-type 1 ige-mediated reaction, delayed type hypersensitivity or as serum sickness, varying in severity from mild discomfort to life-threatening events. we present a case to illustrate that an insulin allergy may complicate hospitalization and often be misdiagnosed. methods: a 66 y.o. diabetic female with a history of "insulin allergy" was evaluated. the patient is a long standing diabetic controlled on oral hypoglycemics but required insulin during acute illnesses and hospitalizations. the patient was unable to recall previous types of insulin she had received. during previous hospitalizations, the patient complained of vague symptoms of fatigue, parasthesia, sweating, anxiety, and palpitations. on one occasion the patient had a syncopal episode with hypotension and on another occasion the patient developed a rash and dyspnea after receiving sq insulin. the physcian intrepreted the findings may be due to hypoglycemic. an allergic reaction was not suspected and the patient never underwent any testing. during a recent hospitalization, the patient's history was reviewed and a formal allergy consult was obtained. she underwent epicutaneous and intradermal testing to human insulin preparations. insulin antibody levels were also obtained. results: the patient had negative epicutaneous testing to all human insulin preparations. however, on intradermal testing, the patient had positive reactions to lispro, nph, and lente and negative intradermal tests to insulin glargine and regular insulin. igg and ige insulin antibody test results were < 1. conclusion: hospitalized patients receiving multiple medications commonly experience pharmacologic, adverse and/or allergic reactions. it is necessary to obtain a thorough history and document all reactions that patients experience to determine what type of event occurred. with a suspicion of drug allergy, skin testing and/or rast assay may provide insight into possible ige mediated reactions. in this case we advised the patient that she may use regular insulin during hospitalizations and that insulin glargine can be used to help achieve optimal glycemic long term control. background: hereditary angioedema type iii (hae iii) is a recently described form of angioedema occurring exclusively in females and characterized by normal c4, c1 inhibitor (c1 inh) protein and function. hae iii is thought to have an x-linked or autosomal dominant mode of inheritance. we evaluated a 13 year old female with recurrent facial swelling, abdominal pain and laryngeal edema with a family history of similar symptoms in several female relatives. case report: a 13 year old african american female presented with a two year history of recurrent lip, tongue and facial swelling. she also had abdominal pain, diarrhea and shortness of breath. episodes were not associated with hives. her symptoms predated menarche and did not correlate with her menstrual cycle. at the time of presentation she described an increase in frequency of her symptoms that did not respond to antihistamines (diphenhydramine, cetirizine) or prednisone. the patient had no other medical problems. family history was significant for recurrent episodes of facial, lip and tongue swelling in a maternal aunt, grandmother and great grandmother. the patient's great grandmother required tracheal intubation with ventilator support for upper airway compromise. the patient's physical exam was unremarkable. laboratory values drawn during an acute episode of swelling revealed: c1 inh function = >68% (normal >68%), c1 inh protein = 323mg/ml (normal 158-413 mg/ml), c4= 21.70 mg/dl (normal 20-59 mg/dl). dna sequencing at exon 8 to investigate the possibility of an unusual c1 inh mutation with normal c1s binding but abnormal kallikrein inhibition was negative. other lab tests included a normal mast cell tryptase of 2.9 mcg/l, a negative rf and ana, a normal angiotensin converting enzyme of 62 u/l (normal 6-64 u/l) and positive skin prick tests to a variety of foods which the patient tolerates. based on two case reports of treatment of hae iii with androgens, the patient was started on danazol 200mg daily with symptomatic improvement. conclusion: hae iii is a rare disease that affects females exclusively. clinically it is indistinguishable from c1 inh deficiency. the mechanism of inheritance remains to be elucidated. it is unclear why danazol appears to ameliorate symptoms even though there is no evidence for c1 annals of allergy, asthma & immunology inhibitor dysfunction in this disorder. we believe this to be the first kindred of hae iii reported in the united states. r. dworski * , m. peters, nashville, tn. a four-month-old female identical twin was evaluated for noisy breathing and recurrent cyanosis. she was delivered at 32 weeks of an estimated gestational age after an uncomplicated pregnancy. at birth she was intubated for 3 hours for respiratory distress but the remainder of her neonatal period was uneventful. at age 3 weeks she developed a noisy breathing often associated with cyanosis, particularly in a supine position or while crying. treatments with inhaled albuterol and prednisolone were ineffective. she had no respiratory infections or symptoms of gastroesophageal reflux disease. her growth was normal. her twin sibling was well. the family history was negative for allergies or respiratory conditions. initially she was diagnosed with tracheomalacia. however, the history of cyanotic episodes prompted a search for a definitive diagnosis. she underwent bronchoscopy which showed tracheomalacia when breathing spontaneously and circumferential narrowing of lower trachea likely due to compression. echocardiogram revealed a double aortic arch. the finding was confirmed by computed tomography angiography which demonstrated the presence of a vascular ring composed of double patent aortic arches, each giving rise to the ipsilateral carotid and subclavian arteries. the airway was normal at the aortic inlet, but narrowed markedly at the level of the two arches. a surgical division of the ductus ligamentous and distal anterior vascular arch was performed. aortic arch abnormalities should be suspected in all infants with hoarse coughing or noisy breathing, especially during inspiration but sometimes also during expiration. the diagnosis should also be considered in older children with recurrent bronchitis or pneumonia. respiratory symptoms are more frequent than gastrointestinal manifestations. diagnosis usually occurs in the first year of life. a surgery is often the treatment of choice. postoperative complications are relatively rare. outcome of surgery should be judged after 12 months, including at least one winter season. malacia can delay extubation and recovery following surgery. surgical cure occurs in approximately 70% of patients. surgery is probably less successful in children with double arches and malacia. a. thatayatikom * , a.j. white, st. louis, mo. background: common variable immunodeficiency (cvid) is the commonest symptomatic primary antibody deficiency syndrome in which b lymphocytes produce low levels of immunoglobulin, leading to recurrent bacterial infection. although hypogammaglobulinemia and susceptibility to the recurrent infection are seen in all patients, other associated conditions such as a non-infectious granulomatous disease have been well described in cvid. corticosteroid therapy has been used with improvement in a subset of cvid with granulomatous disease; however, its treatment remains problematic and a new therapeutic agent is needed. tumor necrosis factor (tnf ) has been demonstrated as a primary mediator in granuloma formation and maintenance. therefore, anti-tnf medications are potentially therapeutic agents of the granulomatous disease. case report: a 22-year-old caucasian male with cvid and severe granulomatous disease was treated successfully with infliximab, a chimeric anti-tnf monoclonal antibody. the patient initially presented with high fever, chills and abdominal pain; subsequently, he developed acute respiratory failure and adult respiratory distress syndrome. the patient was hospitalized and he required intensive care with ventilatory support. his diagnostic tests revealed elevated sedimentation rate and positive epstein-barr virus (ebv) capsid igm antibody. imaging studies demonstrated bilateral diffuse pulmonary infiltrates and hepatosplenomegaly. open lung and liver biop-sies revealed non-caseating granulomatous lesions without evidence of ebv or other infections. high dose corticosteroid therapy was given with partial improvement, then high dose infliximab (10mg/kg) was given weekly with remarkable improvement. the patient was able to wean off ventilator successfully within 3 weeks and his prednisone dose was dramatically decreased. infliximab infusion (5mg/kg) every 8 weeks and low dose prednisone were continued. a follow-up liver biopsy after 6 months of the infliximab showed no granulomatous lesions. infliximab was discontinued after 12 months of the treatment. there was no serious infection or complication during the period of treatment. conclusion: anti-tnf therapy may be a safe and effective treatment and may allow corticosteroid dose reduction. future clinical studies of anti-tnf therapy in cvid with granulomatous disease are warranted. background: chrug-strauss syndrome is a disorder characterized by hypereosinophilia and systemic vasculitis occurring in individuals with asthma. objetive: to present a pediatric case suffering from a systemic vasculitis. this case fulfilled the churg-strauss syndrome clinical criteria and the histophatology findings were compatible with the diagnosis. case: a 14 year female came to our institution with the diagnosis of severe asthma, chronic sinusisits and polyps requiring high doses of steroids. there was no history of administration of antileukotriene receptor antagonists. 2 months before her admission she presented weight loss, fatigue, cephalea and cough. on physical examination, pallor, respiratory difficulty and signs of bronchospasm were evident. tachycardia and hepatomegaly were also documented. the laboratory test showed anemia, eosinophilia 1300/dl, anca+, sgot 246, stgop 253, ige elevated 1345 ui/ml. the chest-x ray showed patchy opacities in both lungs and cardiomegaly. pulmonary scintigraphy reported low perfusion in both lungs, predominantly in the left lung.echocardiography demonstrated signs of myocarditis and eyection fraction of 32%. an open lung biopsy was executed and vasculitis with fibrinoid changes affecting small and medium vessels was reported. treatment was started with oral prednisone 2 mg/kg/d and cyclophosphamide pulses with a satisfactory evolution. discussion: to our knowledge this is the first pediatric case of css reported in mexico. she fulilled the following criteria. asthma, eosinophilia and systemic vasculitis involving the heart, liver and lungs. the disease is extremely rare, specially in mexico. aggressive treatment is necessary as in this case, with a favorable outcome. introduction "all that wheezes is not asthma" is a well-known aphorism among physicians. this same principle exists for patients that present with lip swelling in the allergist's office. we describe a patient who presented with fluctuating lip swelling who was ultimately found to have cheilitis granulomatosa. case history a 26-year-old male with a history of allergic rhinitis and asthma presented to the allergy clinic with lower lip swelling and occasional upper lip swelling. he was receiving allergen immunotherapy for dust mites and trees. the swelling had been waxing and waning for 13 years, but became more persistent for the previous six months. he denied tongue/throat swelling, dysphagia, respiratory distress, or any triggers for the swelling. chapstickâ® and vaselineâ® were used topically on his lips. failed treatments included loratadine, ranitidine, cetirizine, fexofenadine, and montelukast. he was placed on a one-week course of prednisone, which decreased his lip swelling, but it recurred after completion of the treatment. physical exam was significant for diffuse, firm lower lip edema to 3-4 times the normal size. there were no oral lesions or tongue swelling. patch testing to a standard panel, preservatives, oral flavors, and dental acrylate was negative. punch biopsy revealed a noncaseating epithelioid granulomatous inflammation consistent with granulomatous cheilitis. he was placed on minocycline 100 mg by mouth twice daily with little benefit. an 8-week course of oral prednisone resulted in improvement of the lip swelling. conclusion melkersson-rosenthal syndrome (mrs) is a rare syndrome that is characterized by a triad of recurrent facial paralysis, chronic edema of the face and lips, and hypertrophy and fissuring of the tongue. cheilitis granulomatosa is considered a monosymptomatic form of mrs and manifests as a chronic swelling of the lips caused by granulomatous inflammation. the swelling is typically not tender and may be either soft or firm. allergists are often consulted for lip swelling thought due to angioedema. however, as this case illustrates, not all lip swelling is angioedema and one must consider other diagnoses such as melkersson-rosenthal syndrome and cheilitis granulomatosa. progressive multifocal leukoencephalopathy (pml) is a disorder of the nervous system that affects individuals with immune suppression. it has been associated with hiv infection and is present in nearly 10% of patients with acquired immune deficiency syndrome. the jc virus, a common human polyomavirus, causes this demyelinating disorder. progressive symptoms reflect the multifocal distribution of brain lesions, and include mental deterioration, vision loss, speech disturbances, ataxia, paralysis, and, ultimately, coma. in rare cases, seizures may occur. there is no known treatment for pml. we report a 21 year-old (y/o) male with 6 months weight loss and a sudden onset of confusion, lethargy, and progressive loss of cognition requiring hospitalization. upon questioning he was found to have had recurrent upper respiratory tract infections since infancy successfully treated with antibiotics. as a child he had atopic dermatitis, exercise induced asthma, and myringotomy tubes placed twice. at 12 y/o, he underwent a nasal polypectomy. in 2002, at 19 y/o, a squamous cell carcinoma was removed, and he developed benign cervical lymphadenopathy and common warts. a year later he developed hsv esophagitis. the remainder of his history was unremarkable with normal development and growth and no history of drug abuse, multiple sexual partners, or homosexual contacts. on physical examination, he was thin, ill appearing, with oral ulcers, generalized scanty lymphoadenopathy, multiple common warts on both feet, and occasional ronchi. a brain mri showed a demyelinating process consistent with pml. pcr for jc virus was positive, while hiv pcr was negative; total immunoglobulins and cd4 counts were low ( we are reporting a 47 year old female with a 10 year history of moderate persistent asthma, who was started on xolair 150mg sq q 4 wks., and who then presented with a presumed allergic reaction. three hours after her second xolair injection, patient reported developing dizziness, shortness of breath, and felt like she was having an allergic reaction. she was evaluated and observed for two hours in an emergency department. the treating physician reported no wheezing and felt there was no need for treatment. to rule out psychogenic factors, she was given a placebo injection at the next scheduled visit. ten minutes later she reported developing throat tightness and shortness of breath. she had no changes in her peak flows and her lungs were clear. her "symptoms" resolved completely within 5 minutes of receiving placebo epinephrine and nebulized normal saline. patient was informed she had reacted to a placebo injection, as well as placebo epinephrine and albuterol, and counseled. the patient returned to the office every week for the next three weeks to receive blinded injections. she subsequently did not react to either doses of placebo or xolair. she has since tolerated her monthly xolair injections without incident. this case illustrates the importance of ruling out psychologic causes of presumed allergic reactions. introduction :latex allergy, type i ige mediated hipersensitivity, occurs specially in high risk populations, like in patients that have undergone various surgeries. case: a 10 year old boy with asthma and allergic rhinitis since 1996, penicillin allergy and retrospectively, his mother refers lip edema with balloon inflating.at 4 years of age (1998): left orchiorrhaphy because of cryptorchis. between 1999-2004: 4 surgeries because of sacral giant melanocitic naevus.during the fourth surgical intervention (0ct 8 -2004) to collocate a tissue expander, the patient presents perioral and fingertip cyanosis, generalized cutaneous rash and severe bronchospasm.ap:40/22 mmhg, hr 140 x/min. he was treated with iv fluids, steroids, antihistamines and inhaled racemic epinephrine.at the icu his final outcome is satisfactory. laboratory: total ige :27.4iu/l, skin prick test with glove extract, raw and natural latex extract and purified latex proteins(pseudoeveine, molecular hevein, hev b 6.02 and modified hevein)all positive +++. western blot with protein extract of latex positive and elisa with purified latex proteins ( same as above) positive. the last surgery to withdraw the tissue expander was performed with latex free surgical equipment without any problems. discussion: the patient's risk factors for latex allergy are atopy and repetitive exposure to latex articles because of surgery. he presents mild manifestations of latex allergy, till he finally develops full-blown anaphylaxis. diagnosis was made based on clinical history, skin prick test, western blot with protein extract and elisa with purified latex protein. he had a favorable outcome withdrawing latex during the last surgery. introduction: churg-strauss syndrome (css) is a form of primary vasculitis that is a rare diagnosis in an elderly patient. case report: a 75 year old woman presented with a 3 week history of fatigue, vomiting, diarrhea, abdom-inal pain, and right lower leg paresthesia. prior to admission she was being treated for left neck erythema and adenopathy presumed to be cellulitis. she was in good health with no history of atopy until the age of 72, when she developed both chronic sinusitis, requiring bilateral sinus surgery and polypectomy, * and new onset asthma, * that required systemic steroid control. prednisone was tapered 1 month prior to admission. objective findings included coalescent non-blanching petechiae on her abdomen, peripheral eosinophilia of 4800(50%), * normochromic normocytic anemia, rf=124, esr=90, ige=232, igg=1645. ana, p and c-anca were negative. ct showed ascites and pleural effusions. egd revealed duodenitis with ulceration and eosinophilic infiltration on biopsy. echo showed pericardial effusion and septal motion abnormality. troponin of 31 without cad was consistent with subepicardial myocarditis. emg confirmed right peroneal neuropathy.* skin biopsy revealed a dense superficial and mid-dermal perivascular and interstitial eosinophilic infiltrate. additional evaluation excluded malignancy, infection, and abpa. treatment with prednisone, 1mg/kg/day was initiated. a rapid clinical improvement ensued and has persisted. {*acr criteria for css}. discussion: churg-strauss syndrome is a rare form of vasculitis with mean age of onset within the third and fifth decades. it is an uncommon cause (<5%) of systemic vasculitis in patients older than 65. the formes frustes of css is a variant in which early manifestations of the syndrome are hidden by oral and systemic steroids employed in the treatment of worsening asthma often associated with css. this variant makes expedient identification of css more challenging. delayed recognition contributes to a relentless progression of this entity resulting in a systemic vasculitis with multi-organ involvement. early diagnosis, especially in the prodromal and eosinophilic phases, is essential. untreated, css has a high rate of morbidity and mortality. therefore, css and the formes frustes variant must be an integral component in the differential diagnosis of patients presenting with adult onset asthma and/or recurrent sinusitis. common variable immunodeficiency (cvid) is the most prevalent of the primary immunodeficiency diseases. cvid is a heterogeneous group of immunologic disorders of unknown etiology, characterized by impaired antibody responses, hypogammaglobulinemia with normal b cells. the common immunologic defect in patients with cvid is defective antibody formation, and many different immune system defects have been reported in this group of patients. most patients, really, have no identified molecular diagnosis. cvid consists of several different genetics defect. the immunologic defect in cvid is a failure of b-lymphocyte differentiation into plasmacells. b lymphocytes from these patients failed to differentiate into ig-producing cells when stimulated with pokeweed mitogen in vitro, even when cocultured with normal t cells. an overwhelming body of literature suggests that most patients with cvid have intact b lymphocytes of immature phenotype. however the functional classification of cvid patients on the basis of in vitro ig production is time consuming. recently has been proposed a new classification based on the quantitative repartition of memory b cell according to the dual expression of igd and cd27. we present a case of a 14 yr old boy. he presented soon in his life frequent infections, of particular severity: pneumonia, meningoencefalitis, sepsis, bronchitis, otitis, linfoadenitis. he also had a -thalassemia intermedia. this clinical manifestations suggested an immunodeficiency. for this reason at 2 years of age serum immunoglobulin and antibody detection showed a reduction in igg2 subclass and in cd19+ cells, with normal total igg, iga, igm, normal cd4/cd8 ratio, normal cd3, isohemagglutinins and in vitro t cell function. there was also a defective antibody production after tetanus, diphtheria, pertussis immunization. these laboratory findings did not allow, however, a sure diagnosis for cvid. a new immunological evaluation at the age of 11 years old, after the onset of splenomegaly, and enlarged lymph nodes, demonstrated a b memory defect, with a severe deficit of t lymphocytes function in vitro. it was also possible to find a severe deficiency of cd 27 + cells, meaning a defect in memory b cells: we can therfore label this condition as a cvid. in the past two decades there have been conflicting views regarding the clinical importance of igg subclass deficiencies in children. igg2 subclass plays a vital role in the immune response to polysaccharide antigen. isolated igg2 subclass deficiency may be widespread and often asymptomatic in children. however, in association with other subclasses and/or other immunoglobulin classes, there may be a significant, symptomatic outcome. the reported patient was diagnosed with familial dysautonomia (fd) at the age of five weeks, presenting with severe hypotonia and tachypnea. hindered by poor pulmonary function, he was hospitalized over fifteen times for recurrent pneumonias, including four lengthy intensive care admissions. daily inhaled-corticosteroids and brochodilator therapies were initiated, along with chest therapy via a high frequency chest wall oscillator. immunoglobulin levels were measured recently and point to low levels of igg2, igg4 and total iga antibodies: igg1 443 mg/dl (n 330-1065), igg2 57 mg/dl (n 57-345), igg3 50.5 mg/dl (n 7.5-125.6), igg4 <2.0 mg/dl (n 1.8-115.5), and total iga 28 mg/dl (n 33-235). since receiving monthly ivig therapy he had no further recurrence of pulmonary infections and was slowly weaned off daily brochodilator therapy. the currently accepted theory is that low igg2 subclass levels may be associated with increased risk of bacterial infections only in selective groups. fd patients may be in a distinctively susceptible population in which igg2 levels are critical. the older brother, who was also diagnosed with fd, demonstrated igg2, igg4 and iga levels that were slightly higher but nevertheless on the lower end of the normal range. he suffers from less invasive and less frequent bacterial infections. this may support a genetic association between the fd and hypogammaglobulinemia. alternatively, it may signal that fd patients may have a prolonged variant of transient hypogammaglobulinemia of infancy. follow-up immune profile studies, post-ivig trough levels and broader investigations of the fd population are necessary to determine the severity and prevalence of these findings. pulmonary failure is the dominant cause of death in patients with fd. prompt diagnosis and effective treatment of the associated immune deficiency may be proven essential in the effort to enhance and prolong their lives. s. hassan * , j.a. grant, galveston, tx. rationale: common variable immunodeficiency (cvid), a rare primary immunodeficiency presenting in young adults with repeated sinopulmonary infections as a result of profound hypogammaglobulinemia, was first described by suri et al. (ann acad. med. singapore, 1988) . we describe a young man with diagnosed but untreated cvid and its eventual course. case description: a 27-yr-old caucasian male hospitalized secondary to chronic pneumonia and respiratory failure was noted to have non-existent levels of immunoglobulins. history revealed ivig treatment at age 12, stopped after a year due to non-compliance. although untreated, he denied recurrent sinusitis, otitis media, or bronchitis for almost 14 years but notes a recent inability in keeping up with baseball practice. he is the last of ten healthy siblings. patient started monthly ivig infusions but was noted to have hypertension (150/90), tachycardia (120-130), tachypnea (25-30) on the 4th month with o2 saturation of 87-93% and po2 of 49% on room air. with a 2-day history of acute dyspnea, calf muscle and right abdominal pain, he was admitted to the hospital and pulmonary thromboembolism was ruled out. laboratory data: humoral functions (pneumococcal, tetanus toxoid, and hepvac) -undetectable t cell function (mumps, candida, ppd) -normal immunoglobulin (igg, iga, igm) -undetectable flow cytometry -b and nk cell markers normal, mild decrease in the cd4/cd8 ratio high resolution ct thorax -bronchiectasis, bronchial wall thickening, and obstructive changes with airtrapping. 6 minute walk -desaturation to 78% on 4l o2 by nc bnp -462 echocardiogramestimated ef 40-45%; severe pulmonary hypertension. cardiac catheterization -normal coronary arteries, severe pulmonary hypertension (pa pressure 70/40). conclusion: cvid patients have a reasonably good prognosis on treatment. untreated cvid is associated with chronic lung infections, bronchiectasis, pulmonary hypertension and right heart failure. although, lung transplant became available during the early eighties (nejm 1982), this extremely invasive but life saving procedure was undertaken in a patient with cvid and end-stage pulmonary hypertension in 1998 (thorax 1998). lung transplant may be the only way of ensuring survival for this patient. introduction chronic eosinophilic pneumonia (cep) is a rare disorder of unknown etiology characterized as a chronic and relapsing interstitial lung disease with blood or tissue eosinophilia. cep occurs more often in women with preexisting atopic disease. patients with cep respond rapidly to systemic corticosteroids, but often relapse with short, low-dose courses of therapy. while uncommon, extrapulmonary involvement, such as arthralgia, cutaneous purpura, pericarditis, and hepatitis, have been reported. we present a case of a patient who has cep with pericardial effusion. case report the patient is a non-smoking 60-year-old woman with a past medical history significant for allergic rhinitis and asthma who initially presented with a four-month history of worsening shortness of breath, dyspnea on exertion, dry, non-productive cough, and weight loss (approximately five pounds). her symptoms were refractory to increased dosages of inhaled fluticasone. she then developed intermittent fever up to 102â°c. chest x-ray revealed bilateral apical infiltrates. treatment with levofloxacin for seven days resulted in no improvement of symptoms or roentographic findings. thereafter, she presented with chest and abdominal pain, hypotension, and hypoxia. blood work revealed a white cell count of 6800 c/mm 3 with a differential significant for 34% eosinophilia (absolute eosinophil count of 2300 c/mm 3 ). chest ct showed dense consolidation predominantly along the peripheral aspect of the upper and superior segment of the lower lobes, and pericardial effusion. moderate pericardial effusion without evidence of tamponade was confirmed on echocardiogram. left upper lobe wedge biopsy findings included significant tissue eosinophilia, scattered foci of active organizing exudates, and no evidence of granulomatous or necrotizing vasculitis. the patient was treated for cep with a six-month course of prednisone, starting at 60 mg daily, resulting in rapid improvement of her pulmonary and systemic symptoms. background: immunologists are consulted for evaluation of immunodeficiency in patients with recurrent skin infections. disorders of the phagocyte system may be associated with cutaneous infections. methods: case report case: a 15-month-old african american girl (twin a) presents with recurrent skin abscesses. at 13 months of age, she had her first buttocks abscess, which required incision and drainage with oral antibiotics. a month later, she developed another abscess and was found to be neutropenic, with an absolute neutrophil count (anc) of 264/î¼l. cyclic neutropenia was considered and her pediatrician monitored cbcs, which all showed persistent neutropenia (ancs between 68 and 264). at 15 months of age, she was hospitalized for fever with neutropenia. immunology was consulted for evaluation of neutropenia. the rest of the past medical history was unremarkable. she was healthy appearing and growth parameters were appropriate for age. her physical examination was unremarkable. immunoglobulins, b-and t-cell markers, nitroblue tetrazolium, complement assay, hemoglobin, platelets and the peripheral smear were normal. antibodies for hiv, cmv, ebv and parvovirus were undetectable. anti-neutrophil antibodies were positive, establishing the diagnosis of primary autoimmune neutropenia (ain). the abscess healed with oral antibiotics. severe neutropenia (anc 0-280) persisted for three subsequent months without further infections. twin (b) was also found to have persistent severe neutropenia without morbidities, suggestive of primary ain. primary ain is less known among physicians and is typically diagnosed after extensive investigations that exclude other causes of neutropenia. the exact incidence of ain is unknown. it is usually seen in children between 5 and 38 months of age, often with severe neutropenia and self-limiting bacterial infections. the clinical course and presence of antibodies to neutrophil antigens (na1, na2 or cd11b/18) is diagnostic. familial occurrence of primary ain is not reported in the literature. conclusion: primary ain may remain under diagnosed due to lack of characteristic clinical features. although a benign clinical course is likely, severe infections, including pneumonia, sepsis and meningitis, have been reported. genetics may play a role in this disease, as we present primary ain in twins. background: atopic dermatitis (ad) is a chronic inflamatory disease of skin that affects 5% of the wordl population.the natural history of ad in some patients, evolve to the coexistence with other allergic diseases: allergic rhinitis, allergic conjunctivitis and asthma. the sublingual immunotherapy has demonstrated utility in some patients; however, semi-rush immunotherapy to pollens has only showed utility in one animal case published few years ago. case report: a 2-year-old infant was referred to us. he began one year before with skin lesions compatible with ad, six months later began perennial rinhorrea and nasal itching. multiple treatments with topic corticosteroids, moisturizing, antihistamines and topic/systemic antibiotics did not demonstrate utility. our evaluation revealed ad lessions that affected 60% of the total body surface and clinical features of allergic rhinitis (ar).the lab tests revealed eosinophylia (600cell/mm3) in blood cell count, normal levels of total ige but specific ige to dermatophagoides pteronissinus (dpt) was high. the skin prick test reveales the same results. we added environmental control, oral costicosteroids and transfer factor. despite our treatment no improvement was observed. we considered dpt as the principal factor in the maintenance of ad lessions and ar episodes. in the absence of sublingual immunotherapy in our hospital, we decided for semi-rush immunotherapy schedule. we began from 0.1 ml of 1:10, 000 w/v concentrations of dpt until 0, 5 ml of 1:100 w/v concentrations in two months receiving three doses per week. no local or systemic adverse events was reported and the ad lesions and ar symptomatology disappeared in the first month of treatment. at this time, no exacerbations have been documented. conclusion: the semi-rush immunotherapy can be useful and safe for treatmente of ad in some patients in whom specific ige to aeroallergens has been demonstrated. introduction: eosinophilic gastrointestinal disorders are a rare group of disorders that can involve the entire gastrointestinal tract. presentations are varied but may include vomiting, dysphagia, abdominal pain, diarrhea and failure to thrive. the diagnosis is made by endoscopic biopsies which reveals eosinophil rich inflammation in the absence of known causes for eosinophilia. peripheral eosinophils and ige may be elevated but can be normal. we report a patient with eosinophilic gastroenteritis associated with an ampullary tubulovillous adnenoma. methods:a 71-year-old white male with allergic rhinitis and a family history of atopy was admitted for profuse watery diarrhea. he denied any new medications, eating raw foods or recent travels. eosinophils were elevated to 2.4(29% of wbc) and ige was elevated to 3259. multiple stool specimens were negative for ova & parasites and enteric pathogens. serology was negative for strongyloides, trichinella, e. histolytica and toxocara. ast, alt & bilirubin were elevated and a ct scan showed dilated billiary ducts with a possible ampullary mass. biopsy of the ampullary mass revealed a tubulovillous adenoma. biopsies of the duodenum, terminal ileum, colon and rectum were remarkable for focal eosinophilic cryptitis & chronic inflammation in the lamina propria consisting of eosinophils, scattered lymphocytes and histiocytes. all specimens were negative for parasitic infections including duodenal aspirates. he was empirically started on metronidazole and singulair with gradual improvement of symptoms, eosinophils and liver tests. two months after discharge, the patient remained diarrhea free with a normal eosinophil count. conclusion: we report a patient with eosinophilic gastroenteritis and an ampullary tubulovillous adenoma with obstruction of the biliary system. this unique presentation illustrates the diverse nature of gastrointestinal manifestations seen in eosinophilic gastroenteritis. background: zonisamide is an anti-seizure medication chemically classified as a sulfonamide and unrelated to other ant seizure agents. we report a case of hypersensitivity to this agent in a child. method: case report results: this patient is a 22-month-old girl who developed "peeling of her lips" three weeks after starting zonisamide. one week later she developed a rash that began on her face and generalized over several days to her neck, trunk and extremities. there was no respiratory distress, joint complaints and no angioedema associated with the episode, but fever to 103 prompted referral to our hospital on day 6 of the rash. the rash was macular-papular without discrete urticarial lesions. the rash coalesced with underlying erythema on face, chest and neck. the patient has a known history of seizure disorder, asthma, mild eczema, gastro esophageal reflux, development delay, lactose intolerance and failure to thrive. her other medications were, lansoprazole, topiramate, and albuterol. labs revealed a normal white cell count, an elevated sed rate ( 51) and elevated lft's, i.e. sgot 80 and sgpt 180. the only new medication was zonisamide that was discontinued. she was treated with iv steroids and hydroxyzine. the rash started fading by day 2 and the patient's fever resolved by the third hospital day. liver enzymes returned to normal by day 7. conclusion: this relatively new anti-seizure agent can be associated with hypersensitivity reactions in children. introduction: kawasaki disease (kd) is an acute chilhood vasculitis. in addition to the diagnostic criteria a broad range of nonspecific clinical features may be observed including aseptic meningitis, vomiting, diarrhea, abdominal pain, sterile pyuria, arthralgia and arthrtis, pulmonary infiltration, pleural effusion and nonspecific paralytic ileum as manifestation of gastrointestinal vasculitis. we describe a child who developed all features of kawasaki disease included the most rarely reported. patient report: a 2 year-old female presented 15 days of high fever, nonsuppurative cervical lymphadenopathy, petequial rash in legs, swelling of feet, distended abdomen, vomiting, obnubilated and hypoactive, incongruent speech, fisured lips and distended abdomen. lab tests showed: anemia (9.8g/dl), high wbc count (24, 200cells/mm3), thrombocytopenia (47, 000/mm3), hypoalbuminemia (1.1g/dl), lactate dehydrogenase (ldh) 209mcg/l, glutamin transferase (ggt) 190. csf total proteins 129, glucose 60, cells 23, pm 5%, mn 95%, seric complement 88, cultures were negatives. she developed myocarditis, aneurysms in the right and left coronary arteries. on the 25th day presented cardiac failure, pleural effusion, paralytic ileum, hydrops vesicular, mechanic ventilatory assistance was required. the first dose of intravenous immunoglobulin (ivig) (2g/k) was infused, heparin and hydrocortisone. on 45 day a second doses of ivig was infused, because of fever, and abdominal vasculitis. steroids ware discontinued, heparin was suspended and aspirin was added as antiaggregant. discussion: our patient presented an unusual and severe presentation of kd with pleural effusion, nonspecific ileum, cardiac failure secondary to myocarditis, aseptic meningitis and thrombocytopenia; all those manifestations had rarely been reported at the same time. she presented with a devastating evolution. complications were resolved. the lastest studies have shown that treatment with ivig plus corticosteroids significantly reduce serum concentrations of proinflamatory cytokines. in this case antiinflamatory doses of aspirin were contraindicated and steroids were used with satisfactory outcome. limited data is available for nonresponding patients to guide therapy. although multiple doses of ivig are sufficient in some patients, some of them remain refractory to therapy and they need corticosteroids to control the vasculitis process eosinophilia is defined by an absolute eosinophil count above 0.7 x 10 9 and can be seen in association with a broad spectrum of disorders ranging from allergic to malignant. idiopathic hypereosinophilic syndrome (hes) should be considered in any patient with an eosinophil count above 1.5 x 10 9 for more than 6 months without commonly recognized causes of eosinophilia and with evidence for organ damage not otherwise explained in the clinical setting. it is potentially an aggressive disease with mean survival of less than a year without treatment. we present a 39 year old male horse breeder, with eosinophilia lasting more than 10 years. prior to coming to our institution, he underwent extensive medical evaluation including bone marrow and gi biopsies, multiple imaging studies with mri and ct scans of the chest and the head as well as detailed evaluation of his cardiac status. all these tests were normal and the patient was empirically started on treatment for possible hes including trials of prednisone, hydroxyurea, interferon alfa, and imatinib, all without lasting resolution of his eosinophilia and causing significant side effects with profound depression of his immune status. finally, in light of the patient's profession, a strongyloides enzyme immunoassay was done and found to be remarkably positive. duodenal drainage confirmed the infestation with this nematode. within a week of starting treatment with ivermectin, his eosinophil count came down by 50% and eventually normalized. we learn that one should be persistent in excluding all common causes of eosinophilia before considering hes. in case of parasite infestation, premature treatment with immunosuppressors can result in worsening of the infection with potential for poor and even fatal outcome. stool evaluation might not be sensitive enough for detection of parasites and it is therefore necessary to complete a diagnostic work up with appropriate serology. doxil is the pegylated liposomal form of doxorubicin and has been used successfully as a cancer chemotherapy agent in many types of tumors. a hypersensitivity reaction can occur, usually during the first infusion, and appears to be rate related. the symptoms include dyspnea, tachypnea, facial swelling, chills, hives, chest pain, and back pain. we report a case of a hypersensitivity reaction to doxil in a 26 year-old woman with hodgkin's lymphoma. during her first outpatient doxil infusion at 1 mg/min, she developed urticaria, chest tightness, dyspnea, and back pain. these reactions persisted despite being medicated with antihistamines and steroids and immediately resolved during pauses in the infusion. after 23 mg of doxil, the infusion was discontinued. six days later, she was admitted to complete the other half of the dose. she had a negative intradermal skin test to a 1:100 dilution of doxil. she was then premedicated with diphenydramine, dexamethasone, acetaminophen, and famotidine. the doxil infusion was started at 0.4 mg/min and was soon stopped due to flushing of the hands and face. the infusion was decreased to 0.2 mg/min. she was able to tolerate this slow infusion with only mild and tolerable symptoms. when her symptoms worsened, the infusion was stopped for 30 to 60 minutes. she completed the 23 mg infusion of doxil after 13 hours. pre-infusion and post-infusion complement levels were drawn during this second administration of doxil. her pre-infusion c2, c3, c3a, c4, c5, c5a, and bb levels were all normal. her pre-infusion c4a and sc5b-9 levels were high, indicating that she might have had some residual or persistent complement activation caused by her first doxil infusion. her post-infusion c2, c3, c3a, c4, c5, c5a, and bb levels were all normal. however, her post-infusion sc5b-9 levels significantly increased, suggesting complement was activated during the second doxil infusion. given her reaction during her first doxil infusion and a negative skin test to doxil, it is highly unlikely that her doxil hypersensitivity was an ige-mediated process. therefore, in patients with a similar doxil hypersensitivity, we suggest a slow rate of infusion of 0.1-0.2 mg/min, toleration of mild symptoms, 30 to 60 minute pauses during more severe symptoms, and continuation of premedication during the entire lengthy infusion. introduction eosiniphilic esophagitis (ee) is an isolated, severe esophageal eosinophilia. patients are usually young males presenting with vomiting, epigastric or chest pain, dysphagia and obstructive respiratory problems. they are often initially misdiagnosed with and treated for gastroesophageal reflux disease (gerd). distinction between the two diseases can be made with biopsies of the esophageal mucosa. while any eosinophils in the esophageal mucosa indicate pathology, gerd typically presents with up to 7 eosinophils per high powered field (hpf, 400x) while ee most often presents with greater than 20-24 eosinophils per hpf. case report the patient is a 3 and one half year old boy who has experienced severe symptoms of gerd from the age of 6 months. he vomits after meals at least 1-2 times per day. he coughs when he lies down at night and regurgitates phlegm in the early morning. he has complained of discomfort in his lower chest after eating. his weight has remained at 35 pounds for the last six months. the patient was diagnosed with asthma at age 2 and a half; however, there is no family history of asthma or allergies. the patient initially experienced improvement on lansoprazole, but his symptoms recurred when the medication was discontinued and subsequent courses were ineffective. his physical exam was normal barring slightly edematous nasal turbinates. an endoscopic biopsy showed "numerous eosinphils" (later clarified to 38 eosinophils per hpf) in his distal esophagus. the patient showed allergy to milk and wheat on radioallergosorbent (rast) testing. the patient was started on swallowed fluticasone 2 puffs twice daily and advised to see a nutritionist regarding a wheat and milk elimination diet. conclusion ee is an important differential of gerd-like symptoms in childhood. to avoid misdiagnosis it is critical to evaluate the number of eosinophils present in a biopsy specimen to help differentiate between gerd and ee. children with ee are at increased risk of developing esophageal dysmotility and esophageal strictures. patients often have positive skin prick or rast tests to foods and aeroallergens. alternative treatments such as food elimination diets and glucocorticoids (systemic or topical) are effective in treating symptoms which may not respond to reflux medications. introduction in 1992 asherton introduced the term catastrophic antiphospholipid syndrome (caps) to describe patients sharing clinical evidence of multiple (three or more) organ involvement and/or histopathological evidence of multiple vessel occlusions. case report we present a 13 year old female, with lumbar pain, arthralgias, weight loss, fever, malaise, raynaud phenomenom, alopecia, oral ulcers and hepatomegaly. on arrival, she was polypneic with tachycardia, basal hypoventilation, and hepatomegaly was evident. hb: 8.8, leucocytes: 39.300, total lymphocyctes: 8, 300, total neutrophyles: 28, 700, platelets 393, 000. coombs positive. urin exam: proteinuria, leucocyturia and erythrocyturia. creatinine 1.3. diagnosed as sle with pericarditis, cardiac failure and acute pulmonary edema, urinary tract infection and pneumonia, requiring mechanical ventilation and inotropic support, intravenous gammaglobulin and hydrocortisone. acute renal failure and hemodialysis was begun with improvement. suddenly she presented seizures crisis, stuporous, livido reticularis skin and acrocyanosis, external opthamalplexia, bilateral facial diplexia, ocular fundus with arteriolar vasospasm. right facio-corporal hemiparesia, cortical and progressive medular annals of allergy, asthma & immunology segment changes. ct showed multiple left fronto-occipital parietal hypodensities suggestive of lacunar infarcts. diagnosed as neurolupus and caps. initially anti b2 glp1 and anti clp were negative with later positivization. urinary tract infection contraindicated high doses of steroids and, intravenous gamaglobulin and anticoagulation were started. with significant improvement. currently the patient is evolving in a satisfactory way. discussion the literature establishes that catastrophic aps is characterized by elevated mortality. in this patient damage was evident to the cns, pns, kidneys and the skin. with the presence of positive antiphospholipid antibodies with an energic antiinflamatory, immunoregulatory and immunosupressive therapy, the function of each affected organ completely recovered. this case exemplifies that the therapy of caps should be undertaken in a sufficient and early manner given the elevated mortality of this syndrome. patient, a 70-year-old white, male non-smoker physician on high-dose regimen of advair and singulair presents with an 8-day history of progressive chest tightness. pulmonary function tests showed normal (fev 1 of 96%) lung function. in the past, whenever inhaled steroid dosages were lowered, patient experienced a reoccurrence of asthma symptoms, despite consistently normal lung function results. to rule out the possibility of a psychologically induced asthma exacerbation, the patient's fractional concentration of exhaled nitric oxide (feno) levels were measured. the patient's feno level was elevated at 48.9 ppb. values greater than 30 ppb have been described as consistent with airway inflammation. with an increase in the patient's inhaled steroids, the patient had a remission of symptoms within a week. this case is illustrative of an increasingly common clinical picture where a symptomatic asthmatic may have normal spirometry but elevated feno. as devices for measuring feno become more available in the outpatient clinic setting, elevated feno may be an excellent diagnostic marker in assessing whether airway inflammation is being adequately treated in situations where spirometry values are within normal ranges. introduction the autoimmune thrombocytopenic purpura (atp) is characterized by thrombocytopenia and megakaryocytic hyperplasia. the first choice of treatment consists of intravenous gamma globulin (ivig), corticosteroids and anti-d antibodies and the second line measures are immunosuppressant drugs, splenectomy and danazol. case report a 4 years old male presented in the first year of life ecchymosis in several parts of the body intermittently. in april 2003 he presented ephistaxis and lower gastrointestinal bleeding. complete blood count showed platelet count of 45, 000/ul. prednisone was started (2 mg/kg) with no improvement. at that time, danazol, anti-d antibodies, and ivig (2 g/kg) were added. subsequently, the platelet average count diminished to 5, 000. the patient was transferred to our hospital. at his admission he presented cushingoid habitus (figure 1) and acanthosis nigricans. the immunological tests (aan, ch50, c3, c4, immunoglobulins, anticardiolipins and b2 glycoprotein) showed no alterations. bone marrow aspirate demonstrated megakaryocytic hypercellurarity. prednisone dose was tampered when the patient presented secondary glaucoma. patient continued his treatment with danazol and ivig (2 dosages of 2g/kg each), hydroxychloroquine and cyclophosphamide with no improvement. thus, 3 months after the immunosuppressant treatment, splenectomy was performed, obtaining partial improvement. at that time ranitidine and hydroxychloroquine were suspended and cyclophosphamide was changed to azathioprine. last platelet count was 106, 000/ul. conclusion chronic atp in childhood as the present case account for approximately 4-5% of the total atp patients. chronic atp that does not respond to conventional treatment is a therapeutic challenge. in this patient we used first choice and second choice drugs with no improvement, consequently a splenectomy was indicated, not obtaining the desired response at first. the use of immunosuppressant drugs is not common for this disease, but it could be a good alternative for atp resistant to conventional treatment. this are the most important laboratory test of our patient. background: budesonide is the only corticosteroid available for inhalation by jet nebulizer and is indicated for the treatment of asthma in children. objective: to evaluate the distribution and clinical efficacy of inhaled budesonide administered by nebulization with a modified commercial device. methods: a 23 year old male with severe persistent asthma underwent a lefort procedure for multiple craniofacial abnormalities. the external device maintained his mouth open impeding the proper use of controller medications. as a result he developed an increase in his asthma symptoms. he was subsequently treated with nebulized budesonide delivered with a modified jet nebulizer through the end of a plastic tube in a flow-by manner. we then performed dynamic ventilation imaging after administering 33.40 mci of nebulized technetium 99m-dtpa diluted in two ml of normal saline. images were obtained for five minutes at three seconds per frame. spirometry monitoring was not possible given the obstructive nature of the facial device. results: the patient demonstrated improvement of his asthma symptoms. the ventilation scan showed that the patient breathed the technetium dtpa through the specialized device with delivery to his full lung volumes within 12 seconds. conclusions: we report the successful treatment of a patient unable to use the commercially available methods for administration of inhaled steroids. rationale: hp is a non-ige mediated inflammatory response in the lungs due to a variety of organic antigens, including metal working fluids. the wideranging clinical features include acute, subacute, and chronic forms. elevated antineutrophilic cytoplasmic antibodies and platypnea, defined as dypsnea induced by the upright position and relieved with recumbency, have not been previously reported in patients with hp. case: 35-year-old white male tool and dye machinist presented with progressive cough, weakness, dyspnea on exertion, and platypnea. symptoms began 15 weeks earlier with coryza and diffuse myalgias. he had lost 12% of his body weight since symptom onset. examination revealed a pulse of 140, respiratory rate 18, and right basilar crackles. resting pulse ox on room air was 95%, but dropped to 91% upon ambulation. pft's revealed severe obstruction (fev1 42% predicted) with significant reversibility (fev1 +19%), and a dlco of 82% (adjusted for va and hemoglobin). hemoglobin was 17.5 with a normal leukocyte count and differential. c-anca (anti-pr3) was 19.3 (<5), and p-anca (anti-mpo) was 15.9 (<15), both performed by elisa. echocardiogram showed an ef of 50-55% with mild pulmonary hypertension; no shunt was present. chest roentogram was normal, but a chest ct revealed a diffuse ground-glass pattern with scattered centrilobular opacities. biopsy was consistent with hp. he was removed from his work exposure to metal working fluids with full recovery of lung function and resoulution of symptoms. conclusions: hp presents as a constellation of symptoms without a single, unique identifying pattern. platypnea and elevated anca's have been observed in a wide range of disorders, all of which were excluded in this patient. platypnea has been associated with hereditary hemorrhagic telangiectasia, pulmonary avm, hepatopulmonary syndrome, recurrent pulmonary emboli, and patent foramen ovale. elevated anca's has been associated with wegener's granulomatosis, goodpasture's syndrome, churg-strauss vasculitis, drug-induced vasculitis, inflammatory bowel disease, and others. elisa is a more specific modality for anca's than indirect immunofluorescence, but it is less sensitive. the possibility of hp should be considered in patients with either of these two abnormalities. rationale: heart disease is the leading cause of death in america and 70% of persons between 70 and 80 years of age have coronary athersclerosis at autopsy. the presentation in the elderly is commonly atypical. 45% of myocardial infarctions were silent or unrecognized in the framingham cohort. in patients 65 and older, it is estimated that 8-25% will present with dyspnea without any associated chest pain. we present a case of unstable angina presenting as exercise-induced asthma. case: an 81 year-old white male with moderate persistent asthma, hypertension, dyslipidemia, and a long history of allergic rhinitis presented having had an abrupt increase in his usual exercise-induced asthma symptoms four weeks prior. asthma had been diagnosed at age 69 with spiromety showing moderate obstruction and significant but incomplete reversibility. he had a remote history of pipe and cigar smoking, but had quit at age 50. he had been well-controlled since that time with his most recent regimen consisting of fluticasone 100 mcg/salmeterol 50 mcg diskus, one inhalation twice daily. his typical exercise-induced asthma symptoms included dyspnea on exertion and chest tightness without radiation, and were relieved with rest and albuterol. the amount of exertion needed to trigger his symptoms, however, was much less than he had previously experienced, and this remained constant during the four weeks prior to his presentation. one week prior he had a normal ecg evaluation by his primary care provider. six months prior he had a normal nuclear cardiac stress test. physical examination was unremarkale except for moderately decreased aeration and 1+ pitting edema of his lower extremities. cardiology performed a nuclear stress test the next day which was abnormal. catheterization revealed 99% steonsis of his proximal lad. he succefully underwent cabg and is doing well on follow-up. conclusion: the elderly present many challenges to the diagnostician; these include multiple co-morbidities as well as atypical and often late disease presentations. the key to raising suspicion for cardiac involvement in this case was the recognition of the patient's cardiac risk factors in the setting of an abrupt onset of exercise symptoms while lacking other asthma symptoms such as nocturnal cough. cold urticaria is an uncommon form of physical urticaria. this case of a 9-year-old with cold urticaria and angioedema provides additional information regarding an unusual disorder in the pediatric population. an otherwise healthy 9-year-old female presented with a complaint of urticaria precipitated by cold exposure over the preceding 5 weeks. she had no recent illnesses and a past medical history significant only for cat allergy. on multiple occasions the patient noted erythema and pruritus of her arms and face after walking through the freezer aisle of a grocery store. urticaria would then develop on regions where she scratched, spontaneously resolving in 2-3 hours. on one occasion, urticaria appeared diffusely while taking a shower after the patient had been swimming. the urticaria resolved within a few hours after the patient was given diphenhydramine by her mother. three days prior to presentation the patient experienced upper lip angioedema with erythema, globus sensation and difficulty swallowing after drinking a strawberry slushy. the patient denied any respiratory complaints at that time and her symptoms again annals of allergy, asthma & immunology resolved spontaneously. family history was significant for a maternal history of seasonal allergies. upon physical exam the patient was well appearing. she had 2-3 discrete urticaria on each calf. the patient's mother noted that recently these would appear on "cold and rainy" days, attributing them to the fact that the patient's pants left her lower legs exposed. the remainder of her exam was normal and dermatographism was absent. laboratory evaluation consisted of cryoglobulins and strawberry rast, both of which were negative. application of an ice cube to the patient's forearm for 5 minutes resulted in a 9x6 centimeter wheal noted 3 minutes after ice removal. a diagnosis of cold urticaria with associated angioedema was made. the patient's mother opted to use diphenhydramine as needed and an epinephrine autoinjector was dispensed. by 3 months after symptom onset, the patient's only complaint was pruritus of her hands if they became too cold. no urticaria were noted. at 6 month follow-up the patient denied any symptoms for the preceding 2 months and had a negative ice cube test. cold urticaria in the pediatric population is a rare entity and not well understood. this case of a 9-year-old with cold urticaria and angioedema offers additional insight into this unusual disorder. a. khuntia * , m. mcmorris, ann arbor, mi. introduction: chronic granulomatous disease(cgd) is a heterogeneous group of disorders characterized by genetic defects in the ability of phagocytes to generate microbicidal reactive superoxide anions and its metabolites. it manifests early in life, primarily as recurrent infections, caused by catalase-producing bacteria such as staphylococcus aureus, burkholderia cepacia, and serratia marcescens and fungus such as aspergillus fumigatus. the disease may be inherited in an x-linked or autosomal recessive manner, with x-linked disease accounting for 65-70% of cases. the us incidence of cgd is 1/250, 000 live births with an average age at presentation of 3 years for xlinked and 7.8 years for autosomal recessive disease. case report: 18 year old male with history of three separate episodes of pneumonia beginning at age 16. each episode resulted in a hospital admission and intravenous antibiotic therapy after failed oral antibiotic therapy. an extensive pulmonary evaluation was initiated after the third episode of pneumonia, including a chest ct, viral, bacterial and immunodeficiency studies. cbc, complement, immunoglobulins, flow cytometry, viral and bacterial studies were all normal. the ct scan revealed dense nodular opacities in the right upper lobe with surrounding ground-glass opacification and mild bronchiectasis. a subsequent bronchoscopy demonstrated necrotizing granulomatous inflammation. open lung biopsy grew burkholderia cepacia on tissue culture. the clinical history, tissue histopathology and atypical organism found on culture were all suggestive of an underlying immunodeficiency. a neutrophil oxidative burst assay was performed which demonstrated minimal neutrophil activity upon stimulation, suggestive of the diagnosis of cgd. a chemilluscence assay verified the diagnosis of cgd, with minimal fluorescence noted on flow cytometry after neutrophil stimulation. dna analysis demonstrated a p47-phox deficiency, resulting in one of the autosomal recessive and less clinically severe forms of the disease. conclusions: this case of cgd is unusual because of the delayed presentation. it demonstrates the importance of a complete immunological evaluation including an evaluation for neutrophil disorders such as cgd in patients of all ages who present with recurrent and recalcitrant episodes of pneumonia, especially when atypical organisms such as burkholderia cepacia are found on culture. autoimmunity may play a role in the development of premature ovarian failure (pof), but the exact mechanism is not well understood. pof is mainly diagnosed after 19 years of age and most women complain of secondary amenorrhea. pof has been reported in combination with presence of ana and autoimmune diseases, but rarely with jra. here we report two cases of pof and positive ana in pediatric patients, one with clinical features of jra. the first patient, an african american 17-year-old girl, height in 50th percentile, weight in 10th percentile, with tenosynovitis of wrists and arthritis of knees and elbows for the past two years, was referred for further evaluation and management. she did not have her menarche yet and laboratory investigation revealed positive ana. the second patient, an african american 17-year-old girl, 50th percentile for height and weight, was referred to the immunology clinic with chief complaint of primary amenorrhea and delayed development of secondary sexual characteristics and was found to have positive ana without clinical findings of jra. both patients were tanner stage 2 for breasts and tanner stage 2-3 for pubic and axillary hair. both had elevated fsh and lh, karyotype 46xx and small uterus and small ovaries on pelvic ultrasound. antiovarian antibody was not detected in any of the two patients. the bone age was significantly delayed. pof in karyotypically normal women is frequently seen in combination with elevated serum ana. the clinical spectrum of rheumatoid disease associated with pof ranges from asymptomatic ana positivity to typical presentation of jra. women with pof should be monitored for the emergence of autoimmune disorders including jra, and women with jra should be followed for menstrual irregularities and signs of pof. introduction: many u. s. military personnel deployed to the middle east continue to develop infection with leishmaniasis, a parasite transmitted by the sand fly. pentavalent antimonials have been used as an effective treatment for leishmaniasis for many years. in the united states, sodium stibogluconate (pentostam) is the pentavalent antimonial of choice, and is currently being administered under an ind protocol. side effects of therapy include myalgias, arthralgias, rash, malaise, abdominal pain, pancreatitis, and hypersensitivity reactions. the true incidence of hypersensitivity reactions is not currently known. case reports: two u. s. soldiers receiving pentostam for the treatment of cutaneous leishmaniasis were evaluated in our clinic at walter reed army medical center after experiencing urticaria, angioedema, wheezing and dyspnea after medication infusion during the 20-day course of daily therapy. due to the concern of a potential ige-mediated reaction, skin testing was performed. after informed consent, skin testing included a prick test at full strength, followed by intradermal (id)testing. soldier #1 was a 23-year old male reporting lip swelling, throat tingling, dyspnea and chest pain 7-8 hours after treatment #10/20. skin testing to both lots used during the treatment course showed positive values of 8x20mm and 9x14mm respectively at id 1:1000. soldier #2 was a 28-year old male reporting diffuse pruritus, hives, dyspnea, and chest pain 15 minutes after infusion #16/20. skin testing showed positive values of 7x14mm and 8x12mm respectively at id 1:1000. due to clinical symptoms and positive skin testing, therapy was discontinued in each case. one control individual showed negative testing to prick at full strength, id 1:1000, and id 1:100. conclusion: skin testing with pentostam may provide an objective tool for accurate classification of adverse reactions as igemediated. reliance on skin prick testing alone may not be sufficient to detect pentostam skin test reactivity, as both of these patients reacted to id testing only. a prospective study including pre-and post-treatment skin testing should provide more information on the value of skin testing in providing objective evidence for an ige-mediated process and determining the incidence of hypersensitivity to pentostam. introduction: a 3-year-old girl with a history of multiple infections was hospitalized with respiratory distress and hypoxia. her past medical history was significant for hypothyroidism, psoriasis, asthma and multiple pneumonias. a cbc revealed an absence of lymphocytes. laboratory: t and b cell subsets showed no b-cells and very low t cells (<100 cells). inadequate lymphocytes were present for mitogen and antigen studies. serum immunoglobulins were normal and she had antibodies to streptococcus pneumoniae and tetanus. antibodies to rsv, influenza and mycoplasma were absent. chest x-ray revealed interstitial infiltrates bilaterally. a high resolution ct scan revealed septal thickening and confirmed interstitial infiltration. open lung biopsy was consistent with non-specific inflammation with extensive lymphocytic infiltration. bal fluids and biopsy were negative for bacteria, fungi and opportunistic pathogens. clinical course: the patient did not improve with antibiotics and steroids were started. the patient improved rapidly and was discharged to home. biochemical analysis demonstrated a deficiency of adenosine deaminase (ada), a form of severe combined immune deficiency (scid). the patient was started on replacement ada, adagen. a repeat high resolution ct scan showed some improvement. however, the patient continues to be steroid dependant to control her pulmonary symptoms. lymphocyte numbers remain low despite effective ada replacement and the absence of serum datp. she remains clinically stable and receives adagen injection twice weekly. discussion: ada deficiency is a condition, which leads to accumulation of the metabolite datp, which is toxic to lymphocytes. this disease most commonly presents in the first year of life as scid and is fatal unless treated. our case is unusual due to the late onset of severe disease, normal serum immunoglobulin and the presence of some protective antibodies. despite adequate replacement of ada the patient continues to be profoundly lymphopenic, most likely due to steroids. although we do not yet completely understand the underlying lung disease we suspect that the patient has an autoimmune process causing interstitial inflammation. background: atopic dermatitis has a broad range of differential diagnoses. human sarcoptic infestation is characterized by severely pruritic lesions of variable appearance and distribution and may masquerade as eczema. infestation may be difficult to confirm and eradicate. animal transmission has been reported as a source of human infection. objective: to report a case of persistent sarcoptic infestation masquerading as eczema and associated with delusional parasitosis. methods: a 58-year-old female was referred to allergy clinic for evaluation with a two year history of recurrent, pruritic rash thought to be refractory atopic dermatitis. previous ineffective treatments included topical steroid creams, lindane, topical anti-fungals and multiple otc antiitch preparations. at initial evaluation, she had widespread excoriated papules in various stages of healing over 70% of her body. she reputed her dog was diagnosed with recalcitrant mange, which necessitated giving him medicated baths twice daily. results: a clinical diagnosis of subacute sarcoptic infection was made and the patient was prescribed two courses of elimite followed by oral ivermectin. her rash quickly resolved except for post-inflammatory hyperpigmentation. three weeks after resolution of primary lesions, she again complained of pruritic eruptions occurring on easily accessible areas and began bringing in medicine bottles of skin debris and scabs for examination. scrapings, koh preparation and skin biopsy examined microscopically showed no evidence of sarcoptic re-infestation. a diagnosis of delusional parasitosis was made. conclusions: the animal to human transmission of sarcoptic infection seen in this patient is rare and responded quickly to appropriate treatment. despite eradication of the infection, she developed delusional parasitosis, a rare psychiatric disorder characterized by fixed, false belief of an infestation by insects or other creatures. she displayed the classic matchbox sign in which samples of skin, scabs and other detritus are brought in for examination. she is currently receiving psychiatric care. background: thimerosal is a mercury derivative that has been used since the 1930s. it is a commonly used preservative in ophthalmic solutions, otic drops, and vaccines due to its bactericidal property. objective: to report the first case of a generalized reaction to thimerosal found in an influenza vaccine. methods: we present a patient who developed a generalized maculopapular eruption after receiving a thimerosal containing influenza vaccine. patch testing was performed to determine if there was an allergy to thimerosal. results: patch testing confirmed a type iv (t cell mediated) sensitivity to thimerosal, further supported by the prior history of a reaction to a thimerosal containing contact lens solution. the patient was asked to avoid thimerosalcontaining products, including vaccinations, unless the benefit clearly outweighed the potential risk of a reaction. conclusion: physicians need to be aware that thimerosal is found in many products including vaccinations. clinicians should also be aware that allergic reactions do occur with exposure to thimerosal even in vaccines. this is the first case report in the literature of a generalized reactions to thimerosal from an influenza vaccine angioedema is a rare condition that has been described in the literature and exists in both inherited and acquired forms. a defect of the innate immune system, more particularly the complement system, is the inciting culprit. the acquired form of c1 esterase inhibitor deficiency has been divided into two classes and is generally not commonly seen until after the forth decade of life. type 1 acquired angioedema has been described in association with lymphoproliferative disorders, while type 2 is related to excessive complement activation and consumption due to autoantibodies. our case is a 67-year old man referred from an outside physician for further management of idiopathic edema. he first experienced facial edema in april 2002 attributed to sweet myrrh root ingestion. subsequently, in november 2002 he developed diffuse swelling of his upper extremities and tongue without airway compromise. a minimal work-up at that time was inconclusive. he fortunately remained asymptomatic until january 2004 at which time he experienced two episodes of tongue swelling without etiology. he was seen in his local emergency department and treated with diphenhydramine, corticosteroids, and epinephrine on both occasions with gradual improvement of his symptoms. the patient was not on medications commonly associated with angioedema and did not report insect envenomation. subsequently, he was seen by his primary care physician who ordered a number of laboratory tests including a ch50, which was significantly suppressed. in light of this finding, he was referred to our clinic for further evaluation. at the time of presentation to our office, the patient was symptom free. his physical exam was within normal limits. further laboratory evaluation was essentially unremarkable with the exception of comple-ment studies, which are listed in the table. our case demonstrates an elderly patient with evidence of idiopathic swelling. we arrived at our diagnosis of acquired angioedema based on clinical presentation and confirmatory serum complement levels. a low ch50 at time of presentation allowed us to further delineate the etiology of complement deficiency. the fact that our patient did not present with swelling until after age 60 and the paucity of a family history of idiopathic angioedema makes the diagnosis of acquired angioedema probable. measure of serum c1q level confirmed the diagnosis. introduction: certain diseases, widely believed to be of allergic etiology, including atopic dermatitis and episodes of wheezing might be the result of interplay of genetic and environmental factors, at least partially. we describe a child with a rare chromosomal disorder presenting with typical features of atopic dermatitis and recurrent mild wheeze. materials and methods: a new born african-american male was noted to have unusual facial features immediately after birth. the baby was born naturally, without antenatal and neonatal problems. on physical examination, the infant had unusual facial characteristics with tight and taut facial skin, relatively diminished facial pad of fat, pointed chin, and markedly hypertonic extremities. additionally, cardiac exam revealed mumur consistent with uncomplicated asd. frequent reassessments of the infant in the outpatient clinic were done. the child had repeated bouts of wheezing attacks, and facial rashes compatible with the diagnosis of atopic dermatitis. the wheezes were treated in the clinic with nebulaized bronchodilators, and the atopic dermatitis responded reasonably to topical steroid applications and moisturizers as needed. chromosomal analysis of the peripheral blood of the chid confirmed the diagnosis of deletion of long arm (q) of chromosome 1 [46, xy, del (1)(q42q43)]. karyotypic analyses of the mother and father were normal. the child exhibited features of developmental delay, and seizure activities. anti-epileptic drugs (aed) were instituted. initial eeg was normal and the subsequent eeg showed findings of static encephalopathy. ct scan of the brain revealed absent corpus callosum. neurologic evaluations and physiotherapies were requested for improvement of fine motor skills. he did not seem to suffer from any serious infectious or immunodeficient illnesses. his cbc was normal. he continued to have fair gains in his weight, height, and head circumference. his atopic dermatitis and wheezing episodes remained under control. there were a few hospitalizations for break-through seizures and dehydration from gastroenteritis. a subsequent echocardiography confirmed closure of asd. con-clusion: a child with chromosomal anamoly, atopic dermatitis, and mild intermittent wheeze is reported. despite multiple congenital problems, the child continued to have a stable clinical course. etoposide is a chemotherapeutic agent used to treat many solid tumor malignancies. hypersensitivity reactions have been well described and there are a few reported deaths from anaphylaxis. some suggest that the hypersensitivity is an anaphylactoid type reaction as it may occur during the first dose. case reports of cutaneous complications include stevens-johnson syndrome, radiation recall and diffuse erythema. there are four cases in which diffuse erythematous papules developed after etoposide therapy. all rashes spontaneously resolved within three weeks and biopsies demonstrated keratinocytes in a starburst pattern. we report the first case of an immediate etoposide induced skin reaction that evolved into long lasting hyperpigmented plaques. pretreatement was able to prevent this immediate and late reaction on subsequent exposure to etoposide. a 27 year old female with ovarian cancer was treated with bleomycin, etoposide and vinblastine. three hours after initiation of the third dose of etoposide, patient developed pruritic, erythematous macules on her chest, abdomen, face and extremities. the infusion was stopped and decadron administered. over forty-eight hours, the pruritic macules became hyperpigmented plaques on her chest, abdomen, extremities and face. pruritus resolved after a slow taper of prednisone. the darken plaques were treated with multiple topical preparations but persisted for about three months. biopsies demonstrated superficial perivascular infiltration of lymphocytes and a few eosinophils suggestive of a drug eruption. etoposide was considered essential for this patient so allergy was consulted. the literature supports cautious readministration of etoposide with pretreatment and slower infusion rate to prevent immediate hypersensitivity. we could not guarantee prevention of the late hyperpigmented reaction. the patient was pretreated with prednisone and cetirizine. etoposide was administered in an icu with a slower rate of infusion. etoposide was tolerated without immediate pruritus or erythematous reaction. the patient did not develop the delayed darkened plaques. cautious administration of etoposide after premedication and a slow rate of infusion prevented both the immediate and late reaction previously experienced by this patient. eosinophils normally comprise 1-3% of peripheral white blood lymphocytes. peripheral blood eosinophilia is defined as an absolute eosinophil count >500 cells/mm3 and is most often caused by atopy, helminth infections, or collagen vascular diseases. less common causes include adrenal insufficiency and neoplastic processes. eosinophilia can be characterized as mild (<1500 cells/mm3), moderate (1500-5000 cells/mm3) or severe (> 5000 cells/mm3). although severe eosinophilia has been reported in association with adult hiv infection, studies of hiv-infected children have not shown peripheral blood eosinophilia to be a feature of pediatric hiv infection. we report an unusual case of severe peripheral blood eosinophilia in an adolescent male who was subsequently found to be hiv-infected. a previously healthy 15-year-old male presented with 2 week history of fever, diarrhea, cough, vomiting, abdominal pain, anorexia and a 5lb weight loss over the previous 2 months. the patient had recently emigrated from guyana and denied sexual activity, intravenous drug abuse, or other hiv risk factors. there was no known maternal hiv infection. repeated stool specimens were negative for ova and parasites. serologies for e. histolytica, t. canis, and s. stercoralis were negative. an abdominal ultrasound, chest x-ray, serum electrolytes, and liver function tests were all within normal limits. total white blood cell was 16, 500 with 59% eosinophils (absolute eosinophil count of 9, 735 cells/mm3). elisa and western blot were positive for human immunodeficiency virus (hiv-1). cd4+ tlymphocyte count was 1277 cells/mm3 with an hiv-1 rna level of 11, 000 copies/ml. the patients symptoms resolved over the next 10 days without treatment. he was started on combination antiretroviral therapy (zidovudine, lamivudine, abacavir, and efavirenz). absolute eosinophil count continues to slowly decrease with the last count of 3, 605 cells/mm3 three months following the introduction of antiretroviral therapy. severe peripheral blood eosinophilia may be a presenting feature of hiv infection in adolescents. hiv testing should be considered in cases where more common causes of eosinophilia such as atopy and parasitic infections are excluded. triad asthma is well described in adults but not in the pediatric literature. this case highlights the successful treatment of a severe pediatric asthmatic with nasal polyps and aspirin sensitivity. a 13 year-old female presented with severe persistent asthma, eib, allergic rhinitis, chronic sinusitis, nasal polyps, and a history of pneumonia. her asthma symptoms were minimal from age 2 until age 9. she then started flovent and required increasing amounts of inhaled and oral steroids. she required 6 courses of oral steroids per year by age 13. in addition, she had snoring, fatigue, chronic nasal congestion, rhinorhea, and sneezing despite treatment withallegra and rhinocort. she had received immunotherapy from age 8 to 10 with no clinical improvement. since age 8 she had recurrent sinusitis and had required 2 polypectomies. she noted aspirin caused nasal stuffiness and mild wheezing and therefore avoided it. on exam she had allergic shiners, dennie lines, boggy turbinates, nasal polyps, and diffuse wheezing. on evaluation she had severe airway obstruction. her fev1 increased from 36% to 51% with albuterol. her chest ct had a mosaic pattern due to severe air trapping, and her no level was 177. a sleep study showed severe hypopneas, and she had pan-sinusitis on ct. she had multiple positive spts, an eosinophil count of 1100 and an ige of 700. she had a normal sweat chloride and ph probe.the differential diagnosis included churg-strauss, abpa, cystic fibrosis, bronchiolitis obliterans, and triad asthma. after a thorough evaluation, she was diagnosed with triad asthma. with 6 weeks of treatment with oral prednisone, her fev1 improved from 36% to 83%. her inhaled controller therapy was increased and she was placed on xolair. she had a polypectomy and then underwent aspirin desensitization. one year after starting treatment her fev1 remains 83%. she requires albuterol 1x/month and has not required prednisone. her eib, allergic rhinitis and congestion are markedly improved. she has had no further episodes of sinusitis, and a repeat sleep study was normal. in conclusion, we treated a severe pediatric asthmatic with nasal polyps and aspirin sensitivity. this is not frequently reported in the pediatric population, and raises questions about the incidence, optimal long term treatment of triad asthma, and the differences from the adult onset of this disease. a.a. white * , r.a. simon, la jolla, ca. background: human disease from mold has traditionally been isolated to infection, allergic disease, or hypersensitivity pneumonitis. specific diseases or pathologic findings other than those listed above have not been well described. we report a case of acute eosinophilic pneumonia related to mold exposure. case presentation: a 50 year old woman developed dry cough and shortness of breath after stachybotrys mold was discovered in her home. a chest radiograph showed bilateral upper lobe infiltrates which worsened two weeks later. treatment with macrolide and flouroquinolone antibiotics was ineffective. a white blood cell count was 12, 000/cumm with 35% eosinophils. an erythrocyte sedimentation rate was 99 mm/hr. aspergillus ige was negative. treatment with prednisone led to complete resolution of the chest radiographic abnormalities and improvement in pulmonary function testing. this patient was given a diagnosis of acute eosinophilic pneumonia with mold as a likely causal factor. discussion: there is dispute amongst health care professionals regarding the significance of environmental mold contamination in the etiology of human disease. this case represents well characterized disease occurring in the setting of mold exposure. while a causal relationship cannot be established, the temporal relationship of mold contamination, symptom onset, and disease progression is compelling. interestingly, a recent report of mold contamination leading to nonspecific interstitial pneumonia/fibrosis has been described. we have observed a patient in our clinic with similar pathology on biopsy and temporal relationship to mold exposure. to our knowledge, acute eosinophilic pneumonia has not been reported in conjunction with mold exposure. conclusion: this case highlights a new condition in which mold may have a causal role. the mechanism is unknown, but likely is through a non-ige mediated immunologic pathway. public awareness of mold as a health concern is increasing. perhaps similar cases will emerge as a history of mold exposure is offered by patients at the time they are evaluated for lung disease. a stronger correlation may then emerge. scuba diving is a commonly practiced activity which normally carries only minimal risks. any severe allergic reaction such as anaphylaxis, however, occurring during this activity could be a particularly dangerous not only because the swimmer is submerged but also because of the lack of proximity to medical care. we report a case of anaphylaxis occurring during scuba diving resulting from an unsuspected hypersensitivity to a latex component of the scuba diving suit. a 21 yr-old white male developed a severe generalized urticarial rash with angioedema of his lips and eyelids, and difficulty breathing within 5 minutes of his applying the suit and entering the water. after being rescued, he was transported to a nearby emergency department where he received epinephrine, antihistamines, corticosteroids and iv fluids with gradual improvement over a 4 hour period. the patient denied being stung by a marine aquatic organism and there was no prior history of allergy or medications usage prior to his reaction. since subsequent investigation revealed that the scuba diving suit contained latex (brazilian rubber), a specific ige rast was found to be strongly positive (class v) to latex. therefore, the patient was advised to use a suit made of neoprene synthetic rubber (polychloroprene) which is a nonlatex containing product. this case report illustrates the importance of a diligent search for hidden sources of latex products which can produce life-threatening allergic reactions in sensitized patients. there has been considerable debate concerning the safety of immunizing egg-allergic children with the combined mmr vaccine. this concern derives from the possibility of an anaphylactic reaction since the mmr vaccine is prepared from attenuated viruses grown on chick embryo fibroblast cell cultures. we have previously reported the safe administration of the mmr vaccine to 6 severe egg-allergic children without development of an adverse reaction (nsouli, tm, et al. ann allergy asthma immunol. 2004; 90:163) , a finding consistent with the current report of the committee on infectious diseases, american academy of pediatrics, 2003. the present case report describes an anaphylactic reaction in an egg allergic 4 yr-old-white male consisting of generalized urticaria, angioedema, wheezing immediately following the administration of a second mmr vaccine. the history of hives following ingestion of eggs was confirmed by positive specific ige rast testing. the patient's anaphylactic reaction necessitated emergency treatment including epinephrine, diphenhydramine, and corticosteroids in addition to iv fluids. although the administration of mmr vaccine in egg-allergic children is not considered as an absolute contraindication, the present case report suggests that caution should be observed when administering the mmr vaccine in such patients and that careful medical observation be included together with the ready availability of emergency medical equipment. p. buddiga * , r. turbin, a. baisre, l. bielory, newark, nj. introduction: sarcoidosis is a chronic granulomatous disease of unknown etiology that may have a multi-organ system manifestation and is characterized by the histopathological evidence of nonnecrotizing granulomas. case report: a 53 year old african american woman with a 10 year history of type ii diabetes mellitus, hypertension and sinusitis recalcitrant to multiple courses of antibiotics over 3 months was admitted to the hospital with complaints of right eye proptosis, diplopia, headache and right facial numbness.her exam was consistent with an ipsilateral mild optic neuropathy, complete sixth (vi)nerve palsy, trigeminal, ophthalmic and maxillary division numbness.ct and mri of the face, orbit and brain revealed an extensive process infiltrating ethmoid, maxillary and frontal sinuses;orbits and deep facial structures.chest ct revealed bilateral interstitial nodules and symmetric hilar adenopathy. differential diagnoses included sarcoidosis, lymphoma/tumor, wegener's granulomatosis or fungal infection.labs-purified protein derivative test=negative(neg), antineutrophil cytoplasmic autoantibodies=neg. angiotensin converting enzyme=83[8-52 u/l], fungal & anaerobic and acidfast bacilli culture of sinus secretions=neg.ethmoid, adenoid and maxillary sinus biopsies=multiple nonnecrotizing granulomas. on the basis of compatible clinical and radiographic findings, histopathological evidence and exclusion of other diseases with similar findings, the diagnosis of sarcoidosis was established. she was started on parenteral methylprednisolone and subsequently tapered to oral prednisone after 5 days.concomitantly she was started on methotrexate as a steroid sparing agent.most recent chest x-ray after 4 months of treatment reveals near complete resolution of the hilar lymphadenopathy.at 5 months her optic neuropathy and facial dysesthesia had resolved, and she was left with mild persistent vi nerve dysfunction. conclusion:sarcoidosis that manifests itself as sinusitis is an uncommon presentation and the mechanism involved is thought to be a consequence of the destruction of cilia and mucus producing glands by the granulomatous process.review of the literature indicates that this is the eighth case reported and illustrates that a high index of suspicion of other etiologies must be maintained when there is a refractory response to multiple courses of antibiotics in the treatment of sinusitis. j.b. hein * , p. patel, l. bielory, newark, nj. introduction: cid may result in opportunistic infections such as cryptococcal meningitis. we present an unusual case of cryptococcal meningitis in an hiv-negative patient with severe cd4 lymphocytopenia. case: a 40 yearold male with a three year history of sarcoidosis presented with acute onset of right-sided body numbness. the patient had been on prednisone 40 mg/day for 5 months prior to presentation. ct and mri scanning showed no vascular defects, meningeal enhancement, hydrocephalus or mass lesions. gallium scanning revealed normal uptake in the liver and spleen, mild uptake in the lungs and nasopharyngeal region, and asymmetric uptake in bilateral kidneys. the patient's initial wbc was 8, 000 cells/mm 3 , composed of 6970 neutrophils/mm 3 , 50 eosinophils/mm 3 , 50 basophils/mm 3 , 530 lymphocytes/mm 3 , and 400 basophils/mm 3 . repeat studies revealed the total lymphocyte count decreased at 240 cells/mm 3 with cd19 (pan b) cells decreased at 29 cells/mm 3 and cd3 (pan t) cells decreased at 189 cells/mm 3 . cd4 count was 144 cells/mm 3 and cd8 count 50 cells/mm 3 with a cd4/cd8 ratio of 2.9. igg levels were normal at 716 mg/dl. elisa was negative for hiv, and hiv-1 rna by pcr was not detected. serum ace level was 19 u/l and csf ace level was 23 u/l. csf obtained by lumbar puncture stained positive with india ink and culture revealed cryptococcus neoformans. the patient responded to amphotericin b lipid complex 5 mg/kg/day, and his neurological status eventually returned to baseline. conclusions: the severe lymphopenia in this patient caused predisposition to infection with cryptococcus neoformans. the etiology of the profound lymphopenia likely was multifactorial, including mild sarcoidosis activity (lung uptake on gallium scan) and chronic corticosteroid therapy. however, once cryptococcus became entrenched in the patient's csf, the infection itself likely depressed peripheral lymphocyte numbers even further. this case demonstrates the importance of exploring a broad differential diagnosis when faced with lymphocytopenia. background: isosulfan blue 1% is a common dye used in sentinel lymph node dissection. the usage of the procedure and dye has increased in numbers, and although rare, several cases of anaphylactic reaction have been reported. objective: we are reporting a patient who had an anaphylactic reaction to isosulfan blue while undergoing breast cancer excision with sentinel lymph node biopsy. methods: the patient is a 44 year-old woman with breast cancer. she underwent breast mass excision with sentinel lymph node biopsy using the lymphazurin 1% blue dye (isosulfan blue). she has a history of penicillin induced hives but has no other drug allergy. as soon as the dye was injected, she became flushed, hypotensive, and tachycardic. hypotension was refractive to fluid challenge. she was then treated with epinephrine as well as intravenous steroids and cimetidine with relief of symptoms. subsequently, she was evaluated in allergy and skin tests with isosulfan blue 1% at 1:100, 1:10 dilution, and undiluted were performed using histamine as positive control and saline as negative control. this procedure was also performed on two control subjects. results: the patient had a positive skin test (wheal and flare) to isosulfan blue 1% (undiluted) with the control being appropriately positive for histamine and negative for saline. control subjects had negative response to dye and saline and positive response to histamine. conclusions: isosulfan blue 1-% dye may cause anaphylactic reactions in patients undergoing sentinel lymph node dissection. . the positive skin test result to the dye plus the negative skin test responses in the controls suggests that the reaction may be immunoglobulin e (ig e) mediated. eosinophilic duodenitis (ed) and gluten-sensitive enteropathy (gse) or celiac disease (cd) are distinct clinical entities with well-defined clinical and laboratory parameters. ed is a rare condition of unknown etiology, which is manifest by eosinophilic infiltration of the gastrointestinal tract and peripheral eosinophilia. gse or cd is a form of non-ige food allergy caused by immune hypersensitivity to ingested gluten. the simultaneous occurrence of the two entities, however, is a rare event. the following presentation is a case report in which both entities were found in the same patient. an 11 y/o white hispanic male presented with severe, chronic, colicky abdominal pain and headache of 5 months duration. hematologic and immunologic studies were within normal limits. serum ige levels were 356 iu/ml (n= < 200 iu/ml), anti-endosomial ab (+), igg antigliadin: 16 u/ml (n=: 0-12 u/ml), skin tests for food and inhalant allergens were weakly positive (1+). biopsy of the inferior third of esophagus revealed chronic moderate esophagitis; biopsy of gastric antrum revealed lymphatic hyperplasia; duodenal biopsy showed shortening of the villi with the presence of eosinophils. following treatment with esomeprazole 40 mg bid, famotidine 20 mg qd, montelukast 20 md qd, lactobacillus, a diet free of gluten, rofecoxib 25 mg qd and betamethasone for 15 days, betamethasone the patient improved with partial resolution of symptoms. the presence of duodenal eosinophils persisted despite a gluten free diet, and continued to require repeated bursts of prednisone. since to our knowledge this is rare finding in which ed occurred in association with gse, a high index of suspicion for simultaneous occurrence of ed should be raised in any case of gse that fails to respond to a conventional gluten free regimen. we report the evaluation of a 6 month old male presenting with a pustular rash and choking episodes from birth. by age 6 weeks, he had experienced two pneumonias, one with fleeting infiltrates requiring intubation. persistent eosinophilia (5000-9000/ml) and eosinophils on pustule biopsy were noted. persistence of these and subsequent rsv pneumonia and recurrent draining otitis media led to referral. physical examination showed a thriving male infant with multiple erythematous papules and pustules along the scalp, face, axilla, and trunk. eosinophilia was confirmed. quantitative immunoglobulins were abnormal for igg 179 and ige 255 iu/ml. peanut cap rast was 23 kua/l. hib post-vaccination titer, t cell enumeration/stimulation, and nbt were normal. hiv testing, stool eosinophils, o&p, and hemoccult were negative. cxr, hrct, ekg, and echocardiogram were normal. pustule cultures for bacteria, virus, and fungus were negative. skin biopsy revealed numerous eosinophils in the pustule, dermis, epidermis, and perifollicular region. cd1a+ and s-100 staining were negative for histiocytic infiltration. nemo defect/incontinentia pigmenti were considered but testing was negative and karyotype 46, xy. bone marrow biopsy revealed numerous eosinophils at different stages of maturation, and no myeloproliferative or neoplastic changes. bronchoscopy was remarkable for 15% eosinophils on balf. 24-hour ph probe and impedence evaluation was negative. egd with biopsy was normal except for mild eosinophilic infiltration of the proximal and distal esophagus. with the clinical picture of recurrent pruritic crops of sterile pustules and characteristic skin biopsy demonstrating eosinophil infiltration, the diagnosis of eosinophilic pustulosis (ep) of childhood was made. despite no longterm sequelae or other end-organ involvement in ep, the degree and duration of eosinophilia, and presence of eosinophils in the airways and esophagus, raises the concern for other eosinophilic syndromes. following cardiac, cns, pulmonary, and gi systems is warranted. the infants pneumonias were felt to be due to aspiration, and ear infections the result of humoral immunity nadir or draining pustules in the external auditory canals. immunoglobulin levels will be monitored. this case illustrates the heterogeneity of eosinophilic diseases and raises the question of what drives the mechanisms behind malignant and benign disease. introduction: behcet's disease is a chronic, relapsing vasculitic disease characterized by recurrent oral, genital, and gastrointestinal ulcerations, a wide variety of skin lesions, uveitis, and arthritis. pediatric cases of behcet's disease are uncommon with an estimated prevalence of 1 in 600, 000 children under the age of 15. although the disease in children shows similar characteristics as adults, the diagnosis of behcet's disease in the pediatric population remains a challenge. this report describes an 18 year old girl referred to our pediatric immunology clinic for evaluation of recurrent painful oral ulcerations since the age of 7 with no genital ulcerations. the oral ulcers would last for two weeks and heal spontaneously but would reappear 2 to 3 weeks later. the patient had a history of raynaud's phenomenon for the last 6 to 7 years and the recent onset of joint pain. physical examination revealed 4-5 white elliptoid lesions 5-7 mm in diameter on an erythematous base on the tongue and soft palate. skin examination was significant for hyperpigmented patches over the neck, abdomen, and back. there were erythematous, serpigenous lesions on the palms and punctuated necrotic lesions on the finger-tips. pathergy test was positive. laboratory investigation was unremarkable and cultures from the oral ulcers remained negative. the patient was diagnosed with juvenile behcet's disease. she was started on immunosuppressive therapy with low dose prednisone and responded. conclusion: behcet's disease is a difficult diagnosis to make in the pediatric population. this case demonstrates that in children, recurrent oral ulcerations may be the only initial manifestation of behcet, and an important clinical marker for the disease. rationale: relapsing polychondritis is an uncommon severe inflammatory condition with unknown etiology that can present in a variety of manners. we report a 14 year old patient who initially presented with signs and symptoms of anaphylaxis to shellfish and was later diagnosed with relapsing polychondritis. case report: a 14 year old african-american boy with a 6 year history of asthma and fish and shrimp allergy presented to the pediatric intensive care unit on 4/23/03 after an episode of severe shortness of breath. his symptoms started shortly after accidental exposure to shrimp. in the intensive care unit, he was noted to be wheezing and stridorous. an initial chest xray as well as subsequent fiber optic laryngoscopy showed sub-glottic stenosis. he was intubated and received mechanical ventilation for greater than a week. after extubation, he stated that he felt fine, but continued to demonstrate audible stridor. pulmonary function tests demonstrated extra-thoracic obstruction, laryngoscopy continued to show sub-glottic stenosis, and esophagogastroduodenoscopy showed erosive esophagitis consistent with reflux. initial lab tests demonstrated a normal eosinophil count, elevated ige (969 iu/ml), and positive immunocaps testing to multiple foods. the patient was discharged home with minimal stridor and no wheezing. over the next nine months, the severity of his stridor waxed and waned, but in general it worsened in spite of a strict elimination diet and anti-reflux therapy. on 9/25/03 he received an emergency tracheostomy. on 1/26/04, the patient was again admitted to the hospital. at this time he complained of bilateral knee pain as well as significant weight loss. physical exam demonstrated arthritis with effusions of both knees as well as unilateral auricular chondritis and bilateral episcleritis. antibodies against type ii collagen were positive (42.1 eu/ml). the diagnosis of relapsing polychondritis was suggested. conclusion: relapsing polychondritis is a rare inflammatory disorder of the cartilage and connective tissue with an unknown etiology. the wide array of presenting complaints as well as the relapsing nature of this disorder often causes significant delay in diagnosis and treatment. in our case there was a period of nine months between the initial presentation and the time when the diagnosis of polychondritis could be made. d.k. geller * , m. ballow, buffalo, ny. introduction: an 11 yo male previously diagnosed with pandas presented to our immunology clinic for ivig. the patient was healthy until age 8 when he developed facial motor tics associated with group a beta hemolytic strep pharyngitis. he was treated with antibiotics and the tics resolved completely. he has had multiple recurrences associated with strep and other viral infections. the tics improve or resolve completely when he is infection free. he has no history of vocal tics, attention deficit/hyperactivity disorder, or obsessional thinking or compulsive behaviors. laboratory: multiple throat cultures positive for group a beta hemolytic strep, positive antistreptolysin and antideoxyribonuclease b titers. discussion: pandas identifies a subgroup of children with an obsessive compulsive disorder and/or tic disorder whose symptoms seem to be triggered by streptococcal infections. the proposed pathophysiology is an immune-mediated mechanism in which antistreptococcal antibodies, antistreptolysin and antideoxyribonuclease b, cross react with the basal ganglia of genetically susceptible hosts. a few studies have looked at immunomodulatory therapies including ivig for neuropsychiatric symptoms including tic disorders secondary to post-streptococcal autoimmunity. we plan a trial of ivig for this patient given the recurrent nature of his tics and the relation to streptococcal and other viral infections. introduction: the chronic granulomatous disease (cgd) is an inheritable disorder of phagocyte cell respiratory burst that result in life-threatening infections. the pulmonary infection is the primary cause of death in greater that 50% of the cases and the role of surgery in management of this entity remains undefined. case report: a lobectomy was performed in a 2 year-old male who presented a persistent opacity of the medial right lobe with fever, cough, malaise an rapid onset of respiratory failure; skin abcesses were concomitant. his familiar history was unremarkable. a chest tube was placed in a first instance in order to drain empyema, but no progress was observed. a ct scan showed necrotizing pneumonia of the right lung, mediastinal and retroperitoneal limphadenopathy and bronchopleural fistula. a second surgical intervention was undertaken to correct the fistula and pleural debridement was done. at this time, serratia marcenses was isolated from blood culture and lung; a primary immunodefiency was suspected. our evaluation showed nbt reduction on 0% and dyhidrorhodamine assay (dhra) didn't demonstrate and effective oxidative burst. the subsecuent management was based on specific antibiotic to serratia and prophylaxis with tmp-smz and itraconazole. transfer factor to improve the ifn levels was initiated. the patient's mother showed on dhra two granulocyte populations, with and without oxidative burst. a x linked cgd was consistent. medical progress was observed in the next days. conclusion: despite the poor utility showed by the surgical procedures in the complicated pneumonia in cgd patients in many series, attending to the unusual nature of the pulmonary infections and the high mortality and morbidity associated with thoracic surgery; the management of this case showed that an aggressive approach in the diagnosis combined with some procedures used in immunocompetent patients pneumonia may improve the clinical condition in cgd patients. background: takayasu arteritis is a large vessel vasculitis primarily affecting the aorta and its branches. it is most prevalent in women in the second and third decades of life. initial symptoms are systemic and often self-limited, but the disease may progress undetected over years until signs of vascular insufficiency develop. arteritis is commonly seen in the aortic arch and its branches, although the disease is a panarteritis and vascular compromise can occur in many organs. pathologically, involved vessels show intimal proliferation and fibrosis, and scarring of the elastic lamina. case report: we report the case of a 31 year old southeast asian woman who presented with diplopia, ptosis, dizziness, and progressive dyspnea. past medical history was significant for rheumatic fever complicated by aortic valve insufficiency and hypertension. physical findings on admission included hypertension, asymmetric upper extremity blood pressure (left arm 95/50mm hg, right arm 200/50 mm annals of allergy, asthma & immunology hg), wide pulse pressure and a harsh diastolic murmur. admission labs showed anemia (hemoglobin: 11g/dl, hematocrit 33%) and an elevated erythrocyte sedimentation rate of 31mm/hr. transesophageal echocardiography revealed severely dilated aortic root aneurysm with secondary severe chronic aortic valve insufficiency and calcified aortic leaflets not typical of rheumatic heart disease. resection of the aortic valve and aneurysm was performed. pathologic examination of the aortic aneurysm revealed intimal and adventitial fibrosis with focal chronic inflammation and partial loss and fibrosis of media, findings compatible with healed takayasu arteritis. the patient was started on prednisone 100mg by mouth daily for takayasu arteritis and discharged in stable condition. discussion: this is a case of takayasu arteritis masquerading as rheumatic heart disease. the episode of rheumatic fever was likely the initial presentation of takayasu arteritis, as the systemic symptoms of these diseases can overlap. takayasu arteritis is an insidious disease that often leads to a delayed diagnosis with considerable morbidity for the patient. since takayasu arteritis may go undiagnosed until ischemic symptoms develop, physicians should be alert to the possibility of this disease in young women to avert end organ damage and achieve early remission with drug therapy. we present a fifteen year old boy with disseminated papillomatosis and idiopathic cd4+ lymphocytopenia (icl). the warts have been present since he was one year old and have progressively worsened. there are more than fifty warts on each of his hands. his legs have multiple warts and about ten warts recently appeared on his lips and around his mouth. his past medical history is significant for no hospitalizations and no blood transfusions. he has never had problems with other infections, and he had a benign course of chicken pox that spontaneously resolved. he has been on cimetidine for six months without improvement. several topical therapies, including imiquimod, have failed. he has a total lymphocyte count of 1484/ul (normal range, 1288-4512/ul) and a cd4+ count of 301/ul (normal range, 361-1715/ul). the cd8+, natural killer cells, and cd19+ cells were normal. his hiv test is negative. the serum immunoglobulins were normal as well. lymphoctye proliferation studies reveal an absent response to antigens (candida and tetanus) with a normal response to mitogens. further studies showed no other cause of cd4+ lymphocytopenia. this case shows that the diagnosis of idiopathic cd4+ lymphocytopenia should be considered in any patient with widespread viral infection whose hiv test is negative. appropriate evaluation of the cd4+ count should be pursued. j. ko * , a. nowak-wegrzyn, new york, ny. introduction: approximately 40% of children with moderate to severe atopic dermatitis (ad) have food allergies. complementary and alternative medicine (cam) is utilized by an estimated 16-27% of patients with allergies. we present a case of a 4 year-old boy with ad referred after receiving a diagnosis of food allergy by a cam practitioner. methods/case: a 4 year-old boy was referred for evaluation of mild ad and possible food hypersensitivity. his ad started at 1 year of age and was limited to the face. he was initially breast-fed and was switched to milk-based formula at 4 months of age. solids were introduced at 5 months of age without difficulty. he had no immediate reactions or noted worsening of ad due to foods. the patient presented to a naturopath for allergy evaluation. based on electrodermal skin testing results, he was reported to be allergic to milk, egg, peanut, rice, and beef (all of which he had tolerated previously). he was restricted from milk and egg for 4 weeks without noticeable change in his ad, which was limited to the cheeks and controlled on topical pimecrolimus. results: his weight and height were both 75th percentile. physical exam was normal except for 2-3 cm dry, erythematous patches on both cheeks and mildly dry skin on flexor/extensor surfaces of both arms. skin prick testing revealed negative tests to milk, egg, peanut, and dust mite. serum ige testing was also negative. since he had no evidence of ige sensitization to commonly allergenic foods, he was recommended to continue an unrestricted diet and discontinue use of a "sippy" cup. his ad subsequently improved on a skin care regimen of postbathing moisturization and topical pimecrolimus prn. asthma and allergies are the #2 reason for cam use in the us. electrodermal skin testing is a method utilized by naturopathic doctors to detect allergen "sensitivity". however, in two double-blinded trials examining atopic and non-atopic patients, electrodermal testing did not correlate with skin prick testing results, regardless of inter-operator variability. conclusions: allergy patients are seeking cam treatment, and it is important for physicians to be aware of the safety and efficacy of alternative medical practices. the use of electrodermal skin testing has not been proven to detect allergen sensitivity and use of this modality should be discouraged. e.e. mcgintee * , k.e. sullivan, philadelphia, pa. introduction: hematopoietic stem-cell transplantation causes profound tcell immunodeficiency due to the rigorous conditioning involved. following transplant, the t-cell compartment is initially reconstituted through expansion of mature donor-derived t-cells. however, thymopoiesis is necessary to generate naive t-cells with a diverse repertoire. factors affecting thymic function impact the ability of the body to reconstitute the immune system. we report a case of severe t-cell immunodeficiency after two stem-cell transplants for neuroblastoma in a patient with a history of thymic hemorrhage secondary to mediastinal surgery. case: a 5-year-old female with a history of high-risk neuroblastoma was referred for immunologic evaluation due to a significant infectious history since completing her neuroblastoma therapy. she initially presented at 21 months of age with a right atrial mass that was presumed to be an atrial myxoma. she underwent mediastinal surgery to resect the tumor, which was found to be neuroblastoma extending from her right adrenal gland along the vena cava. a ct scan following her surgery revealed an area of hemorrhage in her right thymus. she subsequently received high-dose chemotherapy and two autologous stem-cell transplants. her infection history was significant for multiple episodes of upper respiratory illnesses, sinusitis, and otitis media requiring myringotomy tube placement on two occasions. immunologic evaluation revealed a dramatically low absolute lymphocyte count with deficits primarily in the t-cell compartment, and reduced proliferation in response to mitogens. immunoglobulin levels were normal; she formed protective titers to diphtheria and tetanus but not to any of 14 pneumococcal serotypes. conclusion: stem-cell transplantation often results in severe t-cell immunodeficiency. the thymus plays an important role in reconstituting the t-cell compartment with naive t-cells generated from hematopoietic stem-cells, which restores tcr diversity. as this case illustrates, damage to the thymus can significantly impair the ability to reconstitute the t-cell compartment. a.k. knight * , c. cunningham-rundles, new york, ny. rationale: this is the first case report of oxcarbazepine induced immunoglobulin deficiency. methods: a 49 y/o white female was referred for further investigation of low serum immunoglobulin found as part of an evaluation for chronic bacterial vaginitis. she was taking oxcarbazepine for chronic pain. this was discontinued and immunoglobulin levels and b cell numbers were tested at intervals. specific antibody responses to pneumococcal vaccine were tested. results: at presentation, on oxcarbazepine, immunoglobulin levels were low [igg 576, iga <11, and igm <4 mg/dl] and she had a b cell deficiency [1%, 18 b cells (normal 5-15%, 75-375 cells/cu mm)]. antibody response one month after pneumococcal vaccine was poor (protective antibody to 2/12 serotypes). (7%)] with protective antibody responses to 5/12 pneumococcal serotypes. she continued to have iga deficiency. conclusions: the patient's initial evaluation suggested the diagnosis of common variable immune deficiency with hypogammaglobulinemia and specific antibody deficiency. however, these defects reversed when oxcarbazepine was discontinued. it is unclear if persistent iga deficiency was a pre-existing condition, possibly predisposing her to this adverse reaction to oxacarbazepine, or induced by the oxacarbazepine. immunoglobulin deficiency is a known, though rare, reaction to carbazepine, the parent drug of oxacarbazepine; this adverse reaction can occur with its derivative oxcarbazepine as well. secondary hypogammaglobulinemia should be considered before diagnosing primary immunodefiencies such as cvid and committing the patients to lifelong immunoglobulin therapy. introduction: interferon and glatiramer acetate (copaxone) are indicated for the treatment of relapsing-remitting multiple sclerosis (ms). anaphylactic reaction has been reported as a rare complication of interferon and copaxone use. we report a case of interferon -1a (rebif) and copaxone hypersensitivity associated with positive skin tests and desensitization to interferon -1b (betaseron). case report: the patient is a 28 year-old woman with asthma and allergic rhinitis who was diagnosed with ms in oct '04 after an uncomplicated pregnancy and was subsequently placed on rebif. one month after starting therapy, patient developed wheezing and generalized urticaria after receiving a dose of rebif. the symptoms recurred the next day. her neurologist stopped the rebif and started her on copaxone. two months later she developed episodes of generalized urticaria. the patient was then evaluated in our center and underwent skin testing with interferon -1a intramuscular (avonex), interferon -1a subcutaneous (rebif), betaseron, and copaxone. she had a positive skin prick reaction to copaxone and positive intradermal skin tests to avonex (1:10 strength), rebif (1:1), and betaseron (1:1) after 24 hrs. the intradermal reactions to all 3 interferon formulations continued to progress upto 48 hrs. her neurologist felt that she would benefit from betaseron therapy. the positive intradermal skin test to betaseron was sufficient to warrant desensitization to prevent immediate hypersensitivity reactions. she underwent subcutaneous desensitization as shown in the table. the desensitization was halted at 240 minutes after the patient developed itching of the hands.* she returned in 24 hrs and we restarted by administering 0.1 ml of 1:1 strength betaseron. increasing doses were given until the patient received a full therapeutic dose (0.3 mg in 1 ml). she has since done well with daily doses of betaseron (4.5 mil units). conclusion: we report a ms patient who developed urticaria and asthma exacerbation in response to rebif and urticaria to copaxone. skin tests confirmed an ige-mediated allergic reaction. she underwent successful desensitization to betaseron. to our knowledge, this is the 1st report of desensitization to betaseron as well as extension to previous reported cases of systemic reaction to interferon and copaxone. pentoxifylline (ptx) is a phosphodiesterase inhibitor that has been used for ischemic vascular disease because of its effects on red blood cells and platelets. it has been used for systemic inflammatory diseases such as sarcoidosis because of its ability to inhibit production of cytokines such as tumor necrosis factor (tnf-a). we decided to offer a trial to a patient with chronic urticaria since agents that increase intracellular camp have been shown to inhibit mast cell degranulation. we report a case of a 50 year-old female with a history of allergic rhinitis, hypothyroidism, and diabetes mellitus with recurrent episodes of chronic urticaria since adolescence. she had known allergies to various antibiotics but otherwise had an unremarkable history, family history and social history. she was being treated with fexofenadine 180mg qd, azelastine nasal spray, zafirlukast 20mg bid, hydroxychloroquine 200mg bid, levothyroxine 25mcg qd, doxepin 25mg qhs, metformin 500mg bid, and spironolactone 25mg qd at the time of her initial evaluation. her physical exam was notable only for scattered 2-3 cm urticarial skin lesions as well as areas of hypo and hyperpigmentation from previous excoriations. her nasal turbinates were mildly congested with dull membranes. a previous skin biopsy showed only urticaria with increased numbers of mast cells. her workup included normal cbc, urinalysis, spep and complete chemistry profile, as well as negative ana and anti-thyroid antibodies. pentoxifylline 400mg tid was added to the patient`s regimen. her urticaria resolved within 2-3 weeks and was no longer visible at 2 months follow-up. pentoxifylline is a safe medication with few side effects that may benefit patients with chronic urticaria via several mechanisms, including the inhibition of mast cell degranulation and secretion of various cytokines and chemokines. the beneficial effects of pentoxifylline in the treatment of this patient`s urticaria have been seen in other patients. further study is indicated to determine which patients with urticaria are most likely to benefit from pentoxifylline, as well as elucidate the mechanisms of action by which pentoxifylline ameliorates symptoms of chronic urticaria. c.m. mjaanes * , m. boguniewicz, denver, co. we report the case of an 11-year-old male who since the age of 6 years has suffered from recurrent episodes of left tongue swelling. onset of the swelling is usually abrupt, and generally occurs during the night, awakening him from sleep. he describes a sensation of pain in his tongue but denies any pruritus, throat, lip or eyelid swelling. he has no cough, dyspnea, wheezing, rash, or itchy/watery eyes. the episodes occur infrequently, approximately once every spring . they tend to resolve spontaneously within 4 to 6 hours, however, on 2 occasions, the swelling has lasted for 7-21 days. the patient's current episode has been present for 3 weeks and is progressing. today he reports more pain and increased swelling. the child reports no benefit from oral antihistamines. he was treated with dexamethasone during his initial episode and experienced gradual resolution of the swelling. he has never been treated with topical or systemic epinephrine, or additional courses of systemic steroids. there is no family history of angioedema. the child was referred for evaluation of an immunologic/allergic etiology of his unilateral tongue swelling. laboratory studies obtained early in the course of his current episode revealed the following: c3 level 84 mg/dl; c4 level 14.4 mg/dl; c2 level 22.5 mug/ml; c4d level 0.94 mug/ml; c1 esterase inhibitor function 115% of normal. c1 esterase inhibitor level 17.4 mg/dl; ch50 223 units/ml; ana 1:40, negative; beta-tryptase < 1.0 ng/ml; total tryptase 7.0 ng/ml (all normal). initial evaluation revealed marked swelling along with erythematous and violaceous discoloration of the left lateral and anterior portions of the child's tongue. the remainder of his examination was normal. the patient was referred to the pediatric otolaryngology clinic with a presumptive diagnosis of a glossal hemangioma versus lymphangioma. he underwent a magnetic resonance imaging study which revealed a poorly defined, mass-like enlargement of the anterior and left aspect of the tongue. he was treated with a five day course of prednisolone. after initial regression of the lesion a planned surgical excision was carried out without any complications. in conclusion, this rare case illustrates the unique presentation of glossal hemangioma presenting as recurrent angioedema. highlighted are the differential diagnoses, laboratory studies and clinical features of oropharyngeal swelling. severe tongue swelling. rare skin conditions such as leprosy need to be considered in the differential diagnosis of apparent urticaria and angioedema that is atypical in appearance or response to therapy. a 28 year old male originally from laos presented with chronic recurrent nonpruritic indurated plaques on his face and trunk, and was referred to allergy by his primary physician with a diagnosis of urticaria and angioedema to rule out an allergic reaction to foods. he was otherwise healthy and on no medication, and had a negative personal and family history of atopy. he had moved to the united states from southeast asia in 1990, and visited for several weeks again in 2003. he was treated with prednisone and hydroxyzine without benefit; skin testing to foods was negative, and cbc, differential, sedimentation rate, antinuclear antibody, and liver function testing was normal or negative. a skin punch biopsy from an indurated area on the back showed granulomas with clusters of acid-fast organisms on afb stain consistent with tuberculoid leprosy. as the patient was g6pd deficient, he could not be treated with dapsone and was treated alternatively with minocycline 100mg, rifampin 600mg, and clofazimine 50 mg daily. he was subsequently started on prednisone as he was determined to be having a reversal reaction; his lesions continue to improve. this patient had a rare condition, leprosy, which was confused with urticaria and angioedema. in patients presenting with atypical apparent urticaria or angioedema, especially if response to standard pharmacologic treatment is poor, a skin biopsy is indicated, and may be diagnostic as in this case. introduction: cutaneous flushing about the face of a toddler within minutes of eating specific foods prompts parents and clinicians alike to pursue food allergy testing. auriculotemporal syndrome, also known as frey syndrome, is an isolated and transient facial erythema about the distribution of the auriculotemporal nerve following mastication. we report a child who was referred for food allergy testing and was diagnosed with auriculotemporal syndrome. case history: a 2 yo wf, prior full-term forceps-assisted delivery, has a history of facial flushing within minutes following ingestion of specific foods. the flushing can be induced by a variety of foods, specifically spaghetti, crackers, potato chips and hard candies, and typically resolves within minutes after eating. the child has no respiratory or gastrointestinal distress during the flushing episode. there is no angioedema, urticaria, or other rash elsewhere on her body. within ten minutes of eating a lollipop in clinic, an erythematous, warm macular eruption appeared in a band-like region anterior to her ear extending from her temporal bone to her mandible. this response occurred bilaterally, with a mildly greater intensity on the right side of her face. no sweating or other symptoms developed, and the flushing began to diminish after thirty minutes of observation. discussion: auriculotemporal syndrome is commonly seen in patients who have undergone facial surgery, specifically about the parotid gland. it is believed to be secondary to a disruption in the fibers of the auriculotemporal nerve. it is theorized that the nerve regeneration following an injury may join the parasympathetic fibers of the salivary gland with sympathetic fibers of eccrine sweat glands. mastication then could result in flushing and sweating over the cutaneous distribution of the auriculotemporal nerve that extends from the temporal region to the mandible, anterior to the ear. although rare in children, auriculotemporal syndrome has been associated with forceps delivery. therapy is seldom of benefit or needed, and the syndrome often resolves spontaneously over many years. conclusion: auriculotemporal syndrome leads to a cutaneous eruption temporally related to the ingestion of foods. allergists should maintain an awareness of this rare syndrome to minimize food allergy testing or eliminate unnecessary food provocation challenges or restrictive diets. m. al-ahmad * , s.s. mace, toronto, canada. introduction: ranitidine is a well-known h2-receptor antagonist. anaphylactic reactions are seldom reported despite widespread use of the drug. we report a patient with anaphylactic reaction to ranitidine methods: we report a case of anaphylactic reaction with ranitidine. results: a 45-year-old female with a history of urticaria over one year period, presented with 4 episodes of anaphylactic reactions of increasing severity over 1 year, after ranitidine ingestion. the first two episodes, occurred one hour after ranitidine ingestion, began with a sensation of burning, and itching in the head followed by dizziness, hypotension and near loss of consciousness. the patient had no significant pulmonary or laryngeal symptoms. the fourth episode, occurred 12 minutes after taking ranitidine tablet, was characterized by severe hypotension. two episodes were managed at the emergency department. a skin prick test with a crushed ranitidine tablet demonstrated a positive 20 mm wheal response, which was negative in a control. investigations for carcinoid syndrome and systemic mastocytosis were negative. conclusion: an ige mediated allergy to ranitidine is possible. anaphylactoid reaction to ranitidine is a well recognized entity. however, to our knowledge, few cases of anaphylactic reaction to ranitidine have been described. hypersensitivity reaction to ranitidine should be considered in patients suspected of having drug-related allergy. introduction: severe combined immune deficiency(scid) and cystic fibrosis(cf) may both present in infancy with a history of failure to thrive, diarrhea, and recurrent respiratory infections. although cf is the most common genetic disease occurring in caucasians with an incidence of 1 in 2500 births, scid is a rare condition estimated to occur between 1 in 50, 000 to 1 in 500, 000 births. we report a case of x-linked scid where the diagnosis of cf was originally entertained due to similar presentation and misleading laboratory results. case: 5-month-old caucasian male with 3 month history of recurrent respiratory illnesses, fever, loose stools, thick nasal discharge and failure to thrive. this was his second admission for a respiratory infection. relevant lab results consisted of cultures which grew parainfluenza a virus on np wash and pseudomonas aeruginosa on deep throat culture, chest xray showed patchy infiltrates and a borderline sweat test of 51 mmol/l. despite being treated with broad spectrum antibiotic coverage, albuterol and pulmozyme, his respiratory symptoms were not improving. physical exam revealed a thin infant with palpable though small lymph nodes cervical and groin, diffuse scattered rhonchi and liver edge palpable 3 cm below the costal margin. quantative immunoglobulins were obtained and resulted as an igg of 75, iga of <10, and igm of 13. review of his chest x-ray was significant for absent thymic shadow. lymphocyte count since admission ranged from 400-1000. flow cytometry revealed a cd3/cd4 count of 0%, cd3/cd8 count of 0%, cd56 of 1% and cd19 of 99% of all lymphocytes. t-cell stimulation tests were markedly diminished to both antigen and mitogen. a presumed diagnosis of x-linked scid was made and patient undrewent haploidentical bone marrow transplantation. subsequently, cf gene analysis resulted as negative. discussion: as outlined in the case it is essential to recognize the similarities between the presenting symptoms of cf, a relatively common genetic disease and scid, an uncommon one. although pseudomonas is seen in increased frequency in patients with cf, it is essential to recognize that it is also a leading pathogen affecting patients with antibody deficiency. review of the literature did not reveal any previous cases of individuals with scid reported as having an increased sweat chloride, nor any explanations of why this would occur. while immunodeficiency has previously been associated with some forms of dwarfism, we report the first described case of common variable immune deficiency in a patient with seckel syndrome (bird headed dwarfism). the diagnosis of seckel dwarfism, an autosomal recessive disorder, was made at 6 months of age in this boy based on intrauterine growth retardation, proportional dwarfism, microcephaly, micrognathia, and narrow face with "bird-like" large eyes and beaking of the nose. hematologic abnormalities are reported in an estimated 15% of such patients, and this child developed thrombocytopenia at the age of 3 years. by age 7, he had pancytopenia with hypocellular bone marrow. a low cd4 count (117/ul) was noted and both bactrim and neupogen were begun. his only significant infections, rotavirus and salmonella gastroenteritis, occurred at that time along with frequent otitis leading to pe tube placement at ages 7 and 8 but which subsequently resolved. he has never had opportunistic infections or thrush. by the age of 10 years, he required monthly red cell transfusions for severe anemia. after several months of transfusions, the blood bank reported that he no longer had detectable blood group antibodies during crossmatch; this led to measurement of immunoglobulins. igm was undetectable with low iga (35 mg/dl) and low igg (545 mg/dl). he demonstrated no protective titers to any pneumococcal serotypes after either conjugated or unconjugated pneumococcal vaccines. response to diphtheria, tetanus, rubeola, and influenza vaccines was adequate. total hemolytic complement was normal. he remains lymphocytopenic (alc = 552/ul) with low cd4 (211/ul). after five doses of ivig at 400mg/kg monthly, platelets have remained between 15-20 k/ul and there has not been any improvement in the anemia. although the mechanism for the bone marrow failure in these patients is presumed to be chromosomal breakage, this has not been demonstrated in this child. his karyotype is 46xy with no chromosomal fragility or deletions detected to date. hypogammaglobulinemia should be investigated in any patient undergoing frequent transfusions who loses blood group antibodies, and suspicion of immune deficiency should remain particularly high in patients with severe growth retardation or dwarfism. n.l. rider * , t. craig, hershey, pa. the objective of this study was to assess the effectiveness of physicians at a university primary care clinic in diagnosing and managing adult patients with asthma. a retrospective chart review of 63 adult patients from this clinic was performed. each chart was evaluated using a survey instrument developed from the national asthma education and prevention program (naepp), which consisted of 22 queries. of the charts evaluated 50 met our entry criteria. overall compliance with the naepp recommendations was 34%. adherences to the asthma guidelines in the following areas were: diagnosis (42%), treatment/disease control (60%), monitoring (15%), and education (18%). these data suggest that there is an opportunity to improve the care provided to patients with asthma, especially in the areas of asthma education and monitoring, even in a university outpatient facility. these data also suggest that naepp guidelines have not been effectively incorporated into primary care practices. b.m. wahlers * , l. sherwood, t. craig, hershey, pa. objective: our aim was to evaluate adherence to the national heart lung and blood institute (nhlbi), national asthma education and prevention program (naepp) diagnosis and management guidelines, regarding asthma admissions at a teaching hospital. methods: a retrospective chart review of 197 patients over the age of 18 years admitted to the hershey medical center between 1997 and 2002 with a primary diagnosis of asthma or asthma exacerbation was conducted using a 21-item questionnaire focused on key aspects of asthma care as outlined in the naepp guidelines. results: overall compliance to the guidelines was 61.5%. maximal areas of compliance were noted in regards to pharmacologic treatments utilized (99%, 95%). much lower levels of compliance were noted in areas of patient education (58%), instruction in written action plan prior to discharge (11%), provision of peak flow meter for home use (47%), assessment of asthma symptoms and severity (58%), and inhaled steroid prescription on discharge (69%). conclusion: adequate care in terms of pharmacologic treatments is being given but sub-optimal cares in other areas of the guidelines exist. there continues to be room for improvement in regards to asthma management, most notably in the area of education, documentation of triggers, and preparation for discharge with adequate tools to monitor and control symptoms. background: asthma is one of the most common problems of childhood, responsible for a significant proportion of absence from school because of chronic illness. objective: this study was carried out among the school-aged children (7-18 years) in tehran schools during 2002-2003, in order to determine the frequency of asthma. methods: according to the recommendation of who, a questionnaire was designed, containing 8 standard questions, and the students were given necessary information to complete the questionnaires. the guidance and high school students completed the questionnaires but the parents of primary school students completed them by themselves. results: seven hundred and eight children out of 2000 children had asthma (35.4%); this prevalence was higher in the boys (37.1%), when compared to the girls (33.5%). the prevalence of this disease has been estimated about 39.5% in guidance schools, 35.4% in high schools and 31.6% in primary students. based on this survey, the most common clinical manifestations in asthma were included: prolonged cough lasting more than 10 days (22.4%), and exerciseinduced wheezing or dyspnea (16.9%), followed by repeated dyspnea or wheezing (6.4%). based on the drug responses after receiving solbutamol, the prevalence of asthma was evaluated in the range of 32.2% in primary schools, 16.7% in guidance schools and 22.9% in high schools. conclusions: the prevalence of asthma is high among the students of tehran schools and it needs more careful screening programmes and either more information given to the patients and parents about the disease. in the us, asthma is the most common chronic disease of childhood and affects approximately 5 million children. reasons for inadequate asthma control include: inappropriate therapy, incorrect inhaler technique, poor compliance with treatment, and exposure to environmental triggers. rates for asthma prevalence, hospitalization, and death are highest among children residing in inner cities, and important risk factors for asthma-related mortality include being poor and black. the communities of braddock, north braddock and rankin are among the poorest in allegheny county and are designated areas of greatest health risk. recent statistics have demonstrated an increase in the number of asthma hospitalizations in these communities: 13.6 children per 1000, which is double the average for allegheny county and greater than seven-times the overall us rate of asthma hospitalizations. our goals were to assess asthmatic severity and appropriateness of treatment, provide asthma education, and to ensure access to healthcare for asthmatic children living in these medically underserved and predominantly african-american communities. twenty-seven asthmatic children were identified. of the children assessed 7% were under the age of 2 years, 19% were aged 2-5 years, and 74% were 6-14 years of age. based on nhlbi guidelines the severity of each child's asthma was determined: 41% had mild-intermittent asthma, 15% had mildpersistent asthma, 26% had moderate-persistent asthma, and 18% had severepersistent asthma. the appropriateness of treatment based on severity was also determined. we found that 27% of the children with mild-intermittent asthma, 50% of children with mild-persistent asthma, 60% of children with moderate-persistent asthma and 100% of children with severe-persistent asthma were receiving inappropriate treatment. furthermore, of the inappropriately treated children 92% were undertreated. following the assessment, patients and parents were educated with regard to asthma triggers, pathophysiology, use of peak flow meters, inhaler technique and pharmacologic treatment. patients were also scheduled for outpatient follow-up care. these results demonstrate that inappropriate treatment, especially undertreatment, may be a significant cause of the increased asthma morbidity in this population and underscore the need for aggressive education and innovative methods of ensuring health care. w. li-ling * , t. keng-leong, f.c. stephanie, e. philip, singapore. background: asthma admission is an important indicator of asthma morbidity. little is known about the risk factors associated with asthma admission among high-risk asthmatics. purpose: 1) to characterise the profile of high-risk asthmatics who had previous asthma hospitalization. 2) to identify predictors and risk factors that are associated with asthma hospitalization. methods: data for consecutive high-risk asthmatics who were enrolled into our asthma program from october 2001 to may 2004 were retrieved from our prospective database. high-risk asthmatics were defined as patients who had a clinical diagnosis of asthma and who had at least one hospital admission for exacerbation of asthma in the preceding 12 months or at least one severe exacerbation of asthma in the preceding 6 months requiring unscheduled visit for beta2-agonist nebulisation. a comparison was made among high-risk asthmatics who had at least one or more hospitalization for asthma in the past 12 months prior to the asthma program enrolment with those who were not hospitalized. statistical analyses were performed using spss version 10.1 for windows. results: among 521 high-risk asthmatics, 252 (48.4%) had at least one or more asthma hospitalization in the past 12 months prior to the enrolment into the asthma program. hospitalization was significantly associated with female gender (63.1% with asthma admission v 43.1% without asthma admnission). a significantly higher proportion of asthmatics with no formal education (19.4% v 17.7%), primary education (23.8% v 16.6%) and secondary education (32.1% v 29.3%) were hospitalized for asthma as compared to the those who had tertiary education (24.6% v 36.5%). those admitted were predominantly in lower income group, had poor inhaler technique and have no ownership of an asthma action plan (33.3% v 76.6%). those hospitalized were also younger, median age 37years (19, 62) v 35years (15, 84) and had a lower first peak flow reading, 260l/min (130, 500) v 300l/min (150, 480) . conclusion: among high-risk asthmatics, certain population subgroups are at greater risk for hospitalization for asthma. intervention aimed to reduce asthma morbidity should take the above findings into consideration. introduction an association between asthma symptoms and air quality is well established, but controversy exists concerning the role of various air quality indicators. the association of san antonio air quality with emergency department (ed) visits for asthma at our military medical center has not been defined. the objective of this study is to determine the correlation of selected air quality indicators in san antonio with ed visits for asthma for both the general population and for the pediatric population. methods selected air quality indicators were the 8-hr air quality index (aqi) for ozone, 24-hr aqi for particulate matter < 2.5 î¼m, pollen counts, mold spore counts, and daily high temperature. the number of daily ed visits coded for asthma was obtained retrospectively. pediatric visits (patients < 18 years-old) were evaluated as a subgroup. pearson correlation coefficients (r) were calculated for all data pairs. results during the 331 days of the study period, there were 491 visits for asthma. of these visits, 151 were pediatric. the number of daily visits ranged from 0 to 6 for all visits and from 0 to 3 for the pediatric visits. r values for all visits were -0.067, -0.069, 0.110, -0.011, and -0.218; for pediatric visits, -0.055, -0.036, 0.033, -0.010, and -0.074 for the 8-hr aqi for ozone, 24-hr aqi for particulate matter < 2.5 î¼m, total pollen grains/m 3 , mold spores/m 3 , and daily high temperature, respectively. in addition to calculating r values for same-day air quality indicators and ed visits, r values were also calculated for a 3-day average of air quality indicators with the ed visits. for the 3-day averages, r values for all visits were -0.113, -0.117, 0.127, -0.071, and -0.267; for pediatric visits, -0.081, -0.011, 0.025, 0.017, and -0.063 for the 3-day averages of the 8-hr aqi for ozone, 24-hr aqi for particulate matter < 2.5 î¼m, total pollen grains/m 3 , mold spores/m 3 , and daily high temperature, respectively. conclusion there was no significant correlation between the selected air quality indicators and ed visits for asthma, either for the general population or for pediatric visits. this study provides no evidence that air quality is linked to ed visits for asthma in san antonio but the degree to which air quality in san antonio affects asthma symptoms remains unclear. introduction: the aim of this study was to evaluate the level of no in the exhaled air of patients suffering from chronic cough. methods: the study was performed on 213 young (mean age 28.5 +/-8.2 years), nonsmoking patients with chronic cough referred to the allergy clinic for evaluation. bronchial provocation challenge with histamine was performed according to the method of ryan. exhaled no was measured on-line using a chemiluminescence analyzer (sievers, usa). all patients had resting spirometry within normal values. results: significant bronchoconstrictive response to histamine at a concentration equal to or lower than 8 mg/ml (pc20 8mg/ml) was found in 65 patients (30.5%). these patients had a significantly greater mean concentration of no in the exhaled air (80.6+/-59.4 ppb) than those with a pc20>8mg/ml (28.4 +/-29.2 ppb; p<0.0001). receiver operating characteristic (roc) curve analysis revealed that it is possible to identify from among patients suffering chronic cough those who have significant bronchial hyperreactivity (pc20 8mg/ml). using 40 ppb as a cut-off value for the exhaled no concentration, the specificity for bronchial hyperreactivity was 86.5% and sensitivity 72.3%. conclusion: assessment of no concentration is helpful in the assessment of bronchial hyperreactivity in patients having chronic cough. l. abetz 1* , j. bousquet 2 , e. juniper 3 , e. bateman 4 , h. boushey 5 , w. busse 6 , t. clark 7 , r. pauwels 8 , s. pedersen 9 , 1. manchester, united kingdom; 2. montpelier, france; 3. ancaster, canada; 4. cape town, south africa; 5. san francisco, ca; 6. madison, wi; 7. london, united kingdom; 8. ghent, belgium; 9. kolding, denmark. introduction: the acq has been developed as a measure of asthma control for use in clinical practice or in clinical trials. the reliability, validity and responsiveness have previously been demonstrated for the original 7 item acq, the 6 item (minus fev1 question) and 5 item (minus fev1 and short acting bronchodilator use questions) versions. data from the 1-year gaining optimal asthma control (goal) study was used to assess the predictive value of the acq s 7, 6, and 5 item versions in determining asthma control status. method: receiver operating characteristic curves (roc curves), plotting true positive rates versus false positive rates for different acq cut-points, were used to determine optimum cut points for totally controlled and well-controlled asthma. scores for the 7, 6, and 5 item versions of the acq were examined at 0.25 intervals. results: when predicting totally controlled asthma, the areas under the roc curves (arocc) were 0.88/0.88/0.86 for the 7, 6 and 5 item versions, respectively; and when predicting well-controlled asthma the arocc were 0.86/0.86/0.84 for the 7, 6 and 5 item versions. in both predictive models, the 7 and 6 item versions provided the best arocc. for the 7 and 5 item versions, the best cut-off point to predict totally controlled asthma was <=0.75, with arocc of 0.81/0.79, and corresponding sensitivity of 0.74/0.71 and specificity of 0.89/0.88, respectively. for the 6 item version the best cut-off point was <=0.5, with arocc of 0.82, sensitivity of 0.76 and specificity of 0.87. the best cut-off points for predicting well-controlled asthma were <=1.25 for the 7 item version (arocc=0.77; sensitivity=0.70; specificity=0.83), and <=1 point for the 6 and 5 item versions (arocc=0.77/0.75; sensitivity=0.70/0.69; specificity=0.83/0.81, respectively). conclusion: results indicate the sensitivity and specificity of the acq in predicting asthma control status. a 29 yo black male with asthma and allergic rhinitis developed gradually worsening cough productive of clear to yellow sputum despite treatment with high dose fluticasone, salmeterol, monteleukast, and prn albuterol. asthma history was significant for an intubation at age 10 and pneumonia at age 28. physical exam revealed pale turbinates and expiratory wheezes. pulmonary function test showed a severe obstructive lung defect with fev1 1.52 (38%), improving by 4% after bronchodilator and fev1/fvc ratio 54%. a chest ct revealed significant bronchiectasis in the right middle lobe, lingula and both lower lobes. evaluation for bronchiectasis showed normal quantitative immunoglobulins, subclasses, and humoral responses, rendering innate immunodeficiency less likely. the diagnosis of allergic bronchopulmonary aspergillosis was entertained, but ige was 500ku/l and aspergillus titers were negative. a sinus ct failed to show active disease, yet the patient reported chronic yellow nasal discharge despite courses of antibiotics. although he was sexu-ally active with several male partners, hiv testing was negative 2 times, 6 months apart. evaluation for cystic fibrosis (cf) showed no symptoms of malabsorption and a negative sweat test. other tests revealed normal -1 antitrypsin level, p-anca, esr, ace level, and negative sputum for afb and mycobacteria, helping to exclude other conditions such as 1-antitrypsin deficiency, vasculitis, sarcoidosis, and chronic infection. with no definitive answer, the diagnosis of cf was pursued, but genetic screening as well as mapping were negative. the diagnosis of primary ciliary dyskinesia was then entertained; however, a mucosal biopsy of the nose did not reveal any structural abnormalities. finally, a sperm analysis revealing azoospermia confirmed the diagnosis of young's syndrome, a rare disease with features similar to cf including bronchiectasis, chronic sinusitis and azoospermia. in young's syndrome however, there is an obstructive process rather than a lack of vas deferens resulting in azoospermia and normal sweat chloride, genetic, and pancreatic testing. this case demonstrates the importance of investigating a persistently productive cough in an asthmatic patient and the differential diagnosis as well as the appropriate work up for bronchiectasis. a final diagnosis is important since appropriate management in each situation may affect long term outcome. a.g. palma-carlos * , m.l. palma-carlos, lisboa, portugal. introduction: bronchial challenges are currently done in allergic asthma with allergen, histamine or metacholine.bronchial reactivity to allergens and histamine can probably be variable. purpose to evaluate if the dose of allergen and histamine triggering a significant bronchial obstruction are always correlated in asthmatic patients. methods: a vitalograph model compact has been used throughout the study. allergen challenge has been done with an acqueous solution of house dust mite. bronchial challenges with placebo (sodium chloride) histamine or allergens have been done in all patients. for the provocations with histamine or allergens the threshold dose, inducing a decrease in fev1 greater than 15% has been determined in all the cases, as well for histamine as for allergens. a second challenge has been done in all patients with a supra-threshold dose of histamine or allergen corresponding to the double of the threshold. results: 30 provocations have been done in 10 patients either with histamine or allergen. 6 were allergic and 4 non allergic. the threshold dose for histamine were between 5 and 25 ug. in allergic patients and 250 and 500 ug. in non allergic patients.in allergic patients after histamine threshold challenge mean decrease was for fev1 19, 2% and for fev1/vc 17, 3%. for supra-threshold dose fev1 decreases 37, 8% and fev1/vc 32, 8%. after allergen challenge fev1 decreases 20, 3% and fev1/vc 15, 8%. with supra threshold doses fev1 decreases 28, 6% and fev1/vc 29, 3%. in 4 non allergic patients there was no changes after allergen challenge. a good correlation in constriction induced by histamine or allergen either for threshold or supra threshold doses (p<0.001) was observed but not between the threshold doses of histamine and allergen. conclusions: these results confirm that bronchial obstruction can be triggered by allergens and mediators that the sensitivity of fev1 and fev1/vc for evaluation are roughly comparable after challenge and points to a better sensitivity of a supra threshold dose of allergen or mediators. allergen and histamine challenges don't give the same information. introduction: peak expiratory flow rate (pfr) and forced expiratory volume in the first second (fev1) are currently used in functional evaluation of asthmatic patients but his degree of correlation in obstructive, restrictive and mixed spirometric ventilatory patterns are not well known. the purpose of this study was to evaluate if the correlation between pfr and fev1 2 markers of global airways obstruction is comparable in asthmatic patients with obstruction restriction or both. methods: 152 asthmatic patients, 69 males, 83 females have been studied by spirometry with a vitalograph compact in absence of bronchodilatory or anti-inflammatory therapy. patients have been classified in 4 functional patterns according to vc, and fev1/cv: normal : vc greater than 90% of expected value and fev1/vc greater than 70%, obstructive:vc greater than 90% and fev1/vc greater than 70% restrictive vc, less than 90% and fev1/vc greater than 70% and mixed vc less than 90% and fev1/vc less than 55% presenting a so called functional emphysema. results: according to these criteria 15 patients were normal, 44 restrictive, 15 obstructive and 78 mixed. in all the group the correlation between pfr and fev1 was statiscally significant (p<001) but the correlation coefficient variable. in functionally normal patients r =+0, 74 in restrictive patients + 0, 67 in obstructive + 0, 66 in mixed + 0, 84 and in the sub-group with functional emphysema + 0, 96. for this sub-group the correlation coefficient r allows to define fev1 = 91 + 5, 6 pfr. conclusions: the report between the two most usual assays of global bronchial obstruction depends on the balance between restriction, (either by interstial fibrosis or hyperinflation) and obstruction and is more close when a more marked obstruction coexist with a restrictive pattern (functional emphysema). in practice pfr has the same value that fev1 only in more severe cases of ventilatory failure. the dispersion of values and the standard error or regression do not allow to correlate both data in most patients. introduction: the tenor study longitudinally observes the natural history of subjects with severe or difficult-to-treat asthma. this analysis assessed the association between previous and future asthma exacerbations in tenor. methods: subjects eligible for this analysis were 12 years of age at baseline and had at least one follow-up assessment in year 1 and year 2. recent asthma exacerbations in the past 3 months were defined as: asthma-related emergency room (er) visits, nights of hospitalization, unscheduled physician office contacts; or as a composite measure of at least one of the previous exacerbation events. relative risks (rrs) and 95% confidence limits (95%ci) were generated comparing exacerbations in year 2 relative to year 1. exacerbation rates were defined as the number of events divided by total patient follow-up time. no adjustment was performed for baseline characteristics. results: 2826 subjects were eligible for this analysis. rrs in year 2 vs. year 1 were: 3.9 (95%ci: 3.3-4.6) for unscheduled office contacts, 4.1 (95%ci: 3.48-4.82) for the composite exacerbation measure, 10.2 (95%ci: 7.8-13.4) for er visits and 15.1 (95%ci: 9.8-23.3) for nights of hospitalization. over 37% of subjects with 5 or more exacerbations (composite measure) in year 1 had a similarly high rate in year 2 compared to 3% of patients without an event in year 1 who went on to have 5 or more exacerbations in year 2 (see table) . conclusion: tenor subjects who experienced an asthma exacerbation in year 1 were at statistically significantly increased risk of subsequent exacerbations the following year compared to subjects not experiencing an exacerbation in year 1. this increased risk was consistent for all asthma exacerbation outcomes and most elevated for hospitalizations due to asthma. assessment of recent asthmarelated healthcare use is a critical component of the clinical evaluation of subjects with severe or difficult-to-treat asthma. funded by genentech inc. and novartis pharmaceuticals corp. background: preliminary studies investigating yoga and breathwork for asthma have been promising. several randomized controlled trials have shown a benefit from yoga postures and/or breathing versus control, but the control in these cases involved no intervention other than usual care. this study advances the field by providing an active control. methods: a randomized, controlled, double-blind clinical trial was conducted from october 2001 to march 2003 to determine the effectiveness and feasibility of a yoga and breathwork intervention for improving clinical indices and quality of life for adult patients with mild to moderate asthma. random assignment was made to either a 4-week yoga intervention that included both postures and breathwork, or a stretching control condition. outcome measures were assessed at 4, 8, 12 and 16-weeks and included the mini asthma quality of life questionnaire (mini-aqlq), rescue inhaler use, spirometry, symptom diaries, and health care utilization. results: sixty-two participants were randomized into the intervention and control groups, and 45 completed the final follow-up measures. intention-to-treat analysis was performed. significant within-group differences in post-bronchodilator fev1 and morning symptom score were apparent in both intervention and control groups at 4 and 16 weeks; however, no significant differences between groups were observed on any outcome measures.conclusions: iyengar yoga conferred no appreciable benefit in mild to moderate asthma. circumstances under which yoga is of benefit in asthma management, if any, remain to be determined. in order to investigate asthma mortality trends for the u. s. hispanic population, i have collected and graphed data from the national center for health statistics. mortality data for the hispanic population have been available for the entire united states only since 1997 and readily available for asthma only since 1999. these data indicate decreases in deaths from asthma (j45-j46) from 320 in 1999 to 274 in 2001 with decreases in the non-hispanic population from 4324 in 1999 to 3976 in 2001. rates of death from asthma decreased for the hispanic population from 1.0 per 100, 000 in 1999 to 0.7 in 2001, while that for the non-hispanic population decreased from 1.84 to 1.6. rates for non-hispanic whites decreased from 1.5 to 1.4 in 2001. rates of death from asthma have been twice as high among hispanic women as men. rates of death from asthma for non-hispanic blacks have been more than twice as high as those for non-hispanic whites. (national center for health statistics data dictate racial terminology). data for people of hispanic origin include people of any race. these data are affected by both underreporting of hispanic origin on death certificates and undercoverage in the census and resultant population estimates for a net correction of 1.6%. thus, rates of death from asthma have been lower and have been decreasing faster among hispanics than the rest of the population in the united states. allergic rhinitis and asthma are both highly prevalent diseases and often coexist in patients. rhinitis symptoms have been shown to impact the lower airway. as such, the impact of rhinitis on asthma control may be the greatest in patients with the most severe rhinitis symptoms. therefore, this analysis was performed to determine the impact of baseline rhinitis severity on asthma control in patients with both asthma and allergic rhinitis who received either fluticasone propionate aqueous nasal spray (fpans) or montelukast (mon) added to fluticasone propionate/salmeterol 100/50 mcg (fsc). a total of 863 patients (>15 years) with persistent asthma and seasonal allergic rhinitis received fpans 200mcg qd, mon 10mg qd or placebo (pbo) in addition to fsc 100/50mcg bid for 4 weeks. at baseline, total nasal symptom scores (tnss) ranged from 44 to 400. the analysis was restricted to patients whose pre-enrollment asthma therapy did not include fsc. regardless of baseline rhinitis severity, in patients with both asthma and allergic rhinitis, mon added to fsc resulted in no additional improvements in overall asthma control compared with fsc alone. these data suggest that optimal treatment of the individual conditions should be the goal of treatment for patients with coexistent allergic rhinitis and asthma. (sam40066) introduction recent studies have demonstrated that parainfluenza and coronaviruses are as important triggers of asthma. parainfluenza viruses are one of the main triggers of virus-induced asthma at summer. parainfluenza viruses often cause severe low respiratory tract infections in immuncompromised patients and in patients with bone marrow transplantation. a retrospective study found that 41% of pediatric bmt patients with hpiv infection (47% of viral respiratory infections) developed pneumonia and 6% died. both viruses contributed to fatal asthma. materials and methods for amplification of these viruses, primers which anneal to specific regions of viral genomes: hn-gene for piv1, piv2 and piv3 and spike glycoprotein gene for coronavirus oc43 and nucleocapsid glycoprotein gene for coronavirus 229e were used. pcrdiagnostics was performed on nasal and throat swabs taken from children with atopic asthma exacerbation. results from 02/04 to 05/04 a total of 56 samples (including 28 negative controls) were tested by pcr. 11 positive for respiratory viruses samples noted in children having asthma exacerbations including 23.9% of all tested samples. piv3 was detected in 54.5% of all positive samples, piv2 in 18.2%, and coronavirus oc43 in 27.3%. piv2 and coronavirus 229e were not detected during this study. for negative controls samples were taken from children with atopic asthma in remission. all 10 controls were found to be negative by viral pcr. conclusions respiratory viruses are an important factor in asthma exacerbations in children. piv3 was the most frequently detected among the positive samples. although hpiv-2 was less often positive than hpiv-1 and hpiv-3 infections in this study, the frequency of the detected coronaviruses may have been influenced by the seasonal activity of these viruses. introduction. in budapest all children come under the regular supervision of a specially trained paediatrician. each paediatrician is responsible for an average of 950 children, often seen up to the age of 18 years. methods. a questionnaire was sent to the district paediatricians of budapest in 1995 budapest in , 1999 budapest in and 2003 . the total number of children in their practice and the number of the asthmatics was assessed. the diagnosis of asthma in every case was established in a paediatric hospital, or a special allergy or pulmonology outpatient clinic. results. in 1995, replies were received from 118 paeditricians, who were responsible for the supervision of 104, 087 children, of which 1.88 â± 0.87% had been diagnosed as having asthma. in 1999 replies were sent by 153 physicians, who had a total of 142, 684 children under their care, including 3, 228 asthmatics, a prevalence of 2.26 â± 0.95%. at the end of 2003, 151 paediatricians having 141, 276 children answered, noting 3, 831 asthmatics, a 2.71 â± 1.2% prevalence of asthma. conclusion. the current survey of prevalence of asthma in childhood is by far the largest that has been made. an increasing prevalence of the diagnosis of asthma based on clinical investigations was noted, the differences between the investigated years being highly significant. panel report guidelines for the diagnosis and management of asthma have been available since 1991, to standardize and improve the quality of asthma care. however, asthma remains the leading cause of hospitalization for new york city children. implementation of the guidelines has not been fully embraced in the primary care setting. we attempted to increase primary care practitioners' compliance with the guidelines through extensive training. a hospital based pediatric clinic and 4 school based health clinics in the brooklyn inner city, participated from april 2002 to march 2003 in the program as part of new york city's education and quality improvement project (equip). initially an asthma physician specialist and asthma educator trained the primary care physicians and nurse practitioners in the guidelines. the training was reinforced during monthly luncheon sessions. clinical exam rooms were also supplied with asthma education materials, peak flow meters, and asthma action plans. goals were to identify asthmatics, document asthma severity, give persistent asthmatics written management plans, and utilize appropriate controller medications. compliance was measured by tracking asthma visits with an asthma intake form. prior to this project no consistent attempt had been made in the clinics to regularly classify asthmatic severity, provide written asthma action plans or to place patients on controller medications. after onset of the project a total of 216 asthma visits were evaluated; 104 were from school based health centers and 113 from hospital based pediatric clinic. severity was classified in 83%(179/216) of asthma visits. patients classified as persistent received updated written management plan during 90%(100/110) of asthma visits and 92%(102/110) were placed on controller medications. this asthma management program demonstrated success in improving primary care practitioners' compliance with the naepp asthma guidelines. further studies are needed to determine if compliance with the guidelines persisted after cessation of the extensive training and if such compliance improves asthma outcomes. numerous studies have associated asthma and obesity. although obesity has been identified as a risk factor for asthma, there is limited information on the impact of obesity on childhood asthma. this study examines the effect of body composition on asthma severity and pulmonary function in children. we retrospectively reviewed charts from asthmatic children ages 5 to 18 years, referred to a community-based pediatric pulmonology practice between 1999 and 2003. data were included if asthma was the the primary diagnosis and a baseline spirometry was available. asthma severity was classified and body mass index(bmi) was classified as normal, overweight and obese. spirometry results were reviewed. eighty-five patients were reviewed. thirtyone(36.5%) patients were normal weight; 21(24.7%) were overweight and 33(38.8%) were obese. baseline characteristics such as age, gender and race/ethnicity were similar. asthma severity classification did not differ between normal, overweight and obese children. overall, 34% were classified as intermittent, 53% as persistent mild asthma and 13% as persistent moderate-severe asthma. 21% of children with intermittent asthma were receiving controller therapy compared to 62.5% with persistent mild and 81.8% with moderate-severe asthma(p=0.0001). although healthcare utilization for asthma(emergency room visits/admissions) were significantly different between children with intermittent, persistent mild and moderate-severe asthma(p=0.0004), there was no difference when normal, overweight and obese children were compared. spirometry results showed comparable peak expiratory flow rates(pfr) in all groups; 75% of predicted in normal weight and 79% of predicted in both overweight and obese. mean forced vital capacity(fvc) was 93.9%, 88.5% and 95% and the mean forced expiratory volume in 1 second(fev1) was 85.9%, 81.2% and 86.6% respectively. there was no difference in fev1/fvc; 82.3%, 83.1% and 81.8% and forced expiratory flow in mid-lung volumes (fef25-75); 74.4%, 73% and 76.9% of predicted. in this study we retrospectively reviewed asthmatic children and compared bmi, asthma severity and spirometry. we found no difference in asthma severity classification between normal and overweight/obese patients. regardless of the bmi, all indices of spirometry were similar. further studies are needed to examine the impact of obesity on different asthma related disease outcomes. our objective is to further investigate the effect of budesonide, formoterol, and levalbuterol, alone, and in combination, on tgf-1 production and expression in ragweed (ra) stimulated a549 cells. meth-ods: a549 cells were cultured in duplicate for 24 hours at 37 degrees celcius with 5% co 2 in serum free dmem with or without the following: 10î¼g/ml of ra, 1.0 x 10 -7 m of budesonide, 1.3 x 10 -7 m formoterol, and 1.0 x 10 -5 m levalbuterol. tgf-1 production and expression was measured by a sensitive elisa and mrna assay in cell supernatants and pellets. results: tgf-1 production and expression from a549 cells rose markedly in the presence of ra (952.35 -1268 pg/ml) (59 -71 amol/ml) with significant inhibition following the addition of budesonide, and the combinations of budesonide and formoterol, budesonide and levalbuterol, and budesonide, formoterol, and levalbuterol (p<0.05). combined treatment with budesonide and levalbuterol versus budesonide alone reached significance for production and expression (p<0.05). budesonide and formoterol compared with budesonide alone reached significance for tgf-1 production (p<0.05). conclusion: combination therapy with budesonide and a long or short acting beta-agonist showed greater effect of tgf-1 inhibition compared with budesonide alone. this synergistic effect on the distal airways may prevent a subset of asthmatics from developing airway remodeling. g. tamura 1* , y. sano 2 , k. hirata 3 , s. ishioka 4 , m. nakashima 5 , t. miyamoto 2 , 1. sendai, japan; 2. tokyo, japan; 3. osaka, japan; 4. hiroshima, japan; 5. hamamatsu, japan. tulobuterol tape is the world's first long-acting transdermal preparation of a beta2-agonist designed to release tulobuterol in an optimal fashion. when it is applied once daily at bedtime, the blood concentration of tulobuterol peaks early in the morning and is kept at effective levels for 24 hours. tulobuterol tape has milder and less frequent adverse events than conventional oral tulobuterol preparations, and when used at bedtime can prevent marked drop in peak expiratory flow (pef) early in the morning. consequently, tulobuterol tape has been commonly used in japan as a long-acting beta2-agonist. in the present study, to evaluate its efficacy as a long-acting beta2-agonist and to compare its effects at two different doses, we administered tulobuterol tape at doses of 1 or 2 mg/day to patients with persistent asthma already using inhaled corticosteroids. this study was a randomized, double-blind, double-dummy, parallel-group, multicenter trial of 4-week duration. mean pef in the 1 and 2 mg/day groups were significantly increased from the baseline value by 15.1 and 28.2 at week 1, 19.5 and 32.6 at week 2, 22.6 and 35.3 at week 3 and 23.8 and 35.9 l/min at week 4, respectively. the increase in mean morning pef in the 2 mg/day group was significantly higher than that in the 1 mg/day group at every point of determination. the mean evening pef was significantly increased in both treatments groups compared with baseline values at every point of determination. although the increase in the 2 mg/day group was greater than that in the 1 mg/day group at each point of determination, the difference between groups was statistically significant only at week 1. the safety profiles of the two treatments were similar. in patients with persistent asthma who require inhaled short-acting beta2-agonists while receiving inhaled corticosteroids, tulobuterol tape 2 mg/day significantly improved pef compared with tulobuterol tape 1 mg/day. introduction: on an average, 4% of the 1500 children admitted annually for asthma to children s hospital require admission to the pediatric intensive care unit (picu). these admissions are highest in the months of august, september and october. aeroallergens such as alternaria and ragweed predominate during this season, and allergies to these allergens may account for the increased number of picu admissions for asthma. objective: we hypothesized that the seasonal increase in the admission rate could be related to allergen sensitivity, particularly to alternaria and/or to ragweed that predominate during late summer and fall. method: data was collected from a retrospective chart review of all patients admitted to the picu for asthma exacerbation between 1997 and 2003. skin prick testing (spt) within one year of picu admission was the criteria for inclusion in this study. results: there was a higher prevalence of admissions to the picu for asthma exacerbation during august, september and october (168 out of 416 admissions = 40% of all admissions, p<0.001). sixty-one subjects met the one-year spt criteria for analysis. subjects admitted during august, september and october were categorized as group a, and all others were categorized as group b. sensitivity to a total of 11 aeroallergens (tress, grasses, weeds, ragweed, outdoor molds, indoor molds, alternaria, cat, dog, roach and dust mites) was compared between the two groups. there was no statistical significance in aeroallergen sensitivity to alternaria or ragweed between subjects admitted to the picu in august, september and october (group a) and subjects admitted during the other months of the year (group b). conclusion: asthma exacerbation requiring picu admissions is more prevalent during the months of august, september and october. the increased rated of picu admissions did not correlate with the aeroallergen sensitivity to the prevalent allergens during august, september and october. therefore we suspect other factors such as, viral upper respiratory infections, in addition to aeroallergen sensitivity, which may contribute to severe asthma exacerbation during the late summer and fall months. k. kuzume * , shigenobu, ehime, japan. infantile wheezing may be the result of different phenotypes. the aim of this study was to evaluate the risk factors for allergies and the results of allergyrelated blood tests among infants with different types of allergy symptoms. 2130 infants were examined physically at birth and at 1, 3, 6, 9, and 12 months of age, and questionnaires about number of siblings, the family history of allergy, and feeding methods were given. allergic diseases were diagnosed at 12 months of age, and the subjects were divided into 4 groups: infants with atopic dermatitis (ad) only (a group, n=447), infants with both ad and wheezing (a/w group, n=175), infants with wheezing only (w group, n=155), and infants without allergic symptoms (c group, n=1353). risk factors were then evaluated. 332 patients (198 from the a group, 109 from the a/w group, and 25 from the w group) were given allergy-related blood tests, total serum ige levels, and rast with egg white, milk, and house dust mites at 6 and 12 months of age. the results of the blood tests in 36 control subjects at 6 months of age were compared to the other groups. as shown in table1, there were more male infants in the a/w and a groups than in the c group (p<0.001, a/w vs. c; p<0.01, a vs. c). numbers of siblings were greater in the w and a/w group than in the a or c group (p<0.0001, w vs. a and w vs. c; p<0.01, a/w vs. a; p<0.05, a/w vs. c). the rate of positive family history of allergic diseases was high in the a and a/w groups, compared to the w or c group (p<0.0001, a vs. c and a/w vs. c; p<0.05, a/w vs. w). the rate of breastfeeding at 3 months of age was high in the a group compared to the others (p<0.0001, a vs. c). patients in the w group had lower levels of total serum ige at 12 months of age, compared to patients in a or a/w (p<0.01, w vs. a/w and w vs. a). also patients in the w group had lower levels of rast with egg white at 12 months of age, compared to patients a or a/w (p<0.0001, w vs. a/w and w vs. a). the median of total serum ige levels at 6 months of age was higher in a and a/w but not in w, compared to c (p<0.001, a/w vs. c and a vs. c). in conclusion, there were two different phenotypes of wheezing in infants before 12 months of age. wheezing with ad might be "allergy-related", while wheezing without ad may be related to other factors. as compared to c group: a), p<0.05; b), p<0.01; c), p<0.001; d), p<0.0001 as compared to a group: 1), p<0.05; 2), p<0.01; 3), p<0.001; 4), p<0.0001 as compared to a/w group: f), p<0.05; g), p<0.01; h), p<0.0001 a group, infants with atopic dermatitis only; a/w group, infants with atopic dermatitis and wheezing; w group, infants with wheezing only; c group, infants without allergic symptoms. rast, radioallergosorbent test, n/a, data not available r. amelio 1* , c. capristo 1 , a. capasso 1 , m. miraglia del giudice 2 , n. maiello 1 , f. decimo 1 , 1. naples, italy; 2. napoli, italy. forced oscillation technique (fot) is considered a sensible and specific method to estimate breathing functionality in asthmatic children aged 3 to 6 years, because it doesn't need special collaboration. the aim of our study was to value baseline respiratory resistances with the fot in preschool-aged children with asthma under high dose of budesonide and flunisolide treatment. at this purpose, 40 asthmatic children aged 3 to 6 years were selected: at a first examination (t0) all the patients showed basal value fot at 6hz frequency (rr6) changes major or equal than 35% under 200 mcg of salbutamol treatment. 30 days before the study, children selected didn't take systemic and inhaled steroids, cromons, leukotrienes antagonists, teophylline or anti-histamines and they didn't present upper and lower airways infections; then, two weeks before run-in, all selected patients took beta-2-agonists at least 3 times per week. all the patients were divided in two groups: group i (20 children) under inhalation of flunisolide 40mcg/kg/dose + salbutamol 1500 mcg b.i.d. for 7 days and, for the following two weeks, under inhalation of flunisolide 20 mcg/kg/dose + salbutamol 200 mcg by pmdi+spacer prn.; group ii (20 children) under inhalation of budesonide 0, 5 mg b.i.d. + salbutamol 1500 mcg b.i.d. for 7 days, and for the following two weeks, under inhalation of budesonide 0, 25 mg b.i.d. + salbutamol 200 mcg by pmdi+spacer prn. moreover, we gave diary-card with a simple symptoms score (at t0 and t7 ), to get the real perception of the symptoms in the course of study. however, during the treatment, 4 children have ritired from the study. the results obtained were statistically analysed (t student's test). significant rr6 pre beta-2-agonists and ? value reduction was obtained at t7 and t21 vs. t0. group i had (at t7) such a quick action than group ii reducing airways resistances (p<0, 01). children treated with flunisolide had lower frequency of breathless and nocturnal cough at t7 and lower salbutamol use from t7 to t21 than budesonide group (p=n.s.). in conclusion, fot is actually a safety method to value efficacy of inhaled steroids in preschool-aged children with asthma. introduction: approximately 7.5% of u.s. adults and 6.0% of louisiana (la) adults have current asthma, and over 25% currently smoke cigarettes, according to the 2002 behavioral risk factor surveillance system (brfss). the purpose of this study is to compare asthmatic smokers vs. nonsmokers in la and the u.s. here we address whether asthmatic smokers utilize more medical care services in the er and outpatient clinics, and whether they were able to fully participate in activities of daily living compared to nonsmoker asthmatics. methods: brfss is a state-based, telephone survey of u.s. adults. the survey collects self-reported information about modifiable risk factors for chronic diseases. this study analyzed data from the 2002 brfss survey using sas software. data: out of the current asthmatics, 25% are cigarette smokers in the u.s. in louisiana, 31% of asthmatics are currently smoking, which is significantly higher than the national average (p<0.0001). within the past year, the average number of emergency room visits due to asthma was similar for both locations (la 0.53, us 0.48, p=0.46) . nationally, smokers visited the er significantly more frequently than nonsmokers (s 0.61, ns 0.43, p<0.01). in la, smokers visited the er twice as often as nonsmokers (s 0.80, ns 0.40, p<0 .01) the number of annual routine outpatient checkups for asthma was similar based on location (la 1.39, us 1.66, p=0.06). smokers and nonsmokers had a similar number of checkups nationally (s 1.74, ns 1.64, p=0.32) and in louisiana (s 1.79, ns 1.21, p=0.06). the number of days where asthmatics were unable to perform their usual activities was significantly fewer in la than nationally (la 3.6, us 11.6, p<0.001). smokers had a significantly higher number of missed days nationally (s 17.8, ns 9.6, p<0.0001). in la, there was not a significant difference in the number of missed days based on smoking status (s 4.9, ns 2.9, p=0.47). conclusion: even though louisiana has a lower prevalence of asthmatics compared to the national average, significantly more of our asthmatics are smokers. asthmatic smokers in la and the u.s. utilized the er more than their nonsmoking counterparts. smokers and nonsmokers had similar numbers of routine outpatient visits. asthmatic smokers missed more days, but this was only significantly different at the national level. other research has shown that young age is highly associated with improper use in children using a mdi and holding chamber (arch pediatr adolesc med 2002; 156:378) . the objective of this study was to compare health outcomes achieved by children with asthma using inhaled corticosteroids (icss) delivered by a nebulizer compared with outcomes of children using icss delivered by non-nebulized device. methods: using a managed care organization database (pharmetrics integrated outcomes database), we identified children aged 8 years with an asthma diagnosis and asthmarelated hospitalization/emergency department (ed) visit (july 2000 -june 2002 and with a prescription claim for an ics within 30 days of discharge. we compared relative risk of hospitalization/ed recurrence from day 31-180 (cox proportional hazards regression, covariates=sex, age, current and prior asthma medications, prior oral corticosteroid and short-acting 2 -adrenergic agonist use, initial type of index event) for patients receiving nebulized ics vs other ics by age groups (0-4 years and 5-8 years). results: of 1552 patients with claims for ics, 729 received nebulized ics, of which 480 were aged 4 years; 823 received non-nebulized ics, of which 292 were aged 4 years. postindex hospitalization/ed rates were 12.4%. refill rate was higher for patients using nebulized ics. after model risk adjustment, patients using nebulized ics had a 53% risk reduction for hospitalization/ed recurrence vs those not using nebulized ics (hr: 0.47, 95% ci: 0.28, 0.78). in the 0-to 4-year age group, patients on nebulized ics had a 62% risk reduction compared with patients not using nebulized ics (hr: 0.38, 95% ci: 0.21, 0.69). in the 5-to 8-year age group, patients on nebulized ics had a 52% risk reduction (hr: 0.48, 95% ci: 0.16, 1.46). conclusion: in actual practice, treatment with nebulized ics after an asthma exacerbation is associated with a significant reduction of recurrent hospitalization/ed visits in young children, possibly due to improved technique and compliance. introduction: tenor is a 3-year, multi-center, cohort study of patients with severe or difficult-to-treat asthma. the objective of the tenor study is to better understand the natural history of patients with severe or difficult-totreat asthma. this analysis assessed the frequency of skin testing in this population and characterized the differences between the positive (st+) and negative (st ) subjects. methods: subjects were asked whether they had ever been skin tested and, if so, the test results. those who were st+ were compared to both st and those never tested (stnd) using clinical and other asthma-related characteristics. subjects 12 years of age were included in this analysis. results: 2985 subjects were eligible for this analysis. 85.8% were skin tested in the past, with stnd frequency of 5.1% from allergist sites and 33% from pulmonologist/other sites. of those tested, 93.5% were positive (allergist 95.7%, pulmonologist/other 87.3%). baseline ige for st+ subjects was 104.6 iu/ml vs. 32.4 iu/ml for st ; p<0.0001 (table) . as shown, the age at asthma onset, duration of asthma, rate of atopic disorders, and the rate at which asthma was triggered by aeroallergens differentiated the st+ from the st group. disease severity as evaluated by fev 1 , healthcare utilization, and medication use, however, was similar between the two groups. in general, stnd were more likely to have values closer to the st+ group, suggesting that the majority of those not tested would have been st+, if administered a test. conclusions: the prevalence of st+ subjects from both allergy and pulmonary practices was high, demonstrating that the majority of these severe or difficult-to-treat patients have allergic asthma. st+ patients showed differences in clinical characteristics compared to st , including a greater likelihood of their asthma symptoms being triggered by aeroallergens. these data also show that the clinical profile of stnd patients may be similar to that of st+ patients, suggesting the utility of a more universal allergic evaluation in severe asthmatics. funded by genentech and novartis pharmaceuticals corp. background current national guidelines for the diagnosis and management of asthma such as the naepp epr 2002, classify asthma severity based on frequency of asthma symptoms, medication use, and measurements of lung function by spirometry or peak expiratory flow variability. recently, the utility of spirometry measurements for assigning asthma severity has come into question. here we evaluate the correlation of spirometry measurements with asthma severity in school-aged children who are mostly naive to anti-inflammatory therapy. methods children were participants in a school-based lowincome asthma mobile van program, the breathmobile. recruitment was through referrals by school nurses and community public health clinics, parental response to flyers, and asthma screening questionnaires. spirometry was performed on all children greater than 4 years of age as part of a comprehensive asthma evaluation. asthma severity was assigned based on symptoms only, according to the naepp epr 2002 . results from april 2002 to april 2004 of the 620 children evaluated on the breathmobile, 540 patients were diagnosed with asthma. classification of severity by symptom frequency according to naepp epr guidelines resulted in 28% as mild intermittent (mi), 28% as mild persistent (mip), 32% as moderate persistent (mop), and 12% as severe persistent (sp). the percentage of patients and their mean lung functions at baseline evaluation without bronchodilator challenge are shown in the table. there were statistically significant differences (p<.05) between severity groups which was most pronounced for the fef25-75% when comparing the severe persistent group and the intermittent group. however, mean values appear to be "normal" for all degrees of asthma given current accepted cut-off values, fvc 80%, fev1 80%, fev1/fvc 80%, and fef25-75 60%. conclusion in our study, airflow impairment did correlate with asthma severity, although it was "normal" (fev1 80%) even in children with severe persistent asthma. therefore, a "normal" lung function measurement may be misleading as sole criteria for asthma severity classification. perhaps a higher cutoff point (fev1<90%) might be a better indicator of asthma severity in children. asthma is the most frequently chronic disease in childhood.our main was to know the prevalence of bronchial asthma in children (6-7 and 13-14 years) in the north zone of mexico city and to compare the prevalence obtained by the written questionnaire versus the video questionnaire in the group of 13 to 14 years, according to methodology proposed by isaac. material and methods: by means of a validated and standardized questionnaire (isaac) that was applied to 3500 children from 6 to 7 years and 3899 from 13 to 14. the questionnaires of 6 and 7 years were filled out by their parents. the group from 13 to 14 years answered a questionnaire and a video questionnaire. according to isaac specification and based on a studied population, it was calculated by statcal program the size of the sample. it was choose a haz-ardous sample of 3000 children between 6-7 years and 3000 of the 13-14 group years, both sexes in elementary and high school. measures of central tendency and chi2 were used. results: the final sample size for both groups was 7110 children (3211 of 6-7 and 3899 adolescents), 51.5% men and 48.5% women. the prevalence of the asthma diagnosis for teenagers was of 8 % (p<0.05 ic 7.1-8.7) and it was 4.5% in children (p<0.05 ic 3.8-5.2), wheezing in the last 12 months was 6.8% (p<0.05 ic 5.9-7.6) in children and of 9.9% (p<0.05 ic 9-10.8) for 13-14 years. wheezing induced exercise appeared in 13.1% (p<0.05 ic 12-14.1) in teenager and 3.4 % (p<0.05 ic 2.7-4) in the other group. the severity of asthma showed by nocturnal awakness was 4.3% and 2.6% (p<0.05), number of crisis in the last year 6.3% and 9.3% for children and teenagers respectively (p<0.05). in the video questionnaire of teenagers 7.3% (ic 6.5-8.1) answered affirmative on have displayed a shaken breathing on the last year resting and only 6.8% (ic 6-7.6) in the last month. about exercise question 16.5% confirmed have displayed symptoms, 14.6%(ic 13-15.8) in the last year and 11.1% (ic 10.1-12.1) in the last month. wide-awake at night 7.5% (ic 6.7-8.3) in the last year and 5.2% ) in the last month. conclusions: the prevalence of asthma by diagnosis was higher in teenagers group than in children group. the prevalence of asthma was higher also in this group. rationale: we investigated the relationship of pet exposure and healthcare utilization (hcu) in a cohort of pediatric patients with severe or difficult-totreat asthma in the epidemiology and natural history of asthma: outcomes and treatment regimens (tenor) observational study. we hypothesized that pet exposure would increase hcu due to increased airway inflammation. methods: tenor is a 3-year multicenter cohort study of patients with severe or difficult-to-treat asthma. children ages 6-12 were interviewed at baseline regarding asthma-related hcu in the previous 3 months. patients with pet exposure (ppe, n=370) were compared with patients with no pet exposure (pnpe, n=382). responses were analyzed using fisher's exact test. results: ppe were less likely to have severe asthma by physician assessment (32% vs. 40%; p=0.01). in addition, ppe were less likely to have an emergency room (er) visit (18% vs. 26%; p=0.006) or to have been hospitalized (7% vs. 12%; p=0.02) in the previous 3 months. more pnpe had an ige level >100 iu/ml (74% vs. 63%; p=0.001). ppe and pnpe were similar with regard to presence of allergic rhinitis and skin test positivity. compared with pnpe, fewer ppe with two or more pets had er visits and hospitalizations (table) . among ppe, there were no differences in ige levels or in asthma severity related to the number of pets. conclusions: pet exposure was associated with reduced hcu in the tenor pediatric cohort, with the most pronounced effect seen in reduced er visits and hospitalizations needed by those with multiple pets. ppe had significantly lower ige levels compared to pnpe, regardless of the number of pets. these data support the hypothesis that exposure to pets may paradoxically protect individuals from the development of severe asthma. alternatively, these data may reflect a self-selection in patients with severe or allergic asthma who are likely to avoid having a pet. however, there may be other confounding factors in families with pets that confer a protective effect on asthma severity. introduction: in asthma and other chronic obstructive airway diseases, phosphodiesterase 4 (pde4) is involved in the pathophysiology of the disease and is expressed abundantly in key inflammatory cells. inhibitors of pde4 are investigational, anti-inflammatory agents that prevent the breakdown of cyclic adenosine monophosphate, a natural modulator of inflammation. roflumilast is an investigational, oral, once-daily pde4 inhibitor with demonstrated in vitro and in vivo anti-inflammatory activity, which may translate into clinical efficacy in asthma therapy. this study examined the ability of roflumilast to exert direct or acute bronchodilatory activity in patients with mild to moderate asthma. methods: this was a double-blind, randomized, placebo-controlled, crossover study consisting of three treatment periods of one day each, separated by a 7-to 14-day washout period. during each treatment period, 15 patients with a forced expiratory volume in one second (fev 1 ) of 50% to 90% of predicted received either oral roflumilast 1000 î¼g, roflumilast 500 î¼g, or placebo. the fev 1 was measured twice prior to administration and periodically up to 6 h following treatment. after 6 h, patients inhaled 200 î¼g salbutamol from a metered-dose inhaler; fev 1 was measured 15 min later. adverse events, vital signs, and electrocardiogram results were monitored throughout the study. results: median baseline fev 1 was similar for the three treatment periods. both doses of roflumilast did not lead to statistically significant differences versus placebo in the time-averaged fev 1 over the first or up to 6 h after drug intake (p > 0.05). thus, there was no evidence of a direct or acute bronchodilatory effect with either single doses of roflumilast 1000 î¼g or 500 î¼g. in contrast, inhalation of the short-acting bronchodilator salbutamol led to a distinct improvement in fev 1 versus baseline in all treatments groups with median fev 1 increases of 19%, 21%, and 14% in the roflumilast 1000 î¼g, roflumilast 500 î¼g, and placebo groups, respectively. roflumilast was well tolerated. conclusions: oral, once-daily roflumilast exhibits no direct or acute bronchodilatory activity in patients with mild to moderate asthma as could be achieved with short-acting 2 -agonists. these data support the proposed mechanism of action of roflumilast as an antiinflammatory agent. south africa; 2. guadalajara, spain; 3. munich, germany; 4. weinheim, germany; 5. budapest, hungary; 6. konstanz, germany. introduction: phosphodiesterase 4 (pde4) is found in key inflammatory cells involved in the pathophysiology of chronic obstructive pulmonary disease and asthma. inhibitors of the pde4 enzyme are anti-inflammatory agents that prevent the breakdown of cyclic adenosine monophosphate, a natural modulator of inflammation. roflumilast is an investigational, oral, oncedaily pde4 inhibitor with demonstrated in vitro and in vivo anti-inflammatory activity. this study examined the dose-related efficacy of roflumilast in patients with asthma. methods: patients with stable asthma (forced expiratory volume in 1 second [fev 1 ] 50% to 85% of predicted) were enrolled in this randomized, double-blind, dose-range finding study. after a single-blind placebo run-in period of up to three weeks, patients received oral roflumilast 100 î¼g, 250 î¼g, or 500 î¼g once daily (n = 229, 228, and 233, respectively) for 12 weeks. efficacy was assessed by change from baseline in spirometric lung function fev 1 and forced vital capacity (fvc), as well as morning and evening peak expiratory flow (pef) recorded in patient diaries. safety and tolerability parameters were monitored throughout the study. results: treatment with roflumilast led to dose-dependent and statistically significant increases in fev 1 , fvc (both p < 0.0001), and in morning pef (p < 0.01). at last visit, fev 1 improved from baseline by 260 ml (11%), 320 ml (13%), and 400 ml (16%) in patients treated with roflumilast 100 î¼g, 250 î¼g, and 500 î¼g once daily, respectively. similarly, dose-dependent improvements of 10 l/min, 12 l/min, and 20 l/min in morning pef from baseline were reached. roflumilast was well tolerated at all dose levels tested. the most frequent drug-related adverse events were headache followed by gastrointestinal disorders such as diarrhea and nausea. there were no clinically relevant changes in vital signs, electrocardiogram, or laboratory parameters. conclusions: oral, once-daily roflumilast was associated with dose-dependent, clinically relevant improvements of lung function in patients with stable asthma. roflumilast was well tolerated. j.l. izquierdo 1* , e.d. bateman 2 , p. magyar 3 , u. harnest 4 , p. hofbauer 5 , a. varga 6 , c. schmid-wirlitsch 7 , d. bredenbroeker 7 , t.d. bethke 7 , 1. guadalajara, spain; 2. cape town, south africa; 3. budapest, hungary; 4. munich, germany; 5. weinheim, germany; 6. tatabanya, hungary; 7. konstanz, germany. introduction: phosphodiesterase 4 (pde4) inhibitors are a new class of anti-inflammatory agents for therapeutic use in inflammatory airway diseases. in several studies, the investigational, oral, once-daily pde4 inhibitor roflumilast has provided clinically meaningful improvements in patients with chronic obstructive pulmonary disease and asthma. this study examined the long-term safety and tolerability of roflumilast over 40 weeks in patients with asthma. methods: patients with persistent, stable asthma (fev 1 50% to 85% of predicted at randomization) participated in a double-blind, randomized dose-range finding study and were treated with oral roflumilast 100 î¼g, 250 î¼g, or 500 î¼g once daily for 12 weeks. patients completing the 12-week study per-protocol, then continued treatment in this open-label 40-week extension study. all patients received oral roflumilast 500 î¼g once daily during the extension period. adverse events (aes), clinical laboratory parameters, vital annals of allergy, asthma & immunology signs, and ecg were assessed throughout the extension period. results: a total of 456 patients were enrolled in the 40-week extension study. overall, the most common aes were related to the respiratory system. only a small number of patients (6%) experienced aes that were assessed as at least likely related to study medication. the most frequent drug-related adverse events were headache, diarrhea, and nausea as reported by 3%, 1%, and 1% of patients, respectively. most aes were mild to moderate in intensity and transient in duration; 6% of patients discontinued the study due to aes. most (60%) of these aes leading to discontinuation were assessed as not related or unlikely related to study drug. out of 456 patients, 16 reported serious aes, which were all assessed as not related or unlikely related to roflumilast. no clinically relevant changes in clinical laboratory parameters, vital signs, ecg, or physical examination occurred. conclusions: oral, once-daily roflumilast 500 î¼g administered for 40 weeks was well tolerated in patients with persistent, stable asthma. this study provides evidence that roflumilast is associated with a low incidence of aes, which are mostly mild to moderate in intensity and transient in nature, thus, supporting the potential therapeutic use of roflumilast in asthma. paris, france; 3. madrid, spain; 4. guadalajara, spain; 5. harrow, united kingdom; 6. weinheim, germany; 7. augsburg, germany; 8. munich, germany; 9. kaufbeuren, germany; 10. konstanz, germany. introduction: in asthma, inhaled corticosteroids (ics) have been the mainstay of maintenance treatment. new therapeutic agents are needed that target key inflammatory processes in asthma as effectively as ics but overcome known limitations of ics. phosphodiesterase 4 (pde4) inhibitors are anti-inflammatory agents that prevent the breakdown of cyclic adenosine monophosphate, a natural modulator of inflammation. roflumilast is an investigational, oral, once-daily pde4 inhibitor for potential use in anti-inflammatory asthma therapy. this study compared the standard corticosteroid treatment of twice-daily, inhaled beclomethasone dipropionate (bdp) with oral, once-daily roflumilast in patients with asthma. methods: in a randomized, double-blind, double-dummy study, patients (forced expiratory volume in one second [fev 1 ], 50% to 85% of predicted) received either oral roflumilast 500î¼g once daily (n=207) or inhaled bdp 200î¼g twice daily (400î¼g/day; n=214) for 12 weeks. mean change (lsmean and sem) in lung function parameters fev 1 , forced vital capacity (fvc), and morning and evening peak expiratory flow (pef) from baseline was determined after 12 weeks of treatment. further, symptom score and rescue medication use were assessed. results: both roflumilast 500î¼g and bdp 400î¼g improved fev 1 from baseline to clinically meaningful levels (300 â± 40ml and 370 â± 30ml, respectively; both p<0.0001). similarly, roflumilast and bdp improved fvc (300 â± 40ml and 360 â± 40ml, respectively; both p<0.0001) as well as morning and evening pef (p 0.0003). roflumilast 500î¼g was statistically non-inferior to bdp 400î¼g. roflumilast and bdp led to statistically significant and comparable improvements in asthma symptoms and use of rescue medication. adverse events were generally mild to moderate; the most common drugrelated adverse events reported in the roflumilast group were nausea, headache, and diarrhea. there were no clinically relevant changes in vital signs, ecg, or laboratory parameters. conclusions: roflumilast 500î¼g provided clinically meaningful improvement of lung function parameters, reduced asthma symptoms, and decreased the need for rescue medication. oral, once-daily roflumilast was as effective as inhaled, twice-daily bdp in the treatment of asthma. oral roflumilast 500î¼g was well tolerated. rationale: evaluation of medical claims from commercial health plans permits assessment of therapeutic interventions on resource utilization. this study investigated the impact of controller therapy in children starting asthma maintenance medications. the risk of obtaining prescriptions for oral corticosteroids (ocs), short-acting beta-agonists (saba) or adding another asthma therapy was evaluated. methods: this was a retrospective observational study utilizing medical and pharmacy claims from a large representative managed care plan from 1/1/2000-5/31/2003. children aged 4-17 years old with an asthma diagnosis (icd-9, 493.xx) and an initial pharmacy claim for one of the following regimens: fluticasone/salmeterol in a single inhaler, n=1, 168 (fsc), fluticasone propionate alone, n=2, 473 (fp), montelukast, n=4, 246 (mon), any inhaled corticosteroid plus montelukast, n=1, 009 (ics+mon), and an ics plus salmeterol from separate inhalers, n=296 (ics+sal) were included in the analysis. subjects were excluded if they had received any asthma controller medication in the 6 months prior to the initiation of therapy. regression was used to estimate the incidence rate ratio (irr) for ocs and saba use (negative binomial) and the odds ratio (or) of adding a controller (add) and an ed or hospitalization (ip) event (logistic). all models controlled for demographics, pre-controller asthma-related medications and events, and baseline total health care costs. results: the ratios in the table with a confidence interval excluding unity indicate significantly increased use or likelihood of an event compared to the fsc cohort. controller naã¯ve children started on fsc were less likely to add another controller than mon, fp or ics+sal, and had less use of ocs or saba than the 4 cohorts when studied for 12 months after the initiation of controller therapy. in addition, children treated with ics + mon had a significantly greater or of an ed/ip visit compared to fsc. conclusion: use of fp + sal (fsc) in a single inhaler assures that children are getting more optimal inhaled corticosteroid therapy as well as the benefits from the long acting bronchodilator while avoiding the potential for selective discontinuation of ics in the 2 multiple controller cohorts. a.s. nayak 1* , r. nathan 2 , j. williams 3 , s. kundu 3 , m. lloyd 3 , d. banerji 3 , 1. normal, il; 2. colorado springs, co; 3. bridgewater, nj. introduction: inhaled corticosteroids (ics) are recommended firstline therapy for severe, persistent asthma. systemic exposure to ics may suppress hypothalamic-pituitary-adrenal (hpa)-axis function, particularly at doses required to control severe asthma. ciclesonide (cic) hydrofluoroalkane (hfa) metered dose inhaler (mdi) is a novel and effective ics that is converted in the lungs to its active metabolite, desisobutyryl ciclesonide (des-cic). previously, in short-term studies, cic has been shown to have no effect on serum or urinary cortisol levels, which may be attributed to the low oral bioavailability, high serum protein binding and high clearance rate of cic and its active metabolite. this hpa axis analysis was part of a long-term study evaluating the safety of cic and beclomethasone dipropionate (bdp) hfa-mdi in patients with severe persistent asthma. methods: this was a multicenter, double-blind, parallel-group, 12-month extension of a 12-week double-blind trial of patients 12 years with severe persistent asthma. patients were randomized in a 2:1 ratio (cic:bdp) to receive cic (320 g bid) exactuator or bdp (320 g bid) ex-actuator. after 2 weeks, the doses of both medications could be titrated to 160 g bid as needed for asthma control. hpa-axis function was assessed at selected centers in a subset of patients at baseline and end of study (at month 12 or early termination) by measuring both peak serum cortisol induced by low dose (1-î¼g) cosyntropin and 24-hr urinary free cortisol corrected for creatinine. results: data were available for a small number of patients at 13 centers evaluating hpa-axis (table) . mean baseline levels and change from baseline to end of study values in low-dose cosyntropin peak serum cortisol levels for cic and bdp were comparable. likewise, baseline levels and mean change from baseline to end of study values in 24-hr urinary free cortisol corrected for creatinine were comparable among the two treatment groups. conclusion: these findings demonstrate that cic 320 to 640 î¼g daily for 12 months is safe and has no significant effect on hpa-axis function. a. long 1* , a. rahman 2 , 1. boston, ma; 2. wilmington, de. introduction: little information is available regarding the relationships between asthma severity, disease control, and compliance with medications. methods: physicians' perceptions regarding these variables were determined by internet-based general asthma medication usage survey and patient-specific asthma medication usage surveys between december 18 and 29, 2003, for 406 physicians (100 pcps, 106 pediatricians, 100 allergists and immunologists, and 100 pulmonologists). the patient-specific surveys were based on chart information of 3 randomly chosen patients per physician on controller medication. results: of 1218 patients, 12%, 31%, 43%, and 14% were categorized by their physicians as having mild intermittent or mild, moderate, or severe persistent asthma, respectively. overall, 45% of patients were categorized as having "very controlled" asthma and 58% as being "very compliant" with their current regimen. worse asthma control, decreased compliance, and increased physician visits were all associated with increased asthma severity classification. physicians reported that only 5% of patients with severe persistent disease (n=169) had "very controlled" asthma in contrast to 77% of patients with mild intermittent asthma (n=143). patients with mild intermittent asthma, and mild, moderate, and severe persistent asthma, had a mean of 2.9, 3.4, 4.5, and 5.5 physician visits for asthma, respectively, within the past year. physician perception of patient compliance varied less across the groups, with 55% of patients with severe persistent asthma and 66% of patients with mild intermittent asthma being rated as "very compliant." the incidence of allergic rhinitis was similar among all severity levels (range: 50%-56%), but patients with severe persistent asthma were more likely to have comorbid conditions, including hypertension, chronic obstructive pulmonary disorder, chronic bronchitis, and osteoporosis, compared with patients in other asthma severity levels. conclusions: decreased asthma control and rates of com-pliance, as well as increased physician visits and comorbid medical conditions, may be associated with increased asthma severity classification. rationale: children with asthma frequently have co-morbid allergic conditions requiring medications. the purpose of this study was to assess whether the controller asthma medication selected would reduce the utilization of intranasal steroids (ins) and prescription nonsedating antihistamines (nsa) for children treated for co-morbid allergy. methods: this was an observational retrospective study that utilized the pharmetrics integrated outcomes database that contains administrative medical and pharmacy claims data from over 30 managed care plans across the united states. children age 4-17 years old with a new diagnosis of asthma (icd-9, 493.xx) were identified and observed for 12 months after their initial diagnosis and treatment of asthma (post-index). four cohorts were established based on their controller medication dispensed: montelukast, n=1906 (mon), fluticasone propionate, n=2455 (fp), fp+mon n=287, fp/salmeterol in a single inhaler, n=599 (fsc). results: baseline comorbid diagnosis of allergic rhinitis was observed in 14-20% of the children. the patterns of use of ins and nsa were similar in the 12 months before and the 12 months after the initial asthma diagnosis and treatment. children with a diagnosis of allergic rhinitis were nearly twice as likely to receive a nsa or ins. all 4 treatment cohorts used a similar amount of each allergy medication. the presence or absence of a diagnosis of allergic rhinitis did not alter the findings. the adjusted odds ratio (95%ci) of using a nsa or ins relative to the use of fsc in the post-index period was mon: 0.989 (0.809, 1.208); fp: 0.828 (0.682, 1.007); fp+mon: 1.095 (0.804, 1, 489 ). the table below shows the percent of children dispensed a nsa and/or an ins. the number of units of each allergy medication was also similar across all 4 cohorts. conclusion: the use of mon, fp, fp+mon or fsc for asthma did not alter the rate or quantity of either intranasal corticosteroid or nonsedating antihistamines dispensed to children over the 12-month period. although allergic rhinitis is a common comorbidity of pediatric asthma, the selection of a regimen containing montelukast did not reduce the use of either nsa or ins compared to asthma treatments with fp or fsc. rationale: medication compliance is recognized as a significant challenge in pediatrics.the purpose of this study was to compare inhaled corticosteroid (ics) persistence in pediatric patients using a single inhaler, containing both an inhaled corticosteroid (fluticasone propionate, fp) and an inhaled long-acting beta-agonist (salmeterol, sal) (fsc), to patients receiving fp alone, fp + sal from separate inhalers, or ics + montelukast (mon). methods: retrospective 24-month pre-post database study utilizing medical and pharmacy claims. a total of 4946 subjects 4-17 years of age with a diagnosis of asthma (icd9 493) were grouped into 4 cohorts: fsc [n=1168]; fp only [n=2473] ics+sal [n=296]; and ics+mon [n=1009]. patients were controller naã¯ve for 6 months prior to the index event (the first prescription of the medication of interest). subjects were required to have continuous enrollment of 6 months pre-and 12 months postindex. subjects with cystic fibrosis, copd, bronchopulmonary dysplasia or respiratory distress syndrome were excluded. ics refill rates, as a measure of persistence, were compared between fsc and the ics components of the other cohorts over a 12-month follow-up period. results: mean refill rates over the 12-month follow-up period was significantly greater (p=< 0.05) for fsc (4.48) compared with the mean ics refill rate in the fp alone (3.39) cohort, the ics + sal (3.61) and the ics + mon (3.92) cohort. patients on fsc filled 32% more ics prescriptions than patients on fp alone, 24% more than ics+sal and 14% more than ics + mon. mean refills were generally higher than the median fills as a considerable number of children had only one fill: fsc (35.6%), fp (49.1%), ics (48.3%) + sal (50.0%), ics (36.0%) + mon (18.6%). conclusion: patients using fsc, are likely to fill their inhaled corticosteroids more often over 12-months compared with patients using ics + sal in 2 separate inhalers, ics+mon, and fp as monotherapy. improved persistence with ics has been shown in other studies to decrease morbidity and mortality of asthma. use of fsc, a single inhaler, assures that children are getting more optimal inhaled corticosteroid therapy as well as the benefits from the long acting bronchodilator while avoiding selective discontinuation of ics that may occur when two medications are dispensed. the national health interview survey (nhis) estimates 14.5 million united states residents with asthma. noncompliance with treatment has been estimated as between 20 and 80%. the consequences of noncompliance include absences from work or school, increased emergency room visits, more severe attacks, increased drug side effects, greater cost of care, and death. we questioned compliance in a 47yo man with severe, prednisone dependent eosinophilic asthma because he had persistent symptoms despite treatment with fluticasone propionate/salmeterol xinafoate 500/50 bid, prednisone 20mg to 40mg qd, and budesonide (200 mcg/puff) 2 puffs bid. after discontinuation of budesonide and prednisone and initiation of methylprednisolone 16mg bid for 24 hours and then 16mg qd and beclomethasone dipropionate 2 puffs (80mcg) hfa bid with a spacer, clinical improvement was unexpectedly abrupt. fev1 increased from 58% to 90% of predicted. sputum eosinophil counts decreased from 78% to 2%. because of the sudden improvement with the change to methylprednisolone, compliance to prednisone and fluticasone was questioned. to evaluate compliance, the patient's blood, urine, and sputum were tested for synthetic corticosteroids, without his knowledge, using mass spectrometry. the blood level of methylprednisolone was 2.6mcg/dl and prednisolone was 0.35mcg/dl, documenting use of methylprednisolone and the recently discontinued prednisone. the urine levels were 13mcg/dl of methylprednisolone, 1.3mcg/dl of prednisolone and 0.74mcg/dl of prednisone that further confirmed recent use of prednisone. the sputum testing revealed 0.8mcg/dl beclomethasone, 33mcg/dl fluticasone and 1.8mcg/dl methylprednisolone confirming compliance to inhaled fluticasone and beclomethasone at the time of the test. thus, contrary to our clinical suspicion, the patient was indeed compliant with his inhaled glucocorticoids and prednisone and subsequently with the methylprednisolone. to our knowledge, this is the first case report to document compliance to inhaled and oral corticosteroids by analysis of synthetic corticosteroid concentrations in blood, urine, as well as sputum. if compliance could be documented with certainty, it could potentially minimize the adverse effects of needless escalating steroid doses, reduce the cost of treatment, and minimize morbidity and mortality as well. rationale:the burden of pediatric asthma extends beyond those children with an asthma diagnosis. children with wheezing frequently have a delay in the diagnosis of asthma that may impede instituting appropriate therapy and reducing disease morbidity. this observational study was designed to assess the treatment patterns of children 4-17 years old receiving asthma medication(s) without a diagnosis of asthma compared with children diagnosed with asthma and children without claims for asthma. methods:this was a retrospective cross-sectional study that utilized the pharmetrics integrated outcomes database containing administrative medical and pharmacy claims data from over 30 managed care plans across the united states. three cohorts were selected: children with an asthma diagnosis (icd-9, 493.xx) (dx cohort), children with prescription claims for asthma controllers or rescue medications without an asthma diagnosis (rx cohort) and children with neither an asthma diagnosis nor prescription claims for asthma medications (control cohort). utilization of asthma medications, asthma specific costs and total costs of care were assessed. results: a total of 295, 000 children were identified: 6.7% in the dx cohort, 4.4% in the rx cohort and 88.9% in the control cohort. the potential asthma cohort was 11.1%. total annual non-asthma related costs for the dx cohort was $1, 642 for the rx cohort was $1, 306 and for the control was $802. only 19% and 5% of the total healthcare charges in the dx and rx cohorts retrospectively were asthma related. non-asthma charges were significantly higher in both the dx and rx cohorts compared with the control cohort. in the rx cohort, the ratio of saba prescription claims to asthma controller claims were 1.85-fold higher than in the dx cohort. conclusion: children treated with asthma medications without an asthma diagnosis consume greater health care resources resembling the pattern of health care utilization of children with an asthma diagnosis more closely than controls. further, children with treatment in the absence of an asthma diagnosis appear to be under-treated with controller therapy as recommended by national and international guidelines. background: a recent retrospective study assessed asthma variability in inner-city patients 6 months before and 6 months after enrollment into an naepp guidelines-directed clinical management and educational program. while guidelines-directed care improved asthma symptoms and outcomes, significant variability in disease indices were observed over the 6-month period. the present analysis evaluates resource utilization associated with this variability. method: economic end points, including hospital/emergency department (ed) visits, total unscheduled office visits, sick visits, and days lost from work or school, were collected from 125 inner-city patients aged 18 years (74% female, 69% minority, 80% treated by primary care physicians) enrolled in a guidelines-directed asthma clinical management and education program aimed at minimizing barriers to adherence. patients were stratified into 2 groups: those with high variability in asthma (n=62) and those with low variability in asthma (n=63), with variability defined as number of fluctuations in naepp symptom class in the 6-month postintervention period (high variability = patients with fluctuations higher than the mean; low variability = patients with fluctuations lower than the mean). results: guidelines-directed therapy was associated with improvements in asthma during the 6-month treatment period for both groups. patients in the high-variability group had more ed visits, sick visits, total unscheduled visits, and office visits compared with patients in the low-variability group (see table) . conclusions: despite guidelines-directed therapy and overall improvement in asthma control, patients experienced variability in asthma, indicating that even when their disease is stable, their symptoms continue to fluctuate. as a result, asthma variability may contribute to increased resource utilization. introduction: inhaled corticosteroids (ics) are considered first-line therapy for patients with persistent asthma. ics can lead to oropharyngeal adverse events, which may affect treatment outcomes and adherence. the occurrence of these local adverse events is dependent upon several factors, including dosage and duration of ics treatment. ciclesonide (cic) hydrofluoroalkane (hfa)-metered dose inhaler (mdi) is a novel and effective ics, with relatively low oropharyngeal deposition. cic is converted in the lungs to its active metabolite, desisobutyryl-ciclesonide (des-cic). furthermore, cic undergoes limited conversion in the oropharynx, which may account for its improved safety profile. this oropharyngeal safety profile analysis was part of a long-term study evaluating the safety of cic hfa-mdi vs beclomethasone dipropionate (bdp) hfa-mdi in patients with severe persistent asthma. methods: this was a multicenter, double-blind, parallelgroup, 12-month extension of a 12-week double-blind study of patients 12 years with severe persistent asthma. patients were randomized in a 2:1 ratio (cic:bdp) to receive cic (320 g bid) or bdp (320 g bid) (both ex-actuator). after 2 weeks, the doses of both medications could be titrated to 160 g bid as needed for asthma control.) oropharyngeal adverse events were monitored, and suspected oral fungal infections were verified by positive culture. results: the incidence of oral candidiasis was lower in subjects receiving cic (4.1%), compared with those receiving bdp (10.4%) ( table) . the incidence of pharyngitis and hoarseness was 3.6% and 2.5%, respectively, for the cic group, and 5.2% and 1.0%, respectively, for the bdp group. all local adverse events resolved without sequelae, and there were no withdrawals due to oropharyngeal treatment-emergent adverse events. conclusion: after 12-months of treatment with cic 160 î¼g or 320 î¼g twice-daily, the incidence of oropharyngeal adverse events was low. cic treatment resulted in a much lower incidence of oral candidiasis, compared with similar doses of bdp, reflecting a better local tolerance. objective: to determine the prevalence of asthma and asthma-related morbidity, treatment and asthma-risk factors in a selected population. method: a routine health screening, including tests for asthma, was conducted at the new orleans center for creative arts high school. participants (204) identified their medications and asthma tools in addition to completing the isaac questionnaire. prevalence data included lifetime wheezing, 12 month wheezing, and previous asthma diagnosis. asthma-related morbidity included sleep disturbance, wheezing with exercise, asthma attack rate and night awakening. results: " participants were aged 13-9 years (50.5% african american, 45.1% white) with 31.4% male, 68.6% female. " cumulative asthma prevalence was 18.8%, lifetime wheezing (24%), 12-month wheezing 12.7% with girls reporting 3.36 times more often (95% ci: 1.54, 7.36), and wheezing more than 4 times in 12 months 4.7%. " there was a significant association between race and wheezing in the last 12 months (p < 0.024) with whites reporting 3.78 times more often (95% ci: 2.01, 7.10). asthma morbidity was reported as follows: a. night cough -10.5% b. wheezing with exercise -10.9% " parents with a less education (high school or less) were 8.33 times more likely (95% ci: 7.46, 9.30) to have children who developed wheezing in the past 12 months. " higher body mass index (bmi = 25) was associated with wheezing after exercise (p < 0.008) with a 3.27-fold increase (95% ci: 2.46, 4.31). " among those with current asthma (15/204), 4 were not on any medication, 10 were using bronchodilators, and 5 were on anti-inflammatory medications. three reported using a spacer and 6 reported using a peak flow meter. conclusion: asthma prevalence is higher in this school population than the national average. less parental education, female gender, and bmi = 25 were associated with greater asthma morbidity. the majority of the participants with current asthma reported receiving episodic and inadequate treatment with inhaled corticosteroids. objectives: to determine the prevalence of asthma and asthma related symptoms; to assess its severity among new orleans school children. methods: seven elementary, middle, and high schools in new orleans participated in the screening of 1511 students, 54% female, 45% male, ages 5-18 in the fall, 2000. the 8-item questionnaire was designed by the international study of asthma and allergies in childhood (isaac) to determine asthma prevalence and severity in children. the isaac questionnaire is a validated protocol used on over 500, 000 children in 56 countries. asthma is defined as cur-rent wheezing for the purposes of this study. data was entered using spss 10 and sas 8 software for analysis. results: table: presence of asthma symptoms by ethnicity conclusion: asthma prevalence is significantly higher in inner-city school children in new orleans when compared to the national prevalence (24.6% to 26.4% vs. 7.5%). asthma prevalence and severity do not differ significantly between african-american and caucasian children in new orleans even after removing the effect of gender and age. video is an effective method of teaching pollen identification. projected digital images offer three-dimensional views of unique pollen detail similar to focusing a microscope. the national allergy bureauâ�¢(nab) currently provides pollen counts to the media. these reported levels are obtained by standardized counting methods rather than forecasts based on historical pollination predictions and weather patterns. the american college of allergy, asthma and immunology and the american academy of allergy, asthma and immunology have an interest in ensuring consistent counting and accurate reporting practices. both organizations offer pollen identification training in conjunction with their annual meetings and have used the video for initial training sessions and for experienced counters in advanced courses. there are 112 certified pollen counting stations in the united states and canada with approximately 80 currently active locations. the nab requires the demonstration of ability to count and accurately identify pollen on test slides. an updated recertification process using an interactive web site is currently being developed. ongoing pollen identification training is essential for the continued success of this aeroallergen network. most observers found that the video provided a quality emulation of microscopic viewing and enhanced the depth and detail of individual pollen characteristics. the video received the highest possible ratings by course attendees. in conclusion the video plays a positive role in pollen identification training and the continuing education of experienced counters. the diagnosis and treatment of mold allergies are complicated by the genetic diversity of individual fungal species and the influence of endogenous fungal proteases on extract compositions and potencies. studies examining the biochemical comparability of mold extracts from different sources and their compatibility with other allergens in immunotherapy mixtures are essential to the clinical effectiveness of these products. compositional comparisons of extracts prepared from alternaria, aspergillus and penicillium source materials by 7 u.s. allergen manufacturers revealed variable sds-page protein banding patterns and noticeable differences in total protein and carbohydrate concentrations. alt a 1 levels in alternaria extracts did not correlate closely with total protein levels or with ige-binding potencies measured by elisa inhibition. immunoblot profiles of fungal extracts were more closely related to one another compared to sds-page patterns, suggesting that similar allergenic or antigenic epitopes may be retained in molecules of varying size. parallel elisa inhibition dose-response curves provided statistical evidence that a repertoire of ige epitopes is conserved in many of these products. variations in the potencies of fungal extracts from different manufacturers may result from differences in source materials and/or conditions of extraction and storage. the stability and compatibility of allergen mixtures containing mold extracts were assessed after storage for up to 6 months at 2-8â°c using specific immunoblot and elisa procedures. grass and mite allergens compromised by mixing with mold extracts were stabilized by glycerin. alternaria extracts from different sources produced similar effects on grass allergens when added at comparable strengths. degradative effects caused by aspergillus or penicillium products were more closely related to total fungal protein concentrations than to extraction ratios. structural epitopes on cat, ragweed and fungal allergens were stable after mixing with protease-containing mold extracts, indicating the presence of natural protease inhibitors or allergenic protein sequences distinct from those recognized by these enzymes. allergenic extracts labeled as weight/volume or by pnu have no regulatory requirement for determination of activity. alum-adsorbed allergenic extracts are labeled in pnu and are felt to be depot formulations. the purpose of this study was to develop methods to measure important allergen proteins and specific ige binding capability of these alum-adsorbed allergenic extracts and to begin to assess the potency of these non-standardized extracts. allergen proteins are adsorbed to alum particles making their measurement difficult. in this study allergens were released from center-al â® alum precipitated allergenic extracts using 0.3 m citrate buffer, ph 5. the major allergen contents of several lots of each product were measured using monoclonal antibody elisas for group 5 grasses, cyn d 1 bermuda, bet v 1 birch, ole e 1 olive, and pla l 1 english plantain. these assays were developed and validated by alk-abello and optimized for the citrate releasing buffer. direct binding ige was performed by immobilizing serial dilutions of extract to microtiter plates and then adding specific atopic sera and enzyme labeled anti-ige. the methods used were able to measure in vitro allergen activity in the alum-adsorbed extracts. major allergen content was successfully measured in the extracts and the amount was related to the pnu content. as expected, the variability of the major allergens within a particular extract species was higher than in standardized extracts that are adjusted for potency. the extracts demonstrated specific ige binding ability in the binding assay. the ige binding capability at various dilutions was related to the major allergen content. in conclusion, methods were developed to release adsorbed allergen proteins from alum extracts. the extracts were then analyzed for major allergen pro-teins and the ability to bind ige. major allergen content is currently used to monitor the activity of aqueous and glycerinated extracts and this study demonstrates that implementing these testing procedures will improve the consistency and quality of alum-adsorbed extracts. introduction there are over 5000 species of smut and rust fungi. ustilago maydis, or corn smut, is a basidiomycete fungus that infects ears of corn. it is responsible for a percentage of grain loss in the united states but eaten as a delicacy in mexico. it grows into large tumor-like structures, called galls, dispersing soot-like spores responsible for the common name, "smut." it is readily airborne and believed to be a causal agent for allergic rhinoconjunctivitis. "corn smuts" was added to the standard screening panel for patients presenting for evaluation of rhinitis in the region of middle tennessee. methods using greer laboratoriesâ�¢ corn smut extract 1:20 w/v, patients were tested by prick/puncture method with the hollister-stier quintipâ�¢ device. if negative, intradermal testing was performed. positive and negative controls were assessed. based on current national recommendations, wheals 3 mm greater than negative control were considered positive for prick/puncture testing and wheals 8 mm greater than negative control were considered positive for intradermal testing. results 105 patients were tested between november, 2003 and march, 2004 . 14/105 (13.3%) met criteria for prick/puncture positivity. 52/105 (49.5%) met criteria for intradermal positivity. patients prick positive to corn smut had the following prick positive tests: dust mites 12/14 (85.7%); cat 11/14 (78.6%); local grass mix 10/14 (71.4%); local tree mix 10/14 (71.4%); local weed mix 10/14 (71.4%), mold mix 8/14 (57.1%); cockroach 7/14 (50%); and dog 4/14 (28.6%). discussion allergy testing for aeroallergens is available to a limited number of antigens, of which, only a few are standardized. as time passes, relevant antigens are discovered and their importance further elucidated. this assessment reveals a significant presence of corn smut ige largely accounted for by intradermal positivity which may or may not reflect clinical sensitivity. these numbers are provided so that other clinicians may compare to prevalence in their geographical area. further studies are needed to determine the association of corn smut ige with clinical symptoms. h 1 antihistamines are the mainstay of therapy for allergic disorders, including skin diseases. the most common side-effect of marketed antihistamines is sedation, especially when the clinical symptoms require a higher dose than recommended, a condition commonly encountered in dermatological disorders. the present study describes the pharmacology of a new non-sedating h 1 antihistamine, r129160 (hivenylâ�¢). r129160 binds to the cloned human h 1 receptor with a similar affinity (ki: 19 nm) as the reference antihistamines cetirizine (ki: 50 nm) and loratadine (ki: 37 nm). in vivo, r129160 protects rats and guinea pigs from lethal shock, induced by compound 48/80 and histamine, respectively (ed 50 : 0.06 and 0.055 mg/kg respectively). the compound is at least as effective as cetirizine and loratadine. in rats, r129160 inhibits the histamine-and allergen-induced cutaneous reactions (ed 50 : 1.4 and 2.3 mg/kg) with a similar potency as cetirizine (ed 50 : 0.7 and 2.7 mg/kg) and loratadine (ed 50 : 1.8 and 1.6 mg/kg). even so, in guinea pigs the compound inhibits the histamine-and allergen-induced skin reactions (ed 50 : 0.14 and 1.2 mg/kg) to a similar extent as loratadine and cetirizine. however, in dogs r129160 is more potent in inhibiting the ascaris allergen-induced wheal reaction (ed 50 : 0.024 mg/kg) than cetirizine (ed 50 : 0.14 mg/kg) or loratadine (ed 50 : 0.20 mg/kg). r129160 fails to occupy central h 1 receptors in the guinea pig cerebellum up to 40 mg/kg, in contrast to loratadine (ed 50 : 2.2 mg/kg). in vitro and in vivo cardiovascular safety experiments indicate that r129160 lacks the intrinsic capacity to prolong the qt-interval, even at high doses. as such, r129160 (hivenylâ�¢) is characterized as a potent, non-sedating and cardiosafe h 1 antihistamine. it has been selected for further clinical development, mainly in the field of dermatology. the compound will be a suitable tool to explore the activity of a selective h 1 antihistamine in various indications, without the contamination of the sedative activity often observed with other marketed antihistamines when increasing the dose. ciu represents one of the most clinically perplexing disorders which the allergist-immunologist is faced with. we have previously reported the clinical efficacy of fxt (prozac), an ssri widely used for the treatment of depression, in the management of ciu (nsouli tm, et al. ann allergy asthma immunol 2002; 88:60) . in this presentation we report 2 additional cases of ciu which responded dramatically following the use of fxt. a 41 yr-old female and a 21 yr-old male presented with ciu of 18 and 24 months duration, respectively, requiring oral corticosteroid (cs) therapy for control of their ciu after failure of high dose anti-h1 (hydroxyzine) and anti-h2 (ranitidine) agents (table) . testing for food and latex allergy, viral hepatitis, autoimmune thyroid disease and parasitic infection were all negative. a skin biopsy performed in subject #1 was consistent with an urticarial vasculitis. following one week of oral fxt (40 mg qd [subject #1] 20 mg qd [subject #2]) a striking and complete resolution of urticaria in each patient was observed within 7 to 10 days during which time it was possible to successfully taper the cs. both patients have been maintained on fxt therapy with complete control of their ciu. the very favorable response to fxt therapy in these 2 patients in addition to our first case report suggests that this drug may have a new therapeutic application in the management of recalcitrant ciu. background: ipratropium bromide nasal spray (ib) is indicated for treatment of rhinorrhea caused by common cold (cc), seasonal and perennial allergic rhinitis (ar) in adults and children age 5 and up. symptoms of rhinorrhea from cc or ar in children are similar to those in adults, yet there is little data on the use of ib in children under 5 years of age. objective: evaluate the safety and efficacy of ib nasal spray 0.06% in 2-5 year-old children with symptoms of rhinorrhea from cc or ar. methods: a total of 230 children (43 cc and 187 ar) were treated in an open-label, multi-center study. the cc patients received ib nasal spray (84 mcg per nostril) tid for 4 days, the ar patients received ib nasal spray (42 mcg per nostril) tid for 14 days. effectiveness was measured using a global assessment questionnaire and daily symptom scores reported by the parent. results: from the global assessment questionnaire, 91% and 90% of the parents found ib either "very useful" or "somewhat useful" in the cc and ar groups respectively. regarding effectiveness, 98% (cc) and 87% (ar) of the parents reported that ib had either a "good effect" or "excellent effect" in treating rhinorrhea. moreover, 67% (cc) and 91% (ar) of parents found administration of a nasal spray either "extremely easy" or "very easy." eighty-one percent (cc) and 89% (ar) of the parents reported they would use ib again for their child's allergy symptoms. the daily symptom score (0 = none to 5 = unbearable) for rhinorrhea decreased from 2.9 to 1.3 (-55%, p<0.0001) for cc and from 2.1 to 1.1 (-48%, p<0.0001) from baseline compared to the average on-treatment score, with decreases also seen for stuffy nose and sneezing. the nasal spray was well tolerated with adverse events (ae) reported in 28% of cc and 35% of ar patients. the aes were mostly mild to moderate and no potentially systemic anticholinergic or serious aes were reported. conclusions: ib nasal spray 0.06% administered at a dose of either 42 or 84 mcg per nostril tid is an easy to use, safe, and effective therapy for control of rhinorrhea in children 2 to 5 years of age with common cold or allergic rhinitis. chronic idiopathic urticaria (ciu) represents one of the most clinically perplexing disorders which the allergist-immunologist is faced with. the pathogenesis of the condition derives from the release of potent vasoactive substances including histamine, and products of arachidonic acid metabolism, e.g., prostaglandins and thromboxanes formed by the action of the enzymes cyclooxygenase (cox) of which cox-2 is responsible for pseudoallergic and other inflammatory responses. although a number of therapeutic options exist owing to the plethora of mediators produced, treatment has focused largely on the use of h1 antihistamines and, unsurprisingly, at times without complete resolution of symptoms. in this presentation we report the successful use of a cox-2 inhibitor for the treatment of chronic urticaria. a 10 y/o white hispanic female presented with a 4 month history of chronic urticaria predominantly on the soles of the feet, with unknown precipitating factors, and fail-ure to respond to prior treatment with: cetirizine, steroids, benadryl, ebastine and epinastine. the patient received a blood transfusion 3 years ago and there was no prior history of allergies. skin testing revealed 3+ reactions to dust mite, pollen, cockroach, shellfish, 2+ reactions to corn, milk and ige = 262 iu (nv < 90 iu), aso = 400 ui (nv < 200 ui). after 2 weeks of treatment with rofecoxib (vioxx) 25 mg, and benadryl, the rash resolved. vioxx was continued for 2 more weeks until complete resolution of symptomatology. this case illustrates that the addition of a selective cox-2 inhibitor (i.e., rofecoxib) with an h1 antihistamine may be a more effective regimen for patients with ciu who fail to respond adequately to conventional therapy. introduction: elderly asthmatic patients whose symptoms are controlled by inhaled corticosteroid (ics) therapy may still have breathlessness on exertion. we randomized elderly asthmatic patients stabilized by medium-dose ics therapy into two groups, treated one group with medium-dose ics therapy plus montelukast, a leukotriene receptor antagonist, and the other with increased-dose ics therapy, and compared the effects of the treatment regimens on exercise tolerance. methods:the subjects were 24 patients with bronchial asthma (16 males and 8 females, 70.6â±3.9 years) stabilized by ics therapy (with fluticasone proprionate, fp; 400 mg/day) for three months or more with low peak expiratory flow (pef) rates (<80%predicted, variability<15%). they were randomly divided into two groups (12 patients each) to be treated with ics therapy plus montelukast (400 mg/day fp + 10 mg/day montelukast; m group) or with increased-dose ics therapy (600 mg/day fp; f group). pulmonary function tests, a six-minute walking test, respiratory gas analysis during incremental (15w/min) cycle ergometer exercise were conducted, and exhaled nitric oxide (no) levels were measured before and after two weeks of the study treatment. results: pulmonary function tests showed significant increases in maximal mid-expiratory flow (mmf) and forced expiratory flow at 50% vital capacity (v50) in the m group (p<0.01) but no significant changes in the f group. exhaled no levels decreased significantly in both groups (40.7â±13.9 to 27.5â±9.1 ppb in the m group and 53.1â±17.6 to 38.0â±10.4 ppb in the f group; p<0.01). the six-minute walking distance extended from 531â±64 to 575â±58 m in the m group and from 553â±60 to 570â±58 m in the f group.the peak oxygen uptake (peakvo2) increased significantly in the m group (%peakvo2/w from 76.2â±12.7 to 84.4â±14.6%; p<0.01) but not in the f group (%peak vo2/w from 76.2â±10.7 to 76.4â±10.3%). the peak exercise load also increased significantly in the m group (76.6â±22.0 to 96.1â±23.1 w; p<0.01) but not in the f group (81.2â± 16.2 to 82.2â±14.3w). conclusions: the results indicate that concomitant administration of montelukast is more effective than dose escalation of ics on exercise tolerance in elderly asthmatic patients under medium-dose ics therapy. e. meltzer 1* , y. luo 2 , l. shen 2 , z. guo 2 , c. schemm 2 , y. huang 2 , k. chen 2 , p. king 2 , r. nave 3 , d. banerji 2 , s. rohatagi 2 , 1. san diego, ca; 2. bridgewater, nj; 3. konstanz, germany. introduction: inhaled corticosteroids (ics) are first-line treatment for persistent asthma. ciclesonide (cic) is a novel and effective ics under development. freely circulating, unbound ics is available to cause systemic adverse effects, such as hypothalamic-pituitary-adrenal (hpa) axis suppression. hence, it is important to determine the free fraction of ics in plasma. in separate studies, the protein binding of the active metabolite of cic, desisobutyryl-ciclesonide (des-cic), was evaluated, and the effects of inhaled cic on hpa axis function were determined. methods: human plasma protein bind-ing of des-cic (0.5-500 ng/ml) was determined using equilibrium dialysis. dialyzed samples were analyzed by liquid chromatography with tandem mass spectroscopy to determine free and bound des-cic. in 3 separate clinical studies, the effects of cic (hfa; 320-1280 î¼g daily) and placebo (pbo), via metered-dose inhaler (ex-actuator doses), over 9 days, 4 or 12 weeks, on basal hpa axis function (24-hour area-under-the-curve [auc0-24h] serum or urinary cortisol corrected for creatinine) or stimulated (low-dose [1 î¼g] cosyntropin) serum cortisol were investigated in patients ( 18 years) with persistent asthma. results: the mean % of human plasma protein binding for des-cic was 99%. in 2 studies measuring serum cortisol auc0-24h, there was no difference between pbo and cic (320-1280 î¼g). similar results were observed for 24-hr urinary cortisol corrected for creatinine. in the 3rd study measuring low-dose (1 î¼g) cosyntropin-stimulated peak serum cortisol, after 12 weeks of treatment, there was no significant difference in the mean change from baseline versus placebo for either cic320 (p=0.383) or cic640 (p=0.911). conclusions: the favorable pharmacokinetic profile of cic, in particular the high protein binding of des-cic, may explain the lack of hpa-axis suppression. this appears to result in greater systemic safety. purpose: unscheduled office and ed visits for urgent asthma care are an ongoing point of concern. determining preventive variables regarding these unscheduled visits could have a significant impact on asthma costs and quality of life. objective(s): this research addresses the following question: when stratifying by race, gender, age, metropolitan/rural place of residence and comorbidity, do adults with asthma have fewer ed or unscheduled office visits for urgent asthma care if they: a) have an identified primary care provider, or b) have health insurance? method(s): univariate and stratified bivariate contingency table analyses were performed on weighted 2001 behavioral risk factor surveillance survey (brfss) data. result(s): adults with asthma who had an identified primary care provider were more likely to have no unscheduled office visits (or=1.87) or ed visits (or=2.07) for urgent asthma care. this was also true for adults with asthma who had health insurance (or=1.38 for no unscheduled office visits and or=1.71 for no ed visits). these relationships held when stratifying by race, gender and age. the relationships also held for metropolitan residents. the analysis was inconclusive for rural residency and the existence of co-morbidities. conclusion(s): despite race, gender, age and metropolitan residency, having a primary care provider or having health insurance impact whether or not adults with asthma are more likely to have unscheduled office or ed visits for urgent asthma care. further investigations are needed to examine how these factors impact adults with asthma who are rural residents or who have co-morbidities. d. bukstein 1* , g.a. cherayil 2 , 1. madison, wi; 2. brookfield, wi. introduction: costs for plans to process prior authorizations for non-formulary medications, has been estimated to be $20 to $25 per request. costs for physicians to process these requests has not been extensively studied. methods: dr.bukstein, board certified allergist, developed a data collection tool. the form was utilized by physicians and nurses to document time spent on processing prior authorizations. data collected included, class of medicines requiring the pa, nursing time spent on calling the patient, pharmacist, health plan, nursing time spent completing forms, nursing time clarifying the information for the pa, as well as physician time spent completing pa activities. results: data was collected over 8 weeks in 2003 and 117 requests were processed.the class of medicines most often processed was antihistamines, comprising 66% of requests. nursing calls were tracked and calls to and from patients were the most common call documented. they averaged 5.6 +/-6.5 calls per day per nurse. the nurses spent an average of 17 minutes per patient call. calls to health plans averaged 1.8 +/-1.5 calls per nurse per day and time spent on these call was 8.4 +/-9.5 minutes per call. physician calls documented included 154 calls averaging 1.9 +/-1.2 calls per physician per day. these calls averaged 5.8 +/-5.0 minutes per call.often the results of the prior authorizations were not known on the day of the request. originally 30.8% of requests were granted the same day. retrospective review revealed 98.7% were approved the first time they were processed. salary and benefits were calculated for nurses and physicians. the hourly rate was defined as $21.50 per hour for nurses and $150 per hour for physicians. the costs for the time spent on the 117 prior authorizations were calculated. during the 8 week study period, over 40 hours was spent by nurses on 231 calls and over 8 hours was spent by physicians on 154 calls during the same time period. the total nursing and physician cost in this specialty practice was $17.77 per prior authorization. conclusion: there are substantial costs with processing of prior authorization requests for non-formulary drugs on the physician office side of managed care as well as on the insurance side of the process. specialty physicians should have a different process for obtaining non-formulary medications since almost 100% of their requests are granted. introduction: diabetes mellitus can adversely impact the course and outcome of myocardial infarction (mi). one of the mechanisms underlying this phenomenon is alteration of the course of inflammation and the reparative process following myocardial necrosis. abnormal wound healing, tissue reparation and immune responses in diabetic patients have been intensively studied, but the cellular and the molecular mechanisms are still unclear. transforming growth factor-beta (tgf-beta) is a multifunctional cytokine which plays a critical role in coordination of the course of inflammation and reparation, acting as a potent depressor of inflammation and a stimulator of regeneration. this study investigates the dynamics of serum concentrations of the active form of tgf-beta1 during the period up to the 20th day after the onset of a mi in diabetic and non-diabetic patients. results: in non-diabetics a significant increase was observed in tgf-beta1 on day 2 (5-fold greater than in controls; 1370.0â±306.2 and 269.3â±214.5 pg/ml respectively) with further increases reaching a peak on day 7 (1723.1â±127.6 pg/ml). on day 20 tgf-beta1 decreased to levels less than on day 2, but was still greater than in healthy controls (1265.3â±369.8 pg/ml). in diabetics, concentrations of tgf-beta1 on days 2 (939.7â±155.2 pg/ml) and 7 (965.8â±150.4 pg/ml) after mi were similar to diabetics without mi (724.6â±233.5 pg/ml). only on day 20 was tgf-beta1 increased to levels (1502.8â±285.6 pg/ml) which were 2 fold greater than in diabetics without an mi. thus, in diabetic patients serum concentrations of the active form of tgf-beta1 are much greater than in non-diabetics. mi in patients with diabetes mellitus is associated with a reduced and significantly delayed increase in tgf-beta1. conclusion: tgf-beta deficiency may be a factor associated with low activity of tissue reparation after mi in diabetic patients. introduction helicobacter pylori (hp) is the most common gastrointestinal infection worldwide, but only 10-15% of those infected develop chronic gastritis or peptic ulcer disease. the pathogenesis of ulceration, mechanisms of hp lifelong persistence in gastric mucosa and local immune disturbances induced by this infection are well known, but the mechanisms of resistance and elimination of this infection have not been extensively studied. most study is based only on phenomenological findings, such as absence or low hp colonization in subjects spontaneously producing high levels of il-2. the aim of this investigation was the analysis of the efficacy of the recombinant interleukin (ril-2) roncoleukin (biotech, russia) in treatment of hp-associated gastric ulcer disease. methods 108 patients were randomly divided into two groups. the first group of patients was treated with standard therapy including of two antibiotics (claritromycin and amoxicillin), proton pomp inhibitors and h2 receptor antagonists. patients of the second group were treated with the same therapy, but instead of antibiotics they received 0.1 mg roncoleukin into four to six areas submucously using a gastroscopic method and 0.4 mg roncoleukin dissolved in 400 ml of 0.9% nacl with 4 ml 10% human albumin infused intravenously. this procedure was performed three times at an interval of 72 hours. results immunological findings demonstrated that roncoleukin results in an increase of cd25+, hla-dr+ and cd16+cd56+ cell levels. there was an increase in the serum concentrations of il1 (3 fold), il6 (4 fold) and ifn (more than 20 fold) while the level of tnf and il8 profoundly decreased. one month after the end of treatment, the group treated with ril-2 had hp eradication achieved in 95.4% in comparison to 81.5% of the control patients. in the ril-2 treated group, the ulcer epithelization period was 10.79â±0.46 days while in the normal treatment control group it was 35.23â±1.58 days (p<0.001). conclusion immunotherapy with ril-2 is a more effective method of treatment of helicobacter pylori-associated gastric ulcer disease when compared with traditional methods of treatment employing only antibiotics. introduction the role of different cytokines and the growth factors is now appreciated in progression of essential hypertension. the participation of et-1 and tgf 1 in pathogenesis of essential hypertension especially in the process of fibrosis, hypertrophia of vascular smooth muscular fibers, and cardiomyocytes, and the activation of renin-angiotensin system is now recognized, in addition to effects on myocyte cultures. the aim of the investigation was the study of serum et-1 and tgf 1 levels in patients with essential hypertension. materials and methods 60 patients with essential hypertension (40 males and 20 females) with average age 54.0 â± 5.3 years were studied. all patients suffered from left ventricle hypertrophy documented by echocardiography. the control group consisted of 20 healthy volunteers similar to the investigated patients in sex and age. in all patients the serum concentrations of et-1 and tgf 1 were determined using elisa (biomedica, biosource). results an increase in the serum concentrations both growth factors were noted in the studied group when compared with the control group. the average concentration of et-1 in patients with essential hypertension was 0.64 (0.32-0.91) pmol/l. the level of et-1 in the control group was 0.1 (0.05-0.17) pmol/l (p=0.04). the concentration tgf 1 in essential hypertension patients was 224.2 (125.4-314. 3) pg/ml and in control group was 68.2 (42.5-81.8) pg/ml (p=0.02). there was a positive correlation between the concentrations (spearmen's rank coefficient of correlation was 0.42; p=0.01). con-clusion the increase of the serum concentration of growth factors et-1 and tgf 1 and their co-influence in patients with essential hypertension, suggests a role of these growth factors in the pathogenesis of arterial hypertension. u. kaza 1* , c. lauter 2 , 1. bloomfield hills, mi; 2. royal oak, mi. introduction: few studies have examined the referral patterns for allergy and immunology inpatient consultations in a community hospital. consequently, an invaluable part of physician and housestaff education is missing. our objective was to examine the number of inpatient allergy and immunology consultations, the reasons for consultations and the outcome of the patients in order to improve physician education. methods:we performed a retrospective chart review of all inpatient allergy and immunology consultations in the years 1996-1997 and in 2002-2003 to determine the reasons for consultation, the recommendations made and if they were followed and the outcomes of the patient. results:we reviewed a total of 408 inpatient allergy and immunology consultations. in the 1996-1997 time period 26% of inpatient consults were for asthma, 22% for drug allergy, 12% for rash. in the 2002-2003 time period 25% of inpatient consults were for rash, 21% for drug allergy, 16% for asthma. the top three reasons for consultations remained the same although the order changed. consultations for immune deficiency, angioedema and rashes increased, whereas consultations for asthma and allergies decreased. there were a total of 202 consultations in 1996-1997 and 206 in 2002-2003 . the number of consultations remained the same despite an increase in overall number of hospital admissions from 44, 677 in 1996 to 58, 348 in 2003 . in greater than 95% of consultations, allergists' recommendations were followed. in both of the time periods studied, greater than 70% of patients improved, with less than 9% having no improvement, in the remainder of cases improvement was not applicable. conclusion:in conclusion, we believe that identifying the reasons for inpatient allergy and immunology consultations and examining the most common recommendations, as well as the outcomes of patients will be a valuable guide in the education of our physicians. by incorporating this information into grand rounds and resident conferences, physicians will benefit from learning about when an allergist can be helpful and how to manage some of the more common allergic and immunologic problems in patients that are hospitalized. the high percentage of providers who follow the advice of allergists indicate that allergists have a great deal of educational value to offer other physicians. while complementary and alternative medicine (cam) has generally experienced increased popularity, its utilization by allergy/asthma patients remains uncertain. our private allergy practice surveyed the use of cam in allergy/asthma patients in 1998(1). using a similar questionnaire, we assessed the current interest in cam with our allergy/asthma patients and compared the data to our 1998 survey. we analyzed 103 completed questionnaires from 113 sequential surveys administered. the results were compared to 113 questionnaires reported in 1998. they indicated that in both study periods (1998 & 2004) , the majority of patients wanted to discuss cam (65 and 69% respectively). an equal number (18%) in each study period discussed cam with their primary care provider. sixteen percent (16%) of our respondents sought a cam practitioner for general medical needs in 1998 vs. 19% in 2004. however, there was an increase from 4% to 10% of our patients seeing a cam practitioner for their allergies and/or asthma from 1998 to 2004. sixty-two percent (62%) would like to consider pursuing cam through our allergy spe-cialty practice or other provider. when asked regarding preferred treatment, 62% stated combination traditional with cam, 8% preferred traditional only, 3% cam only, and 27% did not know/doctor s choice. more patients are now seeking chiropractic care (36% to 52%) compared to our 1998 results. acupuncture was the first choice cam modality at 48% in 2004 surpassing vitamin/mineral therapy in 1998. currently, the second and third choices were vitamin/mineral therapy and deep tissue massage. while these numbers were small, we were impressed that currently 10% (two and a half times more since 1998) of patients in our practice were seeking cam allergy/asthma care from outside of our practice. these results demonstrated that more than half of our patients were interested in pursuing traditional with cam options within our office. given this trend, we have begun discussing the concept of integrative allergy, which to us means integrating evidenced-based cam modalities within our traditional allergy/asthma practice. (1) introduction: clinical immunization knowledge is complex and demands ongoing training. nationally, basic immunization and vaccine safety education is limited within traditional medical, nursing, and provider education. project immune readiness (pir), a peer-reviewed, web-based, interactive course, was developed in response to this deficit and the need for standardized resources to provide initial and sustainment training for safe and effective immunization services. it is designed for medical personnel with diverse educational preparation. currently, pir offers 21 course modules addressing 42 hours of instruction on specific vaccines, their respective diseases, and general information on immunization healthcare and vaccination procedures. methods: users completed a pre-test (establishes baseline knowledge), an interactive module, followed by a post-test (to observe change from baseline) for each course in sequence. anonymous user and score data were collected as part of a quality assurance and course validation process. learning gain indices (lgi) were calculated based on average mean pre-test and post-test scores for each module lgi of all modules demonstrated substantial increases in user vaccination knowledge. comparing pre and post-testing is an effective method to assess learning gains. the findings support pir as a successful and valid distance-learning tool that establishes and documents core knowledge of medical personnel administering vaccinations. further research is needed to assess the effectiveness of knowledge acquisition and retention, in addition to variance in vaccine delivery after training. this approach to learning may have value as a resource that supports smallpox and influenza pandemic emergency preparedness plans for just in time training. introduction: variances from practice guidelines for the prescription of auto-injectable epinephrine are well documented among practicing physicians, families, and patients. effective patient education requires provider competency. the current study was designed to survey resident physician perceptions regarding auto-injectable epinephrine education, use, and patient education requirements. methods: residents from primary care disciplines at a tertiary care medical center were invited to complete a voluntary, anonymous questionnaire. a total of 58 surveys were distributed and returned: 22 emergency medicine, 11 family practice, 9 internal medicine, and 16 pediatric residents completed the questionnaire. due to the small sample size, responses from physicians in various disciplines were reviewed as a whole. results: 40 respondents (69%) reported that they had previously prescribed auto-injectable epinephrine for allergic emergencies. the majority (63%) of these prescribers reported that their training was inadequate. 14 respondents (35%) reported no training, while 11 respondents (28%) reported that their training was less than that needed to ensure proficiency. 15 respondents (37%) reported that their training was adequate to ensure proficiency. none reported expertise. only 7 of 40 prescribers (17.5%) reported that either they or their staff always demonstrated proper medication use to the patient. interestingly, 2 of these 7 providers reported they had not been trained on proper use. the table below summarizes resident training and patient education practices. additional physician knowledge deficits included the proper site of medication administration, the proper interval for replacing medication, and the proper place for medication storage. conclusions: of the residents surveyed, who have previously prescribed auto-injectable epinephrine, 63% identified training deficiencies. only 17.5% of prescribers reported that the standard of care requirement to demonstrate proper medication use was always met. there is a clear need to improve auto-injectable epinephrine education in all residency training programs. r. bloebaum 1* , r.k. calabrese 2 , m. 1. houston, tx; 2. new york, ny. introduction: pneumocystis carinii pneumonia (pcp) is a major cause of morbidity and mortality in patients with aids. adverse reactions occur frequently to the most effective medication for both the prevention and treatment of pcp, trimethoprim-sulfamethoxazole (tmp-smx). we looked at the immediate safety and efficacy of three protocols for desensitization in aids patients. methods: by retrospective chart review, we identified 49 patients with aids who had experienced previous mild to moderate hypersensitivity reactions to tmp-smx and required desensitization. patients received one of three desensitization protocols based on illness severity or ward attending preference: a 6-hour intravenous (iv) desensitization, an 8-day oral desensitization, or a 10-day oral desensitization. results: of the 49 patients that received desensitization, 38 (77.5%) completed successfully. of these, 33 subjects had no reaction during the desensitization process; however, seven of these subjects were on steroids for treatment of other diseases. the remaining five successful patients had mild reactions which were treated symptomatically with acetaminophen, antihistamines or both. eleven patients failed to complete the desensitization: six stopped by the attending physician and four dropped out voluntarily. one patient expired during desensitization from extensive disease complications related to the admitting diagnosis. all protocols were equally successful when comparing the immediate success rates, 6/7 (86%) of the 6hour protocol, 4/5 (80%) of the 8-day protocol and 28/37 (75.7%) of the 10day protocol. the 6-hour iv desensitization protocol was most frequently used in the intensive care unit on critically ill patients. two of these patients, counted as successfully desensitized, died 5 and 28 days post protocol completion secondary to extensive comorbid conditions unrelated to the desensitization. conclusion: given the insignificant differences between the success of the 6hour iv desensitization and the oral desensitization protocols, we believe that either may be used effectively. further, in patients with mild to moderate hypersensitivity reactions to tmp-smx, an oral desensitization protocol may be used safely in the outpatient setting if given appropriate lab follow up. a. morales * , e. gonzalez, a. contreras, d. lopez, g. lopez, mexico city, mexico. introduction in 1966 davis describes job syndrome in two women, in 1971 dr buckley reports two children, being known as hyper-ige syndrome (job's syndrome or buckley's syndrome). defined as a primary immunodeficiency, dominant autosomic, characterized by multi-systematic alterations (immunological, skeletal, dermal and dental). it's diagnostic criteria are levels of ige 2000 ui/ml, chronic dermatitis, recurring respiratory infections, cold abscesses, pneumatoceles, infections caused by candida, and finally craniofacial alterations. on another front, extraordinary high levels of ige have been reported in patients with allergic illnesses that increase the risk of anaphylaxis, but do not have the job's syndrome criteria. objetive to determine if allergic patients with ige levels higher than 2000 ui/ml have diagnostic of job's syndrome. material and methods a retrospective revision was realized from may 2001 to april 2004 in files of 27 patients treated in allergy services at the instituto nacional de pediatria with a total ige greater than 2000 ui/ml, by means of a page with recollected dates. results nine women and 18 men were included with an age range of 3 to 18 years, and an average age to 9 years; 22 (81.5%) were diagnosed with allergies; of which 55.6% rhinitis allergy, 51.9% asthma, and 40.7% topical dermatitis of which co-existed in patients. 51.9% presented hereditary antecedents of atopic. the cutaneous tests were positive in 11 (40.7%) with a greater reactivity of dermatophagoids. one syndrome of hyper ige was detected. others diagnosed were found as not allergic were hunter's syndrome and toxocariasis. conclusion there are patients with allergies that have total levels of ige as elevated as 49, 560 ui/ml without correspond to job's syndrome. by which a multi-allergic clinical entity is proposed with levels greater than 2000 ui/ml. introduction home monitoring of lung function in asthmatic patients is used extensively in both clinical and research settings, however, little attention is given to device quality control. objective the purpose of this study was to determine the accuracy, precision and usefulness of the airwatch system (enact health management systems, palo alto, ca, usa). methods the subjects included in this study were submitted to spirometry following american thoracic society guidelines (ats 1995), using collins gs 4g pft system. afterwards, peak expiratory flow rate (pef) and forced expiratory volume in one second (fev1) were determined using airwatch. fev1 and pef measures from both devices were compared, by using two sample t-test and pearson correlation coefficient. results a total of 115 patients (75 females) were enrolled, and their mean age was 43.7 years (9 to 76 years). fev1 measures ranged from 0.54 to 5.81 l (mean 2.43 l), and from 0.62 to 7.44 l (mean 2.51 l), in collins and airwatch, respectively. pef ranged from 107 to 871 l/min (mean 384 l/min) in collins and from 61 to 794 l/min in airwatch (mean 353 l/min). significant difference was noted for pef measures (p< 0.05 and pearson correlation r= 0.61) between the two devices; however, we did not observe this difference when fev1 measures were concerned. regarless the degree of obstruction (high or low flow rates), these results did not change. conclusion airwatch showed great utility for fev1 measures when compared to collins spirometer. although airwatch is able to assess lung function at home, on a daily basis, it is not reliable for pef measures. introduction: epidemiologic data show that poorly controlled asthma is a serious public health problem. the degree of implementation of the naepp guidelines in primary care practice remains to be defined. the objective of this survey was to determine if introduction of an assessment tool into primary care practices along with a specially designed program to implement the guidelines would improve diagnosis and therapy. methods: the asthma care network (acn), a program designed to assist healthcare providers in the assessment and management of their patients with asthma, employs a team of specially trained respiratory care associates (rcas), 100 rns and rts, who visit primary care offices to inform staff about various components of the naepp guidelines and assist in their implementation. .a total of 4901 primary care providers in 2876 sites were recruited as part of the acn program. data from more than 60, 000 patient visits were collected and analyzed between march 2002 and january 2004. the program assessment tool surveyed asthma control and medication prescribing patterns. outcome measures included degree of symptom control, limitation of activity, sleep disruption, use of rescue medication and utilization of urgent care services. these data were collected on an office visit assessment form (ova) completed by both patient and physician. the rcas provided information, education, device training in the use of inhalers and spacers, and a ce course for the staff discussing pathophysiology, assessment and management of asthma. results: a total of 60, 248 ova forms were completed. among all patient including adults (older than 18 years of age) and children (<4-17 years of age), 74% (range 69% to 81%) reported symptoms consistent with lack of asthma control. approximately 70% of the survey group had more than 2 markers of uncontrolled asthma. as a result of this assessment, controller medication use increased by over 30%, 52% of which was an ics-containing medication. conclusion: the information provided to the primary care health care providers resulted in a considerable increase in prescription of controller therapy, and in particular, increased use of ics controller medication consistent with naepp guidelines. background: patients with allergic rhinitis (ar) demonstrate symptoms of allergy to fruits, vegetables and nuts in 48-72% of cases. oral allergy syn-drome (oas), typical for hypersensitivity to plant food, is based on cross-reaction of pollen-allergen specific immunoglobulin e (ige) antibodies with homologous food proteins. the production of th1 and th2 cytokines in allergic rhinitis patients with or without sensitization to food (fruits and vegetables) allergens was assessed. methods: fifty five patients aged 18-38 years with allergic rhinitis were observed. group i -20 patients with ar; group ii -35 patients with ar and oas. sensitivity to pollen allergens was tested by skin prick tests. the allergic reaction to food in patients with oas was proved by a positive history of oral symptoms caused by eating fruits and vegetables and a positive skin prick test with respective food allergens. blood eosinophil counts and total ige levels were determined during the peak of allergic rhinitis symptoms. il-5, il-10 and -interferon levels were measured by elisa. results: 24.5% of patients were sensitized only to grass pollen, 23.3% only to tree pollen and 52.2% reacted to pollens of grasses, trees and weeds. in patients with oas, skin tests were more often positive to birch (57.8%), alder (46.3%), and mugwort (26.7%). the most common food products implicated in oas were hazelnut (69.3%), apple (29.2%), carrot (16.4%), and peanut (12.7%). the allergy to fruits and vegetables was confirmed by positive prick test in 78.4%. during the season blood eosinophil count and total ige levels were elevated in all patients. there was an increase in the production of il-5 to 187.3â±5.4 pcg/ml in group i and to 221.5â±6.2 pcg/ml in group ii (nor-mal=74.3â±3.3 pcg/ml). the levels of il-10 increased to 186â±12 pcg/ml in group i and to 197â±10 pcg/ml in group ii (normal=5.8â±0.25 pcg/ml); the level of -ifn decreased to 287.6â±7.4 pcg/ml in group i and to 272.6â±5.2 in group ii (normal=331â±35 pcg/ml). after sit with pollen allergens the clinical manifestations of allergic rhinitis and oas decreased in 84.6% of patients. conclusion: allergic rhinitis patients' sensitivity to food allergens may cause oas in these patients associated with increased functional activity of th2 responses. patient knowledge and improvement with aller-gen immunotherapy. c.c. randolph * , waterbury, ct. introduction: there is no consensus on objective parameters for improvement in immunotherapy. similarly little is known regarding patient knowledge of immunotherapy. utilizing two published questionnaires (1-2), we assessed clinical improvement based on symptom and medication scoring and knowledge of immunotherapy. methods: the charts of 219 patients of an estimated 530(41%), 109(50%) with allergic rhinitis only and 116 (53%) with concomitant asthma, were retrospectively or prospectively reviewed who had been on immunotherapy to inhalants for 6 months to 6 years, mean 2.7 years, age range 7y-64y, mean 25y, 108 male(49%), 111 female(51%) with 213 caucasian (97%), 2 oriental (1%) and 4(2%) afroamericans .they completed symptom and medication survey (1) every 6 months with range of improvement using a decline in likert scale (+)20 to (-)104, mean 24. 186 (85%) indicated improvement in their symptoms and/or medication .111(50%) completed (2) a 7 question survey of knowledge of immunotherapy. there were 7 questions regarding the outcome of immunotherapy, the years to onset of immunity, the duration until onset of immunity, the danger of immunotherapy and the extract in the vial. the correct responses were recorded to 2/7 (2/111=1.8%), 11(9.9%) 3/7, 19(17%)4/7, 10(9%)5/7, 18(16%)6/7.39(35%) had a perfect response to all questions. 12(11%) had no correct responses. conclusion: the majority of immunotherapy patients improved (85%) by symptom and medication scoring over the mean of 2.7 years but only 35% had complete knowledge of the rationale for immunotherapy. further education and repeated surveying of patients on immunotherapy to assure comprehensive knowledge of immunotherapy and achieve better outcomes is recommended by this investigation. as is unique in this study symptom and medication scoring using the rhinitis /sinusitis questionnaire approved by the acaai and a comprehensive questionnaire assessing knowledge should be conducted periodically ie every 6 months to provide objective parameters for improvement. references: 1.santilli j, nathan r, glassheim j .patient receiving immunotherapy report it is effective as assesses by rhinitis outcomes questionnaire(raq) in private (42)) is a protein involved in the parasite invasion of host erythrocytes and is a leading vaccine candidate for the erythrocyte stage of malaria infection. an increasing number of vaccine clinical trials are being undertaken using various formulations of msp-1(42). comparison of humoral responses among these trials has been limited by the lack of a universal reference standard for specific antibody. the purpose of this study was to develop a human reference standard for msp-1(42) antibody measured in absolute quantity units that could facilitate comparison of interstudy vaccine response. method: we formulated the reference standard by pooling human plasma samples known to contain high titers of msp-1(42) antibody. the specific antibody within the pooled plasma was captured by msp-1(42) adsorbed to nickel resin in a process of immobilized metal affinity chromatography (imac). the intact msp-1(42) antibody-antigen complexes were separated from the nickel resin and total igg in the complexes measured by enzyme-linked immunosorbent assay (elisa). results: our antibody quantitation method yielded a concentration of 48.3 mcg/ml of msp-1(42) antibody in the reference standard. conclusion: the reference standard characterized in this study may be useful as a quantitative working standard for msp-1(42) antibody response in future vaccine clinical trials involving msp-1(42). this standardization may facilitate the clinical development of msp-1(42) as a candidate vaccine for malaria infection. background. specific immunotherapy (sit) is currently one of the most effective and widely used treatment methods of allergic diseases including asthma. efficacy of sit depends on the correct choice of patients, severity of asthma and patient's condition when the sit is begun. according to who recommendations, sit is approved for use in patients with mild to moderate asthma. methods. sit with a saline extract of house dust allergen was administered to 30 patients with mild persistent allergic asthma. injections were performed subcutaneously 2-3 per day. the course consisted of 6766 pnu of allergen and lasted 12-14 days. patients were repeatedly surveyed at 3, 6 and 12 months after sit was completed. dyspnea attacks occurring during daytime and at night were assessed, as was the influence of physical exertion on dyspnea and lung function, and also the number of utilizations of short-acting beta-agonists per day. pulmonary function measurements were performed as was assessment of concomitant allergic rhinitis. 50% of patients received treatment including cromones, and 30% utilized inhaled corticosteroids among whom 13.3% had a dose of 400 mcg per day and 16.7% 200 mcg per day. sit efficacy was assessed by clinical symptoms, pulmonary function measurements and amount of concomitant therapy received. results. the number of daytime dyspnea attacks reduced from 10.70 â± 3.40 per month to 1.20 â± 0.09 during the 3 months following sit, and 76.7% of patients reduced concomitant asthma therapy. at 6 months, dyspnea attacks increased to 2.90 â± 0.75 per month, still significantly less then prior to sit. nocturnal symptoms followed the same pattern, occurring 7.20 â± 1.62 per month prior to sit, 1.01 â± 0.01 per month 3 months after sit and 1.99 â± 0.25 per month at the end of the sixth month after sit. 26.7% of patients had no symptoms of bronchial obstruction during the 6 months after sit and their pulmonary function approached normal values, although 36.7% of patients returned to asthma therapy. nasal congestion decreased from 3.28 â± 1.20 points to 1.98 â± 0.08 (p<0.05), clinical improvement still present for 3 months after sit, but recurring at 6 months after sit. conclusion. sit may be an effective treatment method that improves both asthma and allergic rhinitis for more than 3 months following a brief course, allowing a decrease in the amount of symptomatic treatment. a safe therapeutic vaccine that can alter the allergic response to peanuts would serve a serious unmet medical need. peanut allergy responses are largely associated with downstream events related to antigen specific ige crosslinking of ige receptors and subsequent degranulation of mast cells and basophils. our clinical studies with ragweed have shown that linking immunostimulatory dna (iss) to allergens can decrease ige recognition of the allergen and generate an immunogen that generates protective th1 responses and reduces harmful th2 responses. to test this approach to peanut immunotherapy, we focused on the clinically relevant allergen, ara h 2, as a proof of concept. iss oligonucleotides were linked to ara h 2 at two different ratios: pic (2 iss per protein) and hpic (4 iss per protein). immunogenicity of pic and hpic was evaluated in c3h/hej female mice immunized twice with 5 ug of pic, hpic, or ara h 2. sera were analyzed for anti-ara h 2 igg1 and igg2a responses. spleens were harvested and ara h 2-specific ifng and il-5 responses were measured in vitro. mice were immunized with ara h 2 elicited predominantly igg1 and il-5 responses, indicative of a th2-type response. animals immunized with pic showed significantly enhanced igg2a responses and strong ifng responses, indicative of th1-type responses. hpic immunized mice elicited little antibody response, presumably due to iss blocking b cell epitopes, but did induce ifng responses. to assess allergenicity of pic and hpic, histamine release was measured in blood from peanut allergic donors treated in vitro with pic, hpic, and ara h 2. histamine release was detected at very low concentrations of ara h 2 (0. 01 ng/ml), 10-fold higher concentrations for pic (0.1 ng/ml) and was undetectable at concentrations up to 1000fold higher for hpic (10 ng/ml). an ige binding competition assay also confirmed reduction in allergenicity following the same trend for the iss-linked allergens. linking iss to ara h 2 increases th1 responses to the allergen, blocking ige recognition of epitopes on ara h 2. thus, iss-linked ara h 2 appears to be a promising candidate for a safe immunotherapy product for treating peanut allergic subjects. introduction: immunotherapy has been studied for its adverse effects in some sensitive patients as with worsening of therapeutic response in some amounting to withdrawal of the later. methods: in the allergy center therapeutic trials of immunotherapy(house dust, mixmite) had been undertaken since 1998, in therapeutic dose of 0.02pnu/ml, 0.2pnu/ml, 2pnu/ml, 20pnu/ml, 200pnu/ml2000pnu/ml, 4000pnu/ml(housedust), 0.01au/ml, 0.1au/ml, 1au/ml10au/ml 100au/ml 1000au/ml 2000au/ml(mixmite).patients age 2-65 years, both sex after diagnostic scratch/prick tests with appropriate antigenic preparations reported for local/systemic adverse effects the details of which were as under, results: please see the attached table for details, in some cases worsening of the existing allergic status was noted, which on analysis revealed initially a slow rise in the allergen -specific ige to be later on fol-lowed by rise of igg1 & igg4 & gradual fall of ige.only 1/100 patient could not complete immunotherapy for fear of adverse effects. conclusions: with utmost care/follow-up, no incidence of mortality outcome was reported from 1998to late 2003 the incidence of adverse effects were significantly lowered on pre-medication with anti-histamines significantly more with elderly than younger age. even with all these documented hazards the beneficial effects far exceeded the harmful effects. background: the prevalence of allergic disease in most human population is steadily increasing. seafood allergy is a serious food allergy, although hypersensitive reactions caused by seafood has long been know, biochemical and immunological studies on seafood allergies had only begun lately. shrimp and abalone are the most frequently reported causes early asthmatic response. objective: to investigate cross-reactivity of shrimp, abalone and derp1. methods: shrimp and abalone extracts were prepare from raw seafood. sera from 17 patients from hongkong were studied who had asthma after consumption of seafood. ige elisa analyses comfirmed the combined sensitization to shrimp, abalone and derp1. specific-ige elisa assays were accomplished for shrimp and abalone extracts inhibited by derp1 and derp1 elisa and immunoblot assays inhibited by shrimp and abalone extracts. results: elisa inhibition showed that most ige antibodies against shrimp and abalone were cross-reactive with derp1 and the same time, derp1 elisa was inhibition by shrimp and abalone extract. the elisa inhibition percent (%)of shrimp extract (gm:53.28%) and abalone extract(gm:36.75%) by derp1 were significantly higher than derp1 by shrimp extract(gm:26.64%) and abalone extract (gm:17.59%). (p<0.01). furthermore, and there was a significant correlation of elisa inhibition percent between shrimp extract, abalone extract and derp1 inhibited by each other; sds-page and immunoblot of shrimp and abalone is the 38 and 49kd allergen respectively. conclusion: this indicates that derp1 was the sensitive agent. shrimp, abalone and derp1 demonstrate significant cross-reactivity. these findings confirm that the primary crossreactive allergen of shrimp and abalone is the 38 and 49kd allergen respectively. b. sun 1* , a. wu 2 , n. zhong 1 , 1. guangzhou, china; 2. hong kong. background: the house dust mites (dermatophagoides farinae (derf) are a major source of aeroallergens implicated in the expression of atopic disorders, including asthma, allergic rhinitis, and atopic dermatitis . in particular, strong circumstantial evidence suggests that house dust mites antigens are important precipitating factors of asthma. many house duse mite allergens are proteases that can elicit airway inflammation by stimulating the release of cytokines in bronchial epithelial cells. objectives: we have investigated whether der f allergen proteases induced cytokine production from the epithelial cell line beas-2b. methods: cells were exposed to four different concentrations with serial additions of der f (0.02, 0.2, 2, 20ug/ml) were incubated for 24h to 96h. and compare with those without incubation of allergen. cytokine in the supernatants were assayed by elisa, reverse transcription?pcr was also performed. results: cells treated with der f allergen showed serial changes in the cohesiveness of the monolayer. there was a significant increase in the level of cytokine production compared with the untreaed sample. statistically significantly increased with addition of der f caused the release of il-6 and il-8 in time and concentration-dependent manner (p<0.05, respectively). levels of il-6 and il-8 were elevated 24 h and 48 h after allergen exposure, increasing with time, continued increased levels to be present of il-6 and il-8 in the supernatants at 72 h and 96 h. at the same time show the concentration dependence of induction of il-6 and il-8 expression as well as an increase in the expression of il-6 and il-8mrna. conclusion: hdm-induced airway inflammation may include der f-mediated release of inflammatory mediators, and the proteolytic activity of an allergen may stimulate the release of proinflammatory cytokines from human bronchial epithelium. suggesting that il-6 and il-8 production by bronchial epithelial cells may play a role in the pathogenesis of allergic asthma. the purpose of this study is to delineate the immune injury mechanisms that involved in the autoimmune inner ear disease by introducing plasmid dna encoding of th1 cytokines (inf-g) into the inner ear. b-tubulin is a microtubular protein which we found as an important autoantigenic in meniere's disease as well as other autoimmune hearing loss. hearing loss was induced in mice and guinea pigs when they are immunized with the tubulin molecules. autoimmune hearing loss could be the results of th1 cytokine responses from autoimmune injury. to test the hypothesis, guinea pigs were immunized with 200mg of tubulin in cfa and boosted once more. two weeks later, we introduced 100ug (5ul) of naked dna encoding inf-g was injected into the left side inner ear through round window. same volume of 0.1m pbs was injected into right side as control. abr was recorded before and after the injection. 15 weeks after the injection, the animals were sacrificed and temporal bones were examined with h-e and inf-g immunocytochemical staining. the ears injected with the plasmid dna-inf-g had an enhanced hearing loss (30 db), and degeneration of the spiral ganglion was found in these ears. however, the injection of the naked dna encoding inf-g did not change the expression of the inf-g in the inner ears. these results suggest that autoimmune hearing loss could be the result of th1 responses to inner ear autoantigens. -tubulin is an important molecule in the hair cells supporting cells within the sensory epithelium of organ of corti and found to be an auto autoantigen in autoimmune hearing loss including mã¨niã©re's disease. the object of the study is to induce hearing loss in mice with varying doses of antigen and evaluate the pathogenesis of autoimmune hearing loss induced by -tubulin in mice. mice were immunized with 100, 200 or 300 î¼g of -tubulin and hearing was evaluated by auditory brainstem responses (abr) and distortion product of otoaccoustic emission (dpoae). all mice had hearing loss by abr and dpoae tests and morphological study of temporal bone showed spiral ganglion degeneration and tunel staining positive cells were noted in these immunized mice. thus this study showed that -tubulin is an autoantigen for hearing loss in animal model as in human autoimmune hearing loss patients including mã¨niã©re's disease. supported by nih r0dc005010-01 introduction: oral polio vaccination (opv) in the united states is currently being replaced with inactivated polio vaccination (ipv) given parentrally. while past studies have looked into the relationship of vaccination and asthma prevalence, none have investigated this relationship with regards to vaccination route namely orally versus parentrally. this study investigates the relationship between vaccination rates for the live attenuated orally administered polio vaccine and parentrally administered vaccines(dtp, mmr)and two potentially dependent factors; asthma prevalence rate and asthma-caused death rate. methods: we looked at data from the national center for health statistics yearly publications of health, united states (1983 -1999 and the morbidity and mortality weekly report surveillance summaries . two databases were compiled to cover the 0-4 age population in the united states since this is the primary period of childhood vaccination. one database contained information for asthma related deaths and vaccination rate (dtp, mmr, opv) covering the years 1970-1999 and the other database compiled information for self reported asthma prevalence and vaccination rates(dtp, measles, rubella, opv) covering the period 1983-1999. a t-test was used for statistical analysis. results: statistically significant correlation was found between vaccination rates and asthma prevalence rates. data for dtp (p = 0.012), measles (p = 0.024), and rubella (p = 0.023) indicated a statistically significant positive correlation with asthma prevalence. the oral polio vaccine was the only one of the vaccines that failed to display a significant relationship with asthma prevalence rates (p = 0.133). statistical analysis proved that a correlation between vaccination rates of united states children ages 0-4 and asthma-caused deaths was insignificant (p > 0.05). conclusions: the opv, which is administered orally rather than parentrally, displayed no relationship with asthma prevalence. this could be due to the fact that live attenuated orally administrated polio vaccine may induce mucosal immunity, simulating a normal pathogen route of entry into the body. childhood vaccination had no relationship with asthma-caused death rates. a.s. alfrayh * , riyadh, saudi arabia. introduction: heredity plays a major role in asthma and other allergic diseases, mechanisms underlying the inheritance of these disorders are poorly understood. this study therefore analyzed the risk conferred by family history of asthma and atopy for having childhood asthma. methods : a total of 1601 children between 1-16 yrs selected randomly in three cities in saudi arabia ( hail, taif and gizan )in 1995-1996 . the questionnaire which is similar to the one used in the international study of allergy and asthma in childhood isaac. were self administerd under medical supervision.apart from the demogrphic details, the questionnaire included questions on symptoms and physician diagnosis of asthma, rhinitis, eczema and family history of these conditions. the family members were grouped as immediate family and relatives. asthma and atopy were defined as ever having had physician diagnosis of such conditions information was also available about exposure to cigarette somke at least one member was a smoker in the household and having pets. relative risk for developing asthma was estimated in terms of odds ratio by bivariate analyses using chi square test and p value was considered significant when less than 0.05. results : history of asthma in the immediate family and relatives conferred a 4 fold and 3 fold risk for development of childhood asthma odd ratio ( or )=4.2, 95% confidence interval(ci)=3.3 to 5.5, p=0.00001 and or=3.3, 95%ci=2.5 to 4.3, p=0.00001 respectively. rhinitis in immediate family and the relatives was associated with 3 folds increased risk for childhood asthma or = 3.0, 95% ci = 2.2 to 4.0, p=0.0001 respectively whereas history of eczema conferred over 3 folds risk or=3.4, 95% ci = 2.4 to 4.7, p=0.00001 for childhood asthma when present only in the immediate family. history of eczema in relatives was not associated with any risk. of the environmental factors, exposure to cigarette smoke conferred 2 folds risk of developing childhood asthma or = 2.6, 95% ci = 2.0 to 3.3, p= 0.0001, whereas exposure to pets was not a significant risk foctor. conclusion : presence of asthma and atopy either in the biological parents or relatives constitute a significant risk for childhood asthma.paricularly in the presence of evironmental risk factors. the murine local lymph node assay (llna) has been developed as an alternative to guinea pig models for the assessment of the contact sensitization potential. however, there is a need to develop a non-radioisotopic endpoint for the llna, because of the radioisotopic method's requiring the use of special facilities. in this study, we investigated to evaluate the lymphocyte subpopulations in the lymph node cells following allergen and irritant treatment. female balb/c mice were treated by the topical application on the dorsum of both ears with sensitizers, 2, 4-dinitrochlorobenzene (dncb), toluene diisocyanate (tdi), and a-hexylcinnamaldehyde (hca), and an irritant, sodium lauryl sulfate (sls), once daily for three consecutive days. the lymph node (ln) cells were harvested 72h after the final treatment. phenotypic analysis of lymphocytes subsets was performed with a flow cytometry. the allergens dncb, tdi, and hca and an irritant, sls increased cell number compared to the vehicle. there was an increase in the percentage of b220+ cells in mice treated with dncb and tdi compared to the vehicle control, but not in those treated with sls. mice were treated with dncb, hca and tdi showed a preferential increase in the percentage of b220+cd40+ cells compared with vehicle and irritant-treated mice. there was an increase in b220+cd86+ cells of mice treated with dncb, tdi and hca, but no significant increases were observed in mice treated with sls. mice were treated with dncb, and tdi showed an increase in the percentage of b220+cd23+ cells compared with vehicle and irritant-treated mice. these results suggest that analysis of b cell activation marker, cd40 on b cells may be useful in differentiating allergen and irritant responses in the draining lymph nodes of chemically treated mice. m. frieri * , y.c. huang, east meadow, ny. introduction: nitric oxide (no) is an important biomarker for inflammation in airway epithelial cells and in exhaled breath of asthmatic subjects. we have previously demonstrated no production in antigen-stimulated human bronchial epithelial cells and an effect of omalizumab (monoclonal anti-ige antibody) on no production in those cells [leyko bt et al. j allergy clin immunol 2004; 113(suppl 193) :a668]. in this study, we investigated the potential role of ige and its receptors on a549 cells by characterizing the effect of omalizumab on antigen, egf, and il-1 stimulation of a549 cells in a medium containing atopic serum. methods: a549 human alveolar epithelial cells were stimulated with 100 iu/ml of il-1 , 10 î¼g/ml of ragweed (ra), 1000 au of dust mite (dm), and 40 ng/ml of egf, and exposed to either 10 -7 m budesonide or 0.1 î¼g/ml omalizumab for 6 or 24 hours. no production was measured in duplicate by a highly sensitive elisa. results: omalizumab but not budesonide inhibited no production at 6 hours in a549 cells stimulated with il-1 (17-13î¼m, p<.05)and il-1 +dm (18-14î¼m, p=.08), but not with ra alone. however, at 24 hours omalizumab and budesonide each significantly inhibited no production stimulated by il-1 (29-9î¼m; 29-17î¼m), il-1 +dm (22-12î¼m; 20-14î¼m), and egf (17-9î¼m; 17-13î¼m) (p<.05). conclusion: no production is a marker for inflammation. omalizumab demonstrated a significant anti-inflammatory effect in distal alveolar cells by inhibiting no production stimulated by antigen, il-1 , and egf in a medium containing atopic serum. as persistent inflammation in asthma may play a role in airway remodeling, treatment with omalizumab may have a beneficial effect on chronic airway inflammation in patients with asthma. oral tolerance trigger regulatory mechanisms able to down-modulate antigen-specific t and b cell response. to address the lasting effect of several regimens of oral tolerance to ovalbumin, in naive or antigen primed mice, b-cell function has been focused. furthermore, we analyze specific antibody response up to eight months of post-immunization, proliferative response, b7 (cd80/cd86) expression on b cells and t cell ctla-4 involvement in oral tolerance. a/sn mice were immunized by intraperitoneal route with 50î¼g of ova/0, 1 mg-alum and boost 10 days after priming (dap). ova feeding was done with 25mg at different days before or after antigen priming. in others protocols, mice were fed twice, before and after priming with a total of 50mg of ova. all groups were boosted at 60 or 120 or 180 or 240 dap. the results showed that only mice fed at naive status and those fed twice before and after immunization demonstrated a long lasting of ige ab response inhibition up to 8 months of immunization. these mice showed a marked inhibition of antigen-specific proliferative response that was restored with anti-cd28 mab in vitro stimulation. evaluation by flow cytometry of spleen cells cultured for 48 hours upon ova stimulation, showed an important decrease of b 7.2 expres-sion on b cells of naive fed mice, which remained inhibited until 8 months of immunization. after addition of anti-ctla-4 mab an enhancement of b7.2 expression was detected on b cells of naive fed mice. ctla-4 molecules expression on cd4+ t cells of naive fed mice remained unchanged following ova stimulation while a peak of expression was detected at 96h of ova stimulation in control group. this finding reinforce the t cell anergic status of naive fed mice, due to the less cell division and consequently a low rate of cd4+/cd44high activated cells. the results showed that antigen feeding before immunization induce a long lasting anergy mediated by an impaired t-b cell cooperation and ab production due to the decrease of costimulatory molecules expression on b cells and negative signaling effects by ctla-4 expression. introduction: vascular endothelial growth factor (vegf), basic fibroblast growth factor (bfgf) and fibronectin (fn) can promote angiogenesis, a putative component of airway remodeling. (s)-albuterol can exacerbate airway hyperresponsiveness, bronchospasm and release pro-inflammatory cytokines from small airway and smooth muscle cells. our study evaluated the effects of (s)-albuterol ((s))-and (r)-albuterol ((r)) on secretion of these factors on normal human lung fibroblasts (nhlf) and myofibroblasts (myonhlf) in the presence or absence of tgf 2, il-1 , or allergens. methods: nhlf were stimulated to differentiate to myonhlf with 1000 pg/ml tgf . dose-dependent effects of (s) and (r) [10 -8 to 10 -4 m] were evaluated for secretion of vegf, bfgf and fn by nhlf and myonhlf with and without 1000 au/ml d. pteronyssinus (dp), 1000 pnu/ml ragweed (ra), 100 u/ml il-1 , or 1000 pg/ml tgf 2 into serum-free media (its) at 37 o c with 5% co 2 collected at 24 hr and assayed by elisa. results: in nhlf the following was observed: vegf secretion was 2-fold higher with 10 -7 m (r) relative to (s), p<0.05; bfgf secretion was increased 50%-100% by 10 -5 m (s) relative to (r), p<0.05. a lower concentration of (s) (10 -6 m) in the presence of either dp or il-1 caused a 2-fold increase in secretion of bfgf relative to (r), p=0.02. in the presence of myonhlf the following was observed: 10 -7 and 10 -5 m (s) caused a 50%-100% increase in secretion of fn relative to (r). at 10 -7 m (s), this effect was further increased with the addition of il-1 , p=0.022). conclusion: in a dose-dependent manner, (s)-albuterol stimulated the release of bfgf and fn by nhlf and myonhlf, respectively. this was enhanced by dust mite and/or il-1 , potentially contributing to the matrix remodeling observed in chronic asthma. vegf over-expression can have a protective effect against chronic hypoxia and can recruit immune cells to the alveoli. increased vegf by (r)-albuterol could contribute to such an effect in vivo in asthmatics. bfgf, in bal and sputum of asthmatics, and fn which contributes to subepithelial fibrosis, can promote angiogenesis. increased bfgf and fn by (s)-albuterol could be detrimental over time by enhancing matrix deposition and remodeling in a subset of asthmatics. o. ozdemir 1* , c. moore 2 , y. ravindranath 1 , s. savasan 1 , 1. detroit, mi; 2. new orleans, la. background: mast cells (mc) have been shown to demonstrate natural cytotoxicity against mouse fibrosarcoma cell line in culture when incubated for 24-48h. this effect has been postulated to be mediated through soluble and/or membranous tnf-. more recently; fasl, mc chymase and serine protease granzyme h with its chymase activity were proposed as mediators of mast cell-mediated cytotoxicity. thus, both 'granule-exocytosis' through chymase, granzyme h and soluble tnf-and 'death receptors' through membrane-bound tnf-and fasl pathways appear to be operative in this process. aims: following our earlier observations on long-term liquid culture-grown human bone marrow mast cell cytotoxicity against human leukemia cells in 24-48h co-incubation experiments, we investigated mast cell-mediated cytotoxicity against natural killer/lymphokine-activated killer cell-sensitive cells in short term (12h) cultures without any stimulation for the first time. methods: human bone marrow mononuclear cells were cultured in methyl cellulose supported with il-3, il-6 and scf. mast cell colonies that developed in six weeks were transferred to liquid medium and maintained for 18 weeks before experiments. cytotoxicity was investigated against k562, raji and daudi cells at 12, 24 and 48 hours of co-incubation by our established flow cytometric cell-mediated cytotoxicity assay. results: after 12h co-incubation, 61% (11% early apoptotic and 50% late apoptotic or necrotic death) and 29% (21% early apoptotic and 8 % late apoptotic or necrotic death) target cell kill was demonstrated in daudi and raji cells, respectively. daudi cell killing has stayed stable at 24h (67%; 27% early apoptotic and 40% late apoptotic). despite a small numbers of experiments, daudi cell kill was statistically significant at 12h (p:0.011) and 24h (p:0.011) compared to control. however, k562 cell elimination (18%) has not occurred until 48h. mast cell-daudi cell conjugates were seen on the wright/giemsa slides (figure) . conclusion: our results demonstrate that human mc can cause cell-mediated cytotoxicity against certain cells in relatively short-term. this further suggests possible contribution of 'granule-exocytosis' pathway to mc natural cytotoxicity, indicating a faster mc response in immune surveillance. o. ozdemir 1* , m. buyukavci 2 , y. ravindranath 1 , s. savasan 1 , 1. detroit, mi; 2. erzurum, turkey. background: the effect of melatonin (mlt) on cellular immunity has been controversial. recently, mlt has been demonstrated to activate t and nk cells through its membrane or nuclear high affinity receptors. it was also shown that pharmacological concentrations of mlt (>nm) could be cytotoxic against different human cancers. aims: our aim was to investigate the effect of mlt alone or in combination with il-2 on peripheral blood lymphocytes (pbl), lymphokine activated killer (lak) cell generation and its cytotoxicity. methods: pbl were cultured for 7 days in the presence of mlt at different concentrations (10 -3 , 10 -5 , 10 -7 m) with or without il-2 (100 u/ml). cell viability was determined by trypan blue exclusion test. cell-mediated cytotoxicity of lymphocytes/lak cells against k-562 and daudi cells was studied using our established flow cytometric cell-mediated cytotoxicity assay. results: although 10 -3 m concentration of mlt did not affect cell proliferation much on day 3, it significantly inhibited proliferation by day 7 (p<0.05) consistent with known anti-proliferative effect of mlt. 10 -5 and 10 -7 m concentration of mlt also mildly inhibited proliferation on day 3; however there was a minimal rebound with 10 -7 m concentration by day 7. consistent with the reported mlt-treated pbl's reduced response to mitogens, il-2 and mlt (10 -3 m) combination suppressed proliferation on days 3 and 7; however, with 10 -5 m mlt concentration pbl counts increased gradually from day 3 to 7. although mlt treatment alone did not enhance cell-mediated cytotoxicity, il-2 and mlt combinational treatment at both concentrations (10 -3 and 10 -5 m) increased it significantly compared to baseline activity (figure) . conclusion: il-2 and mlt combination at 10 -5 m concentration resulted in superior lymphocyte proliferation and lak cell-mediated leukemia cell kill. mlt-induced increase in il-2r-expression of pbl shown earlier might be the mechanism for our observations. mlt can be considered in immunotherapy as an adjunct to il-2 treatment. a.e. fusaro * , j.r. victor, c.r. oliveira, c.a. brito, e.a. futata, m. maciel, a.j. duarte, m.n. sato, sã£o paulo, brazil. the maternal exposure to allergens during pregnancy or even in postnatal period may influence the allergy onset to newborns, through antigen or antibody transmission. we sought to verify the effect of maternal antigen exposure before conception, during gestation or in the breastfeeding period on the offspring type i hypersensitivity response. female balb/c mice were immunized or not with ova extract/alum, boosted twice at 10th and 20 th and mated with normal balb/c male on the 21th day after sensitization (das). others groups of immunized mothers also received oral administration with ova along pregnancy, or non-immunized mothers received ova only during breastfeeding. offspring from immunized or normal mice were immunized intraperitoneally with ova at 25 do and boosted on the 10th das. the results showed a important decreased of tgf-levels in the amniotic fluid and milk from immunized mothers before mating in comparison to obtained from normal mothers. ova exposure during pregnancy of immunized mothers decrease significantly the transference of tgf-by breastfeeding, while both tgf-isoforms were founded at high levels in the amniotic fluid. similar levels of tgf-transference by placenta to the newborn was detected in both immunized mother groups. pups from mothers exposed with ag during pregnancy showed an increased spleen cell number, whereas did not produced il-2, il-4, il-10 e ifn-secretion induced by antigen neither altered responsiveness to anti-cd3 or mitogen. maternal ova-immunization induced a marked inhibition of spe-cific ige antibody response in the immunized pups, contrasting to the enhancement of ige responsiveness detected in the immunized pups from mothers which were exposed to ova only at postnatal period. these results showed that preconceptional immunization exert a protective effect on the offspring ige development and an exacerbation of ige responsiveness due to mother antigen exposure during breastfeeding. the findings suggest that rather than in utero antigen priming occurrence, postnatal period may contribute to offspring early life sensitization. financial support: fapesp and lim56-fmusp introduction: the reasons for the increased incidence of allergic diseases in westernized countries are still unknown. mercury is an important pollution factor to which humans are increasingly exposed. prior studies on the effect of mercury on mitogen stimulated human lymphocytes indicated a th2weighted immune response, but the results were inconsistent and difficult to reproduce. phorbol myristate acetate (pma) is a direct activator of protein kinase c, which has been shown to play a role in mercury induced il-4 production in animals. therefore we investigated the effect of mercury on pmaactivated human peripheral blood mononuclear cells (pbmc). methods: pbmc from 8 individuals were cultured for 4 days in culture medium containing pma and ionomycin in the presence or absence of mercuric chloride (hgcl2). il-4 and gamma-ifn concentrations were measured by elisa of culture supernatants. cell death and apoptosis were determined by 7-aad and annexin staining and fluorescence activated cell sorting (facs). cell-proliferation was assessed by 3h-thymidin-incorporation. results: after 4 days of culture, pma/ionomycin-stimulated a small amount of il-4 compared to untreated pbmc (1.7 +/-0.92 pg/ml versus 0.36 +/-1.0 pg/ml). however, mercury induced a more than 30 fold increase in il-4 production when added to pma-activated cells (57.4 +/-45.2 pg/ml, p<0.01). gamma ifn production was strongly increased in pbmc that were treated with pma/ionomycin (>3500 pg/ml versus 417 +/-1045 pg/ml in unstimulated cells) but dropped markedly in cells treated with mercury plus pma/ionomycin. in addition, mercury induced increased cell death, apoptosis and reduced cell proliferation. conclusions: hgcl2 strongly stimulates il-4 production in pma/ionomycin treated pbmc while cell viability and gamma-ifn production drop significantly. these preliminary results suggest that human exposure to mercury may be playing a role in the observed increased incidence of allergic disease in the industrialized world background: mast cells (mc) have been shown to induce natural cellmediated cytotoxicity in long-term (24-48 hrs.) in vitro assay systems. the cytotoxicity is mediated by at least two pathways: secretory via exocytosis of mc granules containing serine proteases such as granzymes, chymase and soluble tnf-and nonsecretory (cell-to-cell contact) via membranous tnfand fasl. chymase induces apoptosis in neonatal rat cardiomyocytes and human vascular smooth muscle cells. the objective of this study was to investigate mc mediated cytotoxicity against nk/lak-sensitive cells in short term (12 hrs.) unstimulated cultures. methods: human bone marrow mononuclear cells were cultured in methylcellulose supported with il-3, il-6, and stem cell factor. mast cell colonies developed at 6 weeks and were transferred to liquid imdm and maintained for 18 weeks. a flow cytometric cytotoxicity assay was used to determine cytotoxicity against daudi, raji, and k562 cell lines at 12 hrs., 24 hrs., and 48 hours. the controls consisted of cell lines without mast cells at 12 hrs., 24 hrs., and 48 hours. results: rationale: to establish the antibody response rate in children with recurrent infections and fully immunized with the pneumococcal 7-valent conjugate vaccine. methods: we have analyzed 39 patients referred to our clinic with recurrent infections despite complete immunization with the pneumococcal 7-valent conjugate vaccine for age, according to acip guidelines. we assessed the patients by checking their immunization status and the antibody titers to all 7 streptococcus pneumoniae serotypes included in the vaccine (4, 6b, 9v, 14, 18c, 19f, 23f) assessed by standardized elisa. the patients were assembled into 3 groups, a non-immunized group with laboratory data prior to the vaccine, and an immunized group consisting of responders and nonresponders according to their antibody titer (<1.3 or >1.3 iu/ml respectively). the data were analyzed using epi info and spss. results: the mean age was 3.3 years for non-responders and 3.8 years for responders. there was no significant statistical difference between the groups regarding age, race and sex. ten patients were identified who failed to respond to all 7 serotypes included in the pneumococcal 7-valent conjugate vaccine. there was no significant statistical difference between the non-immunized and the immunized nonresponders to all 7 serotypes. conclusions: we have identified a special immunological phenotype of specific antibody deficiency (sad) patients with normal total immunoglobulins and normal responses to protein antigens, but who failed to respond to conjugate pneumococcal polysaccharides. a. yates 1* , r. deshazo 1 , j. butler 1 , g. howell 1 , j. farley 1 , h. liu 1 , n. nanayakkura 2 , g.b.yi 1 , r. rockhold 1 , 1. jackson, ms; 2. oxford, ms. introduction: venom from s. invicta consists of 95% disubstituted piperidine alkaloids and is toxic to insects, birds and farm animals. recent reports of morbidity and mortality in elderly patients after massive fire ant stings suggest the potential for systemic mammalian toxicity. we evaluated the toxic responses to systemic administration of two structurally verified, synthetic s. invicta venom alkaloids, solenopsin a (trans-2-methyl-6-n-undecylpiperidine) and its cis-isomer, isosolenopsin a, in rats. methods: sprague dawley rats were anesthetized with isoflurane, paralyzed with gallamine, artificially ventilated and instrumented to record arterial blood pressure (bp; mm hg), heart rate (hr; bpm) and % change in left ventricular contractility (lvc; p/ t). in addition, a group of rats was chronically instrumented to record bp and hr while the animals were conscious and freely-moving. results: solenopsin a at 3 to 30 mg/kg iv dose-dependently lowered bp, hr and lvc. at 30 mg/kg iv, hypotension (-40â±12 mmhg), bradycardia (-27â±8 bpm) and decreased lvc (-41â±17 p/ t) were marked. isosolenopsin a, 15 mg/kg iv, produced responses similar to solenopsin a 15 mg/kg iv. solenopsin a 30 mg/kg iv elicited tonic-clonic convulsions and respiratory arrest in conscious, freely-moving rats. hematuria was seen with solenopsin a, but not isosolenopsin a. superfusion of a working, isolated, perfused rat heart with 10 um of solenopsin a elicited a marked, reversible decrease in lvc, and cardiac arrest occurred with 100 um of solenopsin a. conclusion: the results demonstrate that these alkaloids possess significant depressant activity on the cardiac and respiratory systems of rats. the neurologic and cardiorespiratory effects can account for lethality to small mammals in the wild, and may contribute to adverse cardiovascular effects noted in humans after massive fire ant stings. introduction: during asthma attacks, the ph of exhaled breath condensate (ebc) decreases two log orders (ph=5.0), returning to normal levels after corticosteroid therapy (ph=7.0). ion channels, once thought to participate only in the transport of ions, are now suspected of mediating airway inflammation in asthma as well. to determine whether allergen directly alters airway mucosal ph and ion function, we measured nasal ph and nasal potential difference (pd) before and after nasal allergen challenge (nac). methods: ten allergic rhinitic subjects (meanâ±sem age 28.3 yearsâ±2.9, 7 females) underwent a crossover, single-blinded, placebo-controlled study, where they were challenged with allergen (dust mite, grass, cat) and control diluent in two different occasions in random order via nasal spray. nasal ph was measured on the surface of nasal mucosa with a ph probe. nasal mucosa pd was measured between nasal mucosa and forearm skin. subjects also filled out a nasal symptom scale. measurements were taken at baseline, 1 hour, 4 hours, and 24 hours after nac. results: the nasal symptom score increased significantly immediately after allergen compared to control challenge (13.0â±2.4 vs. 3.7â±1.1 respectively, p=0.003). there were no statistically significant differences in the nasal ph at 1h and 4h, but a significant decrease at 24h compared with baseline (-0.2â±0.1 vs. +0.14â±0.1, p=0.02). the change in ph from 0h to 24h correlated significantly and inversely with change in symptoms (r=-0.59, p=0.007) and number of sneezes (r=-0.65, p=0.002) after challenges. nasal pd did not change significantly after challenges. conclusion: allergen decreases nasal mucosal ph in the very late phase after challenge in allergic rhinitic subjects. decrease in airway mucosal ph during asthma exacerbations may be caused by aggravation of allergic inflammation. nasal potential difference does not change after allergen challenge. funding: niaid, acaai foundation introduction: uv induces differentiation of t-and b-lymphocytes, suppresses natural killer cells, renders a tolerogenic effect and induces apoptosis resulting in local and system immunosuppression. methods: lymphocytes were studied using indirect immunofluorescence methods employing monoclonal antibodies to cd-markers cd4, cd8, cd16, cd25, cd95, hla-i, and hla-ii, from the blood of 14 volunteers (aged 18-24 years) before uv exposure (control), after an exposure of blood in vitro to a dose 1.12 kj, and after 24 hours of exposure of the medial surface of the elbow joint in vivo (s=200 cm2), to a dose of 1.12 kj. results: the direct exposure of blood results in a significant reduction in the number of lymphocytes, probably due to direct phototoxic effects. significant modifications both of the aggregate number of lymphocytes and amount of t-helpers after uv exposure of the skin were not seen. after uv the number of cells which express the marker cd8 is sig-nificantly increased. exposure to uv in vitro induces reduced number of cells bearing cd16. however on in vivo exposure, a significant increase in number of cells which express cd16 was observed. uv exposure of blood reduced significantly the hla-i (9.67â±0.72 reduced to 0.32â±0.54) and hla-ii (dr) (21.56â±1.19 reduced to 18.45â±1.15) expression. uv exposure of skin increased significantly hla-i to 11.56â±0.81, while hla-ii (dr) was insignificantly decreased to 20.65â±2.01. cd95 expression increased from 22.43â±1.12 to 25.95â±1.08 due to blood uv exposure, while there were insignificant reductions in cd4 (39.33â±2.14 reduced to 36.62â±2.34) and cd8 (36.50â±2.03 reduced to 25.75â±2.74) expression. conclusion: uv starts a cascade-like response, including apoptosis, leading to changes in nk cell, helper and suppression lymphocyte numbers consistent with an immunomodulating effect of uv radiation. background: previous investigations have shown the involvement of histamine and histamine receptors (h 1 , h 2 , h 3 , h 4 ) in ige synthesis in atopic and lymphoproliferative diseases. ige responses may depend on the concentrations of histamine and histamine receptor antagonists and agonists. the goal of this investigation was to evaluate the role of the concentration of histamine and h 3 /h 4 antagonists along with the importance of pre-existing levels of ige in determining ige responses. methods: ige synthesis was studied in mnc cultures of patients (7-14 years old) having mild atopic asthma and rhinitis. all patients had high levels of total ige and specific ige to ragweed pollen, house dust mite, epidermal or mold allergens. patients were divided into two groups according to the serum ige and levels of spontaneous ige synthesis: group a -with low levels (4.8â±1.2 iu/ml) and group b -with high levels (9.7â±1.4 iu/ml). the serum level of total ige in group a was 426.1â±24.3 iu/ml and in group b was 570.2â±26.5 iu/ml. fub 181 hydrogenmaleate was used as an h 3 /h 4 specific antagonist. results: histamine in high concentrations (10 -5 m) suppressed and in low concentrations (10 -8 m) stimulated spontaneous ige synthesis. the h 3 /h 4 antagonist fub 181 activity depends on the pre-existing levels of ige. in high concentrations (10 -5 m), the antagonist increased ige synthesis only in group a, but not in group b having high spontaneous levels of ige synthesis. the synthesis in group a increased 1.36 fold (p<0.001), but h 3 /h 4 blockade cancelled the ige suppressive effect of high concentrations of histamine (10 -5 m). the addition of histamine into the mnc culture stimulated ige synthesis 1.56 fold. fub 181 had no effect on ige-stimulatory effects of low concentrations of histamine (10 -8 m). in allergen (ragweed)-stimulated mnc culture, fub 181 had a co-stimulatory effect on ige synthesis induced by histamine. conclusions: the ige stimulating response depends on the concentrations of histamine and the h 3 /h 4 antagonist as well as pre-existing levels of serum ige and ige spontaneous synthesis. introduction: preliminary data has shown that oral contraceptives can precipitate or worsen attacks of hereditary angioedema (hae). it is thought that estrogens affect the synthesis and degradation of bradykinin with resulting edema. objective: our objective is to determine if there is a difference among the various oral hormonal preparations, namely, combined monophasic, combined multiphasic, progesterone only, and hormone replacement therapy, in regards to their effect on frequency of hae exacerbations. methods: patients in this study consisted of women over the age of 18 diagnosed with hae who receive their care at our institution and women meeting the same criteria who are active in the hae foundation and have access to this association's web page. all patients answered a sixteen item questionnaire about past or present birth control pill or hormone replacement therapy usage and its impact on the frequency of exacerbations. results: of the patients who completed the questionnaire, 94% had taken or were currently taking oral contraceptive pills or hormone replacement therapy. of the women whom had taken monophasic birth control pills, 100% worsened with increased number and severity of exacerbations. however, only 75% of the women that had used combined multiphasic birth control pills worsened. all of the women who had tried progesterone only birth control pills worsened. of those on isolated estrogen for hormone replacement, 67% had an increased number of exacerbations. when androgens were used concurrently with oral contraceptive pills or hormone replacement therapy, exacerbations decreased to 60%. conclusion: we are not able to demonstrate a statistical benefit of one oral contraceptive pill preparation over another because of our sample size. however, our preliminary data supports that the oral contraceptive pill which produces less exacerbations and less symptoms is a combined multiphasic pill with concurrent androgen treatment. introduction atopic dermatitis (ad) is associated with multiple immunological abnormalities including imbalances in the subsets of blood circulating lymphocytes forming cellular infiltrates in inflamed skin. many studies of the functional and phenotypic properties of lymphocytes in ad have been limited to either peripheral blood or skin-infiltrating lymphocytes. the purpose of our study was to evaluate and compare the content and phenotypic properties of cd4+ lymphocytes from blood and inflamed skin of ad patients. materials and methods 15 adult (age 18-43 years) patients with chronic ad were selected by the criteria of hanifin. all patients gave written informed consent. the cd4+ lymphocytes of peripheral blood were phenotyped by flow cytometry. skin biopsies were obtained from eczematous areas, then cryosected and double immuno-histochemistry was performed. for phenotyping of lymphocytes in blood and skin a panel of monoclonal antibodies was used including cd3, cd4, cd8, cd25, hla-dr and cla. results immunophenotype analyses of the peripheral blood lymphocytes showed a predominance of cd3+cd4+ cells (86%â±21.3). most cells were cd4+hla-dr+ (14%â±12.6) and cd4+cd25+ phenotype (26%â±13.5). double immunohistochemistry of the skin biopsies revealed in the epidermis rare but constant presence of cd4+cd25+cells (1.0â±6.4 cells/mm 2 ) and cd4+hla-dr+ cells (1.2â±1.3 cells/mm 2 ). in the dermal inflammatory infiltrates the predominant cells were cd4+cd25+ (21.0â±9.7 cells/mm 2 ) and cd4+hla-dr+ (45.0â±6.7 cells/mm 2 ). the dominant inflammatory infiltrate consisted of cd4+cla+ phenotype (62.9â±23.5 cells/mm 2 ) cells. conclusion in ad skin inflammation is associated with the appearance in the circulation of cd4+ lymphocytes in activated form (cd4+hla-dr+) and lymphocytes with regulatory properties (cd4+cd25+). these lymphocytes are recruited from the circulation, having the skin homing properties (cd4+cla+), and form the main constituent of the dermal inflammatory infiltrate. contact dermatitis (cd) comprises a spectrum of inflammatory skin reactions usually caused by exposure to non-immunogenic low molecular weight substances (haptens). failure to diagnose the condition may result in a chronic and disabling condition with impaired quality of life. a 28 yr-old white male presented with a severe, symmetrically distributed facial maculopapular rash with secondary excoriated lesions. prior to the appearance of the rash, the patient had been applying lubriderm as a skin moisturizer for dry skin. a standardized thin layer rapid use epicutaneous (true) test containing 23 chemical agents suspended in a vehicle and attached to an adhesive backing was applied to the patient's back. at 48 hrs, a positive reaction was observed at the skin site of the paraben mix application. the lubriderm preparation used by the patient contained paraben, in contrast to a newer preparation, advanced therapy lubriderm, which is paraben-free. complete resolution of the facial lesions occurred following discontinuation of the lubriderm and the use of oral and topical corticosteroid therapy. this case report illustrates how a commonly used moisturizer can contain a sensitizing agent that could be detected by standardized patch testing which should be a part of the diagnostic armamentarium of every allergist-immunologist. we report how a commonly used and effective moisturizer (lubriderm) can cause severe allergic cd and that the use of a standardized thin layer rapid use epicutaneous (true) patch test panel can be an effective diagnostic tool for the detection of the offending agent. rationale: this study aimed to establish the possible differences of cutaneous sensitization to common aeroallergens in children under 1 years old. methods:the study was conducted between 2003-2004 and included 120 infants from silesia/southern part of poland/.these infants were refered to our allergy unit due to respiratory symptoms like rhinitis, otitis, pharyngitis, cough, bronchitis recurring;eye's symptoms/ conjunctivitis/ and oral symptoms. the skin prick test/ spt/ to major aerollergens in our environment(hdii, birch, alternaria, cladosporium and trees)were done to 6-months-old and 1-yearold children. a spt of 3 mm or larger was considered as positive. patients were classified into three groups: i:positive family atopy ii:smoking ciggarettemother/ or father iii:cat or dog at home iv: coexisting food allergy results:58, 8 % of examined children were boys. the prevalence of sensitisation found were as follows:latex 38, 1%, birch 32, 8%, dpii-28, 6%, grass pollen 28, 1%, alternaria-8, 4%. positive spts to latex were first seen in the 6-months-old group and this prevelance doubled until they finished 1 year. conclusion: in our study, cutaneuos sensitisation start to appear in 6-months-old chlidren. background: propylene glycol (pg) may induce allergic contact dermatitis (acd) and skin irritant reactions. topical formulations frequently contain pg. it is present in low concentration (5%) in pimecrolimus cream 1%, a non-steroid inflammatory cytokine inhibitor. objectives: this study was designed to assess the incidence of cutaneous responses to pimecrolimus cream in patients allergic to pg and to determine their nature (acd or irritation) and severity. methods: in this double-blind, randomized, vehicle-controlled, withinpatient study, 20 subjects allergic to pg underwent 48-hour patch-testing (pg 30 and 100%, pimecrolimus cream and vehicle) followed by a 7-day repeated open application test (roat). application sites were assessed by the investigator using a scale ranging from 0 (no reaction) to 7 (spreading bullous reaction) at 0, 48, and 120 hours after patch removal and at the completion of the roat. results: pg allergy was confirmed by patch-testing in 16 patients. two patients showed a positive patch-test reaction with pimecrolimus cream and vehicle, indicating an acd. in contrast, no patient demonstrated signs of acd when pimecrolimus cream was applied under normal conditions, i.e. without occlusion (roat). the statistical analysis showed that there were significantly less reactions at pimecrolimus patch-test sites than at the pg patch-test sites (p<0.01 for both pg concentrations, one-sided exact binomial test) and that the median severity was lower with pimecrolimus cream vs. pg (p=0.02 and p<0.01 for pg 30% and 100% respectively, wilcoxon signed-rank test). conclusions: this pilot study suggests that pimecrolimus cream 1%, when applied under normal conditions, can be used safely in patients with pg allergy. introduction: chronic idiopathic urticaria is not always responsive to antihistamine therapy. multiple alternative agents have been tried. we report two cases where tacrolimus has been successful in treating this condition. methods: this is a case report of two patients who have chronic idiopathic urticaria and have been treated with tacrolimus. patient #1 is a 27 y/o wm who pre-sented with urticaria that had been going on several months. the duration of his urticarial lesions was <24 hours his urticaria was treated with several medications including: hydroxyzine, cyproheptadine, ceterizine, montelukast, colchicine, and dapsone. he was intolerant to hydroxychloroquine. montelukast seemed to provide some modest benefit but he continued to have daily urticaria with >50 lesions/day after two months of therapy. tacrolimus was added to montelukast at 1mg bid. patient #2 is a 64 y/o wf with a history of biopsyproven urticaria. she had suffered from episodic urticaria since the age of six that was responsive to systemic steroids. after thirty years of having no urticaria, she developed recurrent urticaria at age 62. at this time, she was treated with hydroxyzine, doxepin, montelukast, loratadine, ceterizine, fexofenadine, colchicine, dapsone, and even prednisone with very little improvement in symptoms. she was then started on tacrolimus 1mg bid as monotherapy while she was having daily urticaria. results: after one month of treatment with tacrolimus 1mg bid, patient #1 had a decrease in the number of urticaria. his dose of tacrolimus was increased to 3mg/day, and after four weeks, his urticaria resolved. he remained on tacrolimus for a total of six months which was tapered and discontinued. he continues to be in remission from urticaria. patient #2 had complete resolution of her hives after just two doses of tacrolimus. after two months, she remains free of urticaria on tacrolimus 1mg bid. conclusion: for patients with severe chronic urticaria unresponsive to multiple therapies, tacrolimus, like cyclosporine, may be efficacious. tacrolimus may also be truly immunomodulatory and capable of inducing remission of urticaria. s.v. gerasimov * , lviv, ukraine. introduction. recent studies suggest that probiotics can be useful in prevention and treatment of atopic dermatitis (ad) in children. as clinical effect of probiotics varies greatly depending on the specific strain, we are currently conduct a search for the most promising probiotic to be used as complementary therapy in infants and young children with ad. methods. we studied 23 infants aged 25-51 weeks (36â±8) with ad established using hanifin and rafka criteria. patients were evenly allocated among probiotic (n=11) and nonprobiotic (n=12) treatment groups using quota allocation system. severity of ad was defined using scorad index and infant`s quality of life was assessed using idqol index. patients were examined before and 4 weeks after the treatment with/without probiotic powder formulation (b. infantis, l. acidophilus dds-1, 10 billion cfu/day, dds-junior, uas laboratories). we compared pre/posttreatment values of indices above and amount of mometasone furoate (0, 1%) used employing a paired or unpaired t-test. results. at baseline, infants in either groups were comparable on age, gender, duration of the disease, scorad and idqol indices, and medication taken for the previous 4 weeks. before entering the study all patients were maintained on allergen elimination diet due to milk and egg white allergy. after the treatment with/without probiotics the mean scorad index decreased from 42, 2 to 32, 7 (p=0, 14) and from 51, 5 to 31, 3 (p=0, 06), respectively. however, the mean amount of mometasone furoate used in non-probiotic treatment group was significantly greater (7, 8 g vs 2, 1 g, p=0, 03), despite the same recommendation on the use of the drug was given. additionally, parents of children taking probiotics reported an improvement in infant`s quality of life as seen on the decrease of idqol index from 21, 1 to 12, 0 (p=0, 04). in non-probiotic group decrease in idqol was not significant (24, 2 to 19, 5; p=0, 14) . there were no adverse events in any of the treatment groups. conclusions. our preliminary results suggest that some probiotics may have a corticosteroid-sparing effect and improve quality of life of infants with ad. there is a clear trend towards reduction of scorad index, which did not change significantly, probably due to a limited number of patients involved. introduction : the aim of this study was to analyze the risk factors of severe atopic dermatitis(ad) in the first 6 months of life. methods : the children aged less than 6 months with ad were divided into two groups according to six area six sign in atopic dermatitis(sassad) score. children with score less than 14 was classified as mild ad(n=90) and those with score above 15 as severe ad(n=44). these patients were fed with breast milk or cow's milk formula, and no allergenic food was given except rice and some vegetables. we analyzed the gender, feeding patterns, family history of allergy, number of siblings, total ige and specific ige to common food allergens (egg white, cow's milk, wheat, soy) by cap-feia assay. total eosinophil count was 1863â±2032 /ul in severe ad and 686â±539 /ul in mild ad(p<0.001). results : 1) total ige was 180.6â±245.1 u/ml in severe ad and 32.2â±50.7 u/ml in mild ad(p=0.002). specific ige to egg white, wheat and soy (19.03â±29.72 u/ml, 4.68â±10.62 u/ml, 7.07â±22.01 u/ml in severe ad; 1.78â±3.54 u/ml, 0.15â±0.99 u/ml, 0.09â±0.30 u/ml in mild ad; p<0.05) were associated with severe ad, but cow milk(4.34â±16.6 u/ml in severe ad, 0.80â±4.17 u/ml in mild ad) showed no difference. 2) gender, feeding patterns, family history of allergy and the number of siblings were not significantly associated with severe ad. conclusion : severe ad is associated with sensitization to food allergens in the first 6 months of life, although they are not fed with those foods. background: atopic dermatitis (ad), an inflammatory skin disease diagnosed primarily in children, has been shown to have a negative impact on quality of life (qol). pimecrolimus cream 1% is a non-steroid, topical calcineurin inhibitor with demonstrated efficacy in the acute treatment and longterm management of pediatric and adult ad. in a 24-week, double-blind, vehicle-controlled study, a secondary aim was to evaluate the impact on parent's quality of life of a pimecrolimus-based or corticosteroid (cs)-based treatment regimen of children with ad. methods: 275 children aged 3 months to 11 years (mean 5 years) with mild to severe ad were randomized 2:1 to receive treatment with pimecrolimus or vehicle cream. emollients for dry skin and pimecrolimus or vehicle bid were applied at the first signs of ad. for severe flares, a mid-potency topical cs (fluticasone or mometasone) indicated for once-daily use in ad replaced the evening study drug application for a maximum of 3 weeks or until all ad resolved. parents completed the parent's index of quality of life-atopic dermatitis (piqol-ad), a 28-item validated questionnaire, which measures parent's needs-based qol, at baseline, week 12, and study completion. change in piqol-ad scores at baseline and week 24 were compared between treatments. a negative change indicated improvement. results: parents of patients in both groups reported improvement in piqol-ad scores at week 24, with greater improvement for the pimecrolimus group. the mean change in piqol-ad score from baseline to week 24 was -3.3 in the pimecrolimus group vs. -2.6 in the cs-based treatment group (37.6% vs. 26.8% improvement, respectively). ancova analysis, using treatment and center as main effects and baseline score as a covariate, compared the change in piqol-ad score in two treatment groups. pimecrolimus treatment demonstrated a more favorable change (-1.2) which approached statistical significance [p=0.056; 95%ci= (-2.5, 0.0)]. conclusion: a treatment regimen utilizing pimecrolimus cream 1% had a beneficial effect on parent's quality of life compared to a corticosteroid-based regimen. this benefit was consistent with other measures of efficacy studied. introduction: atopic dermatitis is a chronic, inflammatory and recurrent skin disorder . its prevalence has increased in recent decades but little is known about it in mexico city. the aim of this study was to evaluate the prevalence and severity of atopic eczema in a pediatric population. methods: a cross-sectional questionnaire survey (isaac phase i questionnaire) was conducted on random samples of schoolchildren aged 6 to 7 years and 13 to 14 years from educational centers of four northern counties from mexico city. those children with a positive response to being questioned about the presence of an itchy relapsing skin rash in the last 12 months were considered to have atopic dermatitis. children whose symptoms resulted in sleep disturbance for 1 or more nights per week were considered to have severe atopic eczema. statistical analyses were done with spss 6.0 for windows, chi square . the size of the sample was determined folowing the isaac specifications and calculated with the statcal program. results: complete data was available for 3211 children aged 6 to 7 years in 45 schools and 3899 children aged 13 to 14 years in 47 high schools. 51.5% males and 48.5% females. response rates were high ( 91.4 % for those aged 6 to 7 years and 100% for those aged 13 to 14 years). the prevalence of symptoms of atopic dermatitis in the last 12 months was 9.6 % at age 6 to 7 and 9 % at age 13 to 14 years. medical diagnose of atopic eczema was 4 % and 2.4 % for children aged 6 to 7 years and 13 to 14 years, respectively. reported eczema accounted for 12.4 % and 11.3 % at age 6 to 7 and 13 to 14 years, respectively. children with symptoms of severe atopic dermatitis accounted for 1 % of all those with symptoms of atopic dermatitis. we also found that the majority of the children begun with skin manifestations of atopic dermatitis before the age of 4 years old. conclusions: the prevalence of atopic eczema was very similar for both groups of ages. our results agree with those found in other two studies acomplished in other mexican cities (cuernavaca and chihuahua) and with those from other countries of latin america like brazil, chile and costa rica. although, we found lowest values than those from sweden, japan and australia. studies that include objective skin examination are required to confirm these findings. a. kaplan 1* , s. meeves 2 , y. liao 2 , s.t. varghese 2 , g. georges 2 , 1. charleston, sc; 2. bridgewater, nj. introduction: the symptoms of chronic idiopathic urticaria (ciu) can have a profound impact on patient health and quality of life. the safety and efficacy of fexofenadine (fex) bid for the treatment of ciu has been previously established in two multicenter, double-blind, randomized, placebo-controlled trials. this study evaluated the efficacy and safety of a qd dose of fex hcl 180 mg, as this dosing schedule could offer advantages in terms of patient compliance and convenience. methods: this multicenter, randomized, double-blind, parallel-group, placebo-controlled study consisted of a single-blind placebo run-in period of 2-5 days, followed by a 28 (â±4)-day treatment period. males and females aged 12 years with a diagnosis of ciu and with active disease were enrolled. patients were randomized 2:1 to receive either fex hcl 180 mg qd or placebo qd. the primary endpoints were change from baseline in mean daily number of wheals (mnw score) and mean daily severity of pruritus (measured on a 5-point scale) over the 28-day treatment period, as assessed reflectively by the patient. secondary efficacy measures included a modified total symptom score (motss), comprising sum of number, frequency, size and duration of lesions, and severity of pruritus. mnw and pruritus severity were also assessed instantaneously at trough drug levels (immediately prior to dosing). results: over the 28-day treatment period, patients treated with fex (n=167) experienced significantly greater improvements in mnw and pruritus scores compared with the placebo group (n=92) (p<0.0001 for both). similarly, over the treatment period, and at individual weekly timepoints, the mean reductions in am reflective, pm reflective and mean daily motss were significantly greater for patients in the fex group compared with those in the placebo group (p 0.0052 for all comparisons). the mean reductions in instantaneous mnw and pruritus scores were greater with those who received fex than those who received placebo (mnw: p=0.0154; pruritus score: p=0.00088). there were no significant differences in the frequency of treatment emergent adverse events between the two treatment groups, and no clinically relevant changes were observed with respect to clinical laboratory data, vital signs or ecgs. conclusion: this study demonstrated that a qd dose of fex hcl 180 mg offers effective and well-tolerated relief from the symptoms of ciu. introduction: the wheals and pruritus associated with chronic idiopathic urticaria (ciu) are often so debilitating that they have a profound impact on patient quality of life. specifically, ciu has been shown to negatively affect patient mobility, sleep, energy levels, social interaction and emotional wellbeing. the purpose of this study was to examine the impact of treatment with fexofenadine hcl (fex) 180 mg on health-related quality of life (hrql) among patients with ciu. methods: as part of a multicenter, randomized, double-blind, parallel-group, placebo-controlled study, designed to evaluate the efficacy and safety of a once-daily dose of fex 180 mg in ciu, the impact of treatment on hrql was also examined. patients were asked to complete the dermatology life quality index (dlqi) and the work productivity and activity impairment questionnaire (wpai) at baseline and at weeks 2 and 4 (final visit or early termination). the primary endpoint was mean change from baseline in dlqi total score, using the mean data of evaluations performed at weeks 2 and 4 as the post-baseline measure. secondary endpoints included change from baseline in individual dlqi domains and wpai scores. additional analyses were conducted to examine the reliability, validity and responsiveness of the hrql measures. results: a total of 254 patients were included in the hrql population: n=163 fex, n=91 placebo. patients in the fex group experienced significantly greater improvements in the mean dlqi total score than those in the placebo group (p=0.0029). this pattern was repeated with respect to the individual domains of symptoms and feelings (p=0.0071), daily activities (p=0.013), leisure (p=0.0425) and personal relationships (p=0.0023). both treatment groups reported improvements in productivity, as measured by change from baseline using the wpai. patients randomized to fex experienced significantly less impairment while working (p=0.0455) and performing activities (p=0.0088) than those who received placebo. the dlqi was demonstrated to be reliable (cronbach's alpha=0.87); both the dlqi and wpai were found to be valid and responsive instruments in this ciu population. conclusion: this study demonstrated that a once-daily dose of fex 180 mg improves the hrql of patients with ciu, as assessed by change in dlqi total score. t. algozzine 1* , a. lee 2 , s. wong 3 , l. anzisi 4 , 1. manchester, nh; 2. centerport, ny; 3. syosset, ny; 4. mamaroneck, ny. symptoms of allergic and non-allergic rhinitis may significantly impact a patient's quality of life, by causing fatigue, headache, cognitive impairment and other systemic symptoms. appropriate management of allergic rhinitis is important in the effective management of coexisting or complicating respira-tory conditions (e.g. asthma, sinusitis, or otitis media). in addition, many commonly used over-the-counter (otc) antihistamines can cause performance impairment that may impact daily activities. we designed a brief ten-question allergy survey in an attempt to determine how patients were being treated for their allergies, evaluate a patient's self-assessed impact of their allergies on their daily activities, and identify any difference in treatment outcomes between primary care and allergist practices. patients were invited to complete the surveys anonymously. completed surveys were collected and entered into a microsoft access database for evaluation. minitab was utilized for statistical calculations. four hundred and thirty seven patients completed the survey. fifty-eight percent of survey respondents were women and 89% were adults (age >18). of those patients surveyed, 53% (n=233) were under the care of an allergist. compared to primary care, patients treated by allergists reported more allergies (3.4 vs. 1.8, p <0.001) and received more medications on average (2.3 vs. 1.4, p<0.001). pollen was the most common allergy type reported among all patients. while the majority of all patients (69%) received prescription medications, more primary care patients received no therapy or only otc treatment when compared to allergist patients (46% vs. 17%, p<0.001). seventy-four percent of primary care patients reported their allergy symptoms were controlled compared to 63% of allergist patients (p<0.05). patients receiving treatment from an allergist reported less impact of their allergies on daily activities (a lower score signified less impact) compared to patients seen in primary care (2.27 vs. 3.84, p<0.001). the results of our survey suggest that allergists treat more complex patients. these patients had multiple allergies, more uncontrolled symptoms, and utilized more prescription medications. despite these findings, patients treated by allergists reported less impact of allergies on their daily activities. introduction the patogenic mechanism of nasal polyps are unknow.they frecuently are associated with aspirin intolerance, intrinsic asthma, chronic sinusitis, young sindrome, cystic fibrosis, kartagener syndrome and churg-strauss syndrome.chemical mediators found in nasal polyps are as follows: histamine, serotonin, leukotrienes, norepinefrine and possibly pgd2.recently, leukotrienes have been implicated in mediation of bronchoconstriction and inflammatory leukotriene levels have also been shown to be elevated in some patients with sinonasal polyposis (figure 1 ) hypothesis antileukotrienes might play a significant role in controlling polyposis and symptoms secundary to sinonasal disease, and they might viable alternative to longterm, oral steroid therapy and repeat surgical debridement purpose this study was undertaken to evaluate the potential role of leukotriene receptor antagonist on recurrent polyposis associated with asthma and improvement of some factor implicated with them design of study:clinical assay, prospective, triple blind. materialsand methods:the study involved 30 patients 12 (40%) males and 18 (60%) women, mean age 20.7 years, with a range 16-45 years selection criteria:inclusion criteria: nasal polyps associated with astha, allergic or non allergic.exclusion criteria: patients with any concurrent illness, use of sistemic or local corticosteroidsor any kind of antileukotriene within 1 month prior to the beggining of the study.we made an alleatory selection 10 patients recived montelukast (10 mgs/day), and nasal steroids, beclometasone (600 mgs/day) for 6 months.10 patients recived loratadine plus pseu-doefedrin5mgs/120 mgs/day and nasal steroids, beclometasone, 10 patints were operated of fees and transnasal endoscipic polypectomy plus montelukast and nasal steroids, beclometasone ige serum levels 2.skin prick test 3.sensitivity in vitro 4.ct scan 5. celullarity on nasal lavage (eosinophils and neutrophils)6.proinflamatory cytokines (il4-il5-il8) on nasal lavege by elisa test. results ther was a tendency for more improvement of the group 3 ( surgery-montelukast-local steroid) of symptoms and objective measurments, in second place of improvement the group 1 montelukast-local steroid) and the worse on improvement subjective and objetive was group 2 local steroid and loratadine-pseudoefedrine use as placebo introduction: sensory perceptions of intranasal corticosteroids (ins) vary among products and can be unpleasant and affect adherence to therapy. methods: we conducted a cross-sectional study of 120 patients across 4 allergy and immunology clinics in the united states. respondents were asked to choose between pairs of hypothetical ins that differed by sensory attribute composition. based on prior research, we measured 6 salient sensory attributes: smell, taste, aftertaste, throat rundown, nose runout, and feel of spray in nose/throat. each attribute was described in 3 intensity levels, such as "no taste" (low), "weak taste" (moderate), and "strong taste" (high) ( table) . other outcomes included an importance score for each sensory attribute and patients' willingness to adhere to an ins having the lowest levels of each sensory attribute compared to one with moderate levels. results: preferences decreased with increasing intensity level of each sensory attribute. the most important attribute was aftertaste in 28% of patients, taste in 19%, throat rundown in 18%, nose runout in 12%, smell in 11%, and feel of spray in 7%. only 5% had more than one attribute tied for most important. if instructed to take ins daily for 3 months, 77% of patients stated that they would definitely be able to follow their doctor's advice (willing to adhere) if given an ins containing the lowest level of each sensory attribute compared with 4% for one having moderate levels (p<0.01). conclusions: patients' preferences decrease with increasing intensity levels of each sensory attribute and affect patients' willingness to adhere. tailoring ins to patient preferences may lead to improved treatment satisfaction and adherence. introduction:a high prevalence of rhinitis and asthma comorbidity has been persistently noticed in epidemiological studies in last years. our objective was to evaluate the prevalence of rhinitis and asthma comorbidity in a portuguese population including both atopic and non-atopic patients. methods: a retrospective study was performed. clinical records from patients attending an immunoallergology outpatients'clinic during 39 months (from january 1998 until june 2001) were reviewed. data were collected concerning clinical history of rhinitis and/or asthma, aeroallergens'skin prick tests and respiratory function evaluation. results: among the 3582 patients attending an appointment during the study period, 2448 (68.3%) had rhinitis and/or asthma (56.2% f; 43.8% m;mean age 26 +/-19 years). patients with respiratory disease included 1983 atopic (81.0%) and 465 non-atopic 19%). diagnosis of asthma, rhinitis or of both diseases was made in 170 (8.6%), 581 (29.3%) and 1232 (62.1%), respectively, in atopic patients and in 56 (12.0%, 265 (57.0%) and 144 (31.0%), respectively, in non-atopic patients. rhinitis was diagnosed in 87.9% of atopic asthmatic and in 72-0% of non-atopic patients with asthma. in patients with rhinitis, asthma was also diagnosed in 67.9% of atopic patients and 35.2% on non-atopic patients. conclusions: in this study population rhinitis was frequently diagnosed in patients with asthma and vice-versa, thereby leading to a high prevalence of this comorbodity. this association was more frequent in atopic patients. our data are comparable to those we found in recent literature. these results suggest that clinical investigation of asthma should be mandatory in management of patients with rhinitis as well as asthmatic patients should be routinely submitted to clinical evaluation of rhinitis. introduction: cetirizine hcl (c) has been shown to be more effective than fexofenadine hcl (f) in controlling seasonal allergic rhinitis (sar) symptoms at 21-24 hr post-dose, however, the efficacy of c and f was comparable between 0-5 hr post-dose. response to treatment in the middle of the dosing interval needed to be addressed. methods: this randomized, double blind, placebo (p)-controlled study was designed to compare the efficacy and tolerability of a single dose of c 10 mg, f 180 mg, and p between 5-12 hr postdose in ragweed-sensitive sar subjects. subjects meeting entry criteria were exposed to pre-determined controlled levels of ragweed pollen in the eeu during priming and double blind treatment. subjects assessed rhinitis symptoms at half hr intervals during pollen exposure; at priming, at the qualifying period, at baseline, and from 5-12 hr post-dose. the primary efficacy endpoint was the change from baseline in total symptom severity complex (tssc) score at 12 hr post-dose. tssc score was the sum of severity ratings (0=absent to 3=severe) for 4 symptoms: runny nose, sneezing, itchy nose/palate/throat and itchy/watery eyes. results: a total of 599 subjects (mean age 32.8 y; 58.9% females) were randomized: c, 249; f, 250; p, 100. baseline characteristics were comparable among groups; tssc: c=9.2, f=9.2, p=8.9. c produced a 26% greater reduction in tssc score at 12 hr (-4.3, p=0 .001) and a 14% greater reduction overall (i.e., average over the 5-12 hr post-dose period) (-5.0, p=0.006) compared with f (-3.4, -4.4, respectively). both c and f reduced tssc score more than p (12 hr, -1.9; overall, -2.3, p<0.001) including all individual symptoms (p<0.05). c however, was more effective than f for runny nose and sneezing at 12 hr and overall, itchy/watery eyes at 12 hr, and itchy nose/throat/palate overall (p<0.05). rates of discontinuation due to adverse events (aes) were low: c, 0.4%; f, 0%; p, 1.0%. the incidence of treatmentemergent aes was similar: c, 25.3%; f, 29.6%; p, 35.0%. somnolence occurred in 0.8% of subjects on c, and 0% on f or p. conclusion: c produced a greater improvement in rhinitis symptoms compared with f and p, at 12 hr post dose and over the 5-12 hr post-dose period. all treatments were safe and well tolerated. background: medication utilization patterns of patients suffering from seasonal allergic rhinitis (sar) are not well documented, and although many anti-allergic medications are prescribed for daily use, actual usage is unknown, but recognized to be quite variable. methods: 1821 subjects with positive ragweed skin tests were mailed a survey during the third week of ragweed season, soliciting the nature and severity of sar symptoms, usage patterns and reasons for choice of anti-allergic medication. results: 550 subjects completed the survey (30.2%). the prevalence of symptoms were, in decreasing order: sneezing (91.5%), runny nose (82.4%), itchy/gritty eyes (80.4%), stuffiness (78.5%), itchy nose (71.3%), watery eyes (64.7%), itchy palate/throat (56.9%), post-nasal drip (55.6%), red/burning eyes (49.1%), headache (36.5%), itchy ears (34.0%), cough (30.0%), shortness of breath (15.7%), and wheeze (15.5%). sar patients used antihistamines most frequently (94.7%), followed by decongestants (63.1%), combination (antihistamine/decongestant) products (52.0%), and intranasal corticosteroids (42.5%). medications were mostly taken intermittently rather than daily (antihistamines 68.0%; nasal corticosteroids 71.8%), conclusion: a constellation of nasal symptoms were the most common seasonal allergic manifestations, followed by ocular, palatal and ear irritation. antihistamines were the most frequently used medication to treat symptoms, succeeded by decongestants (alone or in combination). a significant proportion of subjects took their allergy medication, including nasal corticosteroids, intermittently rather than regularly, underscoring the relevance of single-dose evaluations of drug efficacy. a.k. ellis * , e. rafeiro, j.d. ratz, j.h. day, kingston, canada. background: traditional assessment of seasonal allergic rhinitis (sar) medication efficacy utilizes randomized controlled trials over 2-4 weeks in season. an additional study method employs single-dose responses using controlled allergen challenge such as the environmental exposure unit (eeu). a comparison of allergic symptoms generated by controlled allergen challenge to those occurring in ragweed season symptoms has not been done. methods: 1821 subjects with known sar to ragweed were mailed a survey during the third week of ragweed season, soliciting the nature and severity of sar symptoms. subjects participating in a subsequent controlled allergen challenge study using the eeu, were again asked to complete a similar survey that documented symptoms generated in this model. those who completed both surveys comprised the primary analysis group. results: 550 subjects completed the ragweed season survey, 516 subjects completed the eeu survey, and 270 completed both. symptoms generated by eeu exposure were similar to those elicited during ragweed season, with the exception of cough (68% vs. 27%, respectively, p <0.01). subjects reported that symptoms were more severe in the eeu than those experienced on a typical ragweed season day, but less severe than those during peak ragweed season days. conclusion: allergic upper respiratory tract symptoms produced during controlled ragweed pollen exposure in the eeu were similar in nature and degree to those expe-rienced during ragweed season, supporting evidence that the eeu is a valid model for studying sar. r. nave 1 , m.a. wingertzahn 2* , s. brookman 3 , s. kaida 4 , t. shah 2 , 1. konstanz, germany; 2. florham park, nj; 3. princeton, nj; 4. tokyo, japan. rationale: ciclesonide (cic) is a new corticosteroid under development for treatment of allergic rhinitis (ar). cic is a pro-drug that is hydrolyzed to the active metabolite desisobutyryl-ciclesonide (des-cic) in the target tissue. cic has low oral bioavailability and is highly bound to plasma proteins; therefore cic administered as a nasal spray is expected to have minimal local and systemic effects. objective: the primary objective was to evaluate the safety and tolerability of repeated escalating doses of cic (50-800 mcg/day) given as a nasal spray for 14 days to healthy and asymptomatic subjects with sar. secondary objectives were to determine pk of cic and des-cic and to evaluate the effect of cic on endogenous cortisol. methods: this was a single-center, randomized, placebo-controlled, double blind, modified sequential dose study. six cohorts were randomized. cohorts i-v consisted of healthy subjects given doses of cic up to 400 mcg bid. cohort vi (asymptomatic sar subjects) received 400 mcg bid. each cohort was comprised of 6 subjects who received cic and 2 subjects who received placebo. safety assessments were conducted by recording adverse events (aes), clinical laboratory, eye, and nasal examination findings. serum and urine samples were taken for evaluation of cortisol levels. cic and des-cic serum concentrations were determined by lc-ms/ms. results: no trend was observed for aes when comparing cic and placebo treatment. additionally, no subject experienced a serious ae or withdrew from the study due to an ae during the trial. cortisol levels showed no differences between the dose groups or between activetreated subjects and placebo-treated subjects. additionally, serum concentrations of cic and des-cic in the majority of serum samples were shown to be below the lower limit of quantification (lloq; 25 pg/ml for cic and 10 pg/ml for des-cic), therefore no descriptive statistics could be calculated. con-clusions: ciclesonide nasal spray, at the doses evaluated, was safe and well tolerated in healthy and asymptomatic sar subjects with no detectable effects of cic on serum or urinary free cortisol concentrations. additionally, no pk parameters could be calculated for cic nasal spray, as it was virtually undetectable in serum despite the use of a sensitive assay. the preferred treatment for allergies is avoidance. air filtration is logical but room air purifiers have been of limited efficacy. zephyrâ�¢ is a new device which creates an envelope of air 99% free of allergenic particles around the head of the sleeping person. allergic rhinitis frequently causes daytime somnolence. this is a pilot study of the effectiveness of zephyr on symptoms of seasonal allergic rhinitis (ragweed hay fever) and on daytime sleepiness. methods: subjects age 12 to 45 with ragweed hay fever were studied in the ragweed season using each subject as his/her own control. usual allergy medicines were not allowed, except loratadine for rescue. outcome measures were a symptom score, juniper rhinitis quality of life questionnaire, a tolerability rating, and epworth sleepiness scale. during the first week subjects qualified by symptom scores, then entered the one-week treatment period with zephyr. the third week was a post-treatment observation period. results: of 13 participants, 10 (77%) showed symptom improvement. the whole group averaged 26% reduction in morning symptoms and 24% reduction in evening symptoms. sleepiness scores improved 29%. rhinitis qol improved 33%. the zephyr system was well tolerated as evidenced by the response to several statements regarding zephyr use and tolerability: (scoring: 1 = strongly disagree, 5 = strongly agree) "the system did not bother me while i was sleeping." (mean score 4.8) "the noise level did not affect my ability to sleep." (mean score 4.7) "the temperature was just fine for me." (mean score 4.8) "the system did not get in my way during sleep." (mean score 5.0) conclusions: zephyr significantly reduced seasonal hay fever symptoms and daytime sleepiness, improved quality of life, and was well-tolerated by subjects. zephyr may provide maximal environmental control of bedroom allergen exposure irrespective of ambient airborne allergen levels in the room. nasal congestion is an important symptom that is associated with significant morbidity in the rhinitis sufferer. disrupted sleep leading to daytime fatigue, loss of concentration, and decreased productivity are potential results of this symptom. a study employing online interviews with 1200 rhinitis sufferers from harris interactive's online database was conducted in order to understand the symptoms they identify with most and to determine the impact nasal congestion had on their daily activities. respondents were at least 18 years of age and experienced nasal congestion from seasonal allergic, perennial allergic, and/or perennial non-allergic rhinitis. the results showed that 60% of the respondents agreed nasal congestion is the most bothersome symptom of rhinitis; 37% experienced nasal congestion daily, while 35% experienced it several times per week. not surprisingly, sleep was the most important factor affected by nasal congestion. two-thirds (66%) of the respondents felt their sleep had been moderately or significantly impacted by nasal congestion, and more than half (56%) felt it was difficult to get a good night's rest because of congestion. sleep was interrupted or disturbed by nasal congestion approximately 3 nights per week, on average. furthermore, sleep disruption from nasal congestion contributed to daytime fatigue; 62% of the respondents indicated that they were typically tired or fatigued during the day when they experience nasal congestion. in addition, 42% felt that activities requiring concentration, such as reading, were moderately or significantly impacted by nasal congestion. this study confirms that nasal congestion causes the rhinitis sufferer significant problems beyond that of just a stuffy nose. consequently, healthcare providers need to ensure that their rhinitis patients who have nasal congestion as their primary complaint are managed effectively. desloratadine (dl, clarinex â® ) is a non-sedating oral antihistamine that is metabolized to 3-oh dl. however, a phenotypic polymorphism has been observed in some patients that results in reduced formation of 3-oh dl. the prevalence and safety profiles of such poor metabolizers of dl were examined in pharmacokinetic and clinical trials. a poor metabolizer was defined as a subject having a 3-oh dl to dl auc ratio of <0.10, or a dl half-life of 50 hours. in pediatric studies, where a sparse sampling approach was uti-lized to screen for poor metabolizers, a plasma concentration ratio of 3-oh dl to dl of <0.10 at 12 hours classified a subject as a poor metabolizer. a total of 3, 748 adult and pediatric subjects (2-70 years old) were phenotyped with a single dose of dl or loratadine. the overall prevalence of the poor metabolizer phenotype was 6% (228/3748). this prevalence was comparable for adult (70/1194, 6%) and pediatric subjects (158/2554, 6%), and greater in both populations among blacks (16% pediatric, 18% adult) than caucasians (3% pediatric, 2% adult). pharmacokinetic analysis found that exposure to dl was approximately 6-times higher in poor metabolizers than in normal metabolizers. there was no apparent difference in dl exposure among poor metabolizers in different age groups (6-months to <2-years, 2-to <6-years, 6-to <12-years, and 12-years) when treated with age-appropriate doses. the multiple-dose (7-35 days) safety profile of dl was examined in pediatric poor metabolizers (2-11 years) in 5 placebo-controlled trials, and in adult poor metabolizers (20-70 years) in pharmacokinetic trials. pooled ae rates were low and comparable between the poor metabolizer and placebo subjects, as shown in the table below with all aes that appeared in >2% of subjects in any treatment group (or >3% in adult poor metabolizers). there was no difference in cardiovascular safety profile or ecg results (including qtc interval) among these groups. in conclusion, (1) expression of the dl poor metabolizer phenotype is independent of age, but higher in blacks than in caucasians, (2) exposure to dl in poor metabolizers is independent of age when administered at age-appropriate doses, (3) the safety profile of dl poor metabolizers is not different from that of placebo at all ages down to at least 2-years old. these results are consistent with the high therapeutic index of dl. desloratadine (dl, clarinexâ®) is extensively metabolized to 3-oh dl and subsequently glucuronidated. the enzyme responsible for the formation of this active metabolite is unknown. poor metabolizers of dl represent a subset of the population that has a reduced ability to form 3-oh dl. a poor metabolizer was defined as a subject having a 3-oh dl to dl exposure ratio of <10%, or dl half-life of 50 hr. pk parameters from adult and pediatric poor metabolizers following repetitive administration of dl were characterized in clinical pharmacology trials and are summarized in the table below. exposure to dl [auc(0-24hr)] in poor metabolizers was approximately 6-fold greater than the corresponding values in normal metabolizers; cmax was 3to 4-fold greater. the magnitude of the reduction in the formation of 3-oh dl and the concurrent increase in exposure to dl associated with the poor metabolizer phenotype was similar in pediatric and adult subjects at age-appropriate doses. despite the increased exposure to dl in poor metabolizers, there was no increase in adverse event frequency or changes in electrocardiographic parameters. a: dose normalized to 5 mg. b: least squares mean ratio: anova of log-transformed data extracting sources of variation due to age group and metabolizer status. the ratio is a contrast of metabolizer status. c: lower and upper 90% confidence interval based on log-transformed data. introduction: many patients with seasonal allergic conjunctivitis (sac) complain of symptoms of dry eyes. we have previously reported that patients with sac experience discomfort from dry eyes anywhere between 2 to 6 days per week and that the overall severity of the dry eye symptoms tend to range from mild to severe. this preliminary cross over study evaluated the benefits of nedocromil sodium 2% ophthalmic solution used twice daily, compared with nedocromil sodium 2% ophthalmic solution used with refresh (ocular lubricant), for the treatment of dry eye symptoms in association with sac during 8 weeks. methods: patients who had a minimum of two-year history of sac and dry eyes, a positive skin prick test towards grass pollen and between the ages of 18 to 65 were enrolled. patients were evaluated on four visits and completed a daily diary, which included scales for grading allergic conjunctivitis and dry eye symptoms. at each clinic visit they completed the osdi and the rqlq (rhinitis quality of life questionnaire). the osdi (ocular surface disease index) was developed to assess dry eye symptoms and the impact on vision related functioning. the rqlq evaluates quality of life in patients with allergic conjunctivitis. at the last visit, both the patient and the physician assessed the treatment and the effectiveness, if any, of the addition of refresh to nedocromil sodium 2% ophthalmic solution. daily grass pollen counts were preformed using a burkhard sampler. results: 19 patients (7 male and 12 female) were enrolled and 3 dropped out. patients experienced minimal symptoms at the start of the season due to low concentration of grass pollen. preliminary analysis carried out using a paired t-test was preformed on the ocular average scores for the two treatment periods. there was no significant difference between the 2 treatment groups for redness, light sensitivity and tearing of the eyes. a reduction in dry eye symptoms was reported in all patients using refresh eye drops and the number of drops required varied between patients. during the treatment periods there was improvement in patients rqlq. conclusion: patients preferred the addition of refresh eyedrops in alleviating sac and dry eye symptoms. further studies need to be carried using refresh eye drops in larger number of patients with sac and dry eye symptoms. c. laforce * , raleigh, nc. introduction: the objective of this study was to determine the ability of azelastine nasal spray to improve rhinitis symptoms and quality of life parameters in seasonal allergic rhinitis patients remaining symptomatic after treatment with fexofenadine. methods: this placebo-controlled, double-blind study began with a 1-week, open-label lead-in period, during which patients received fexofenadine 60 mg bid. after 7 days, patients who improved less than 25% to 33% on fexofenadine were randomized to treatment for 2 weeks with: (1) azelastine nasal spray, (2) azelastine nasal spray plus fexofenadine, or (3) placebo. the primary efficacy variable was the change from baseline to day 14 in thetotal nasal symptom score (tnss), which consisted of runny nose, sneezing, itchy nose, and nasal congestion scores recorded twice daily in patient diary cards. in addition, quality of life was assessed using the rhinitis quality of life questionnaire (rqlq). results: after 2 weeks of treatment, azelastine nasal spray (p<.01) and azelastine nasal spray plus fexofenadine (p<.01) significantly improved thetnss compared to placebo. based on 90 patients with complete tnss and rqlq data, the overall rqlq score also was significantly (p<.01) improved compared to placebo. conclusions: azelastine nasal spray was an effective treatment for patients with seasonal allergic rhinitis who did not respond well to fexofenadine and significantly improved quality of life parameters compared to placebo. the results of this study indicate that azelastine nasal spray is an important alternative to oral antihistamines and should be considered in the initial management of seasonal allergic rhinitis. w. berger * , mission viejo, ca. objective: to evaluate improvement over time with azelastine nasal spray in the treatment of patients with moderate-to-severe seasonal allergic rhinitis (sar) who remained symptomatic after treatment with loratadine or fexofenadine. methods: the studies were 2-week, multicenter, double-blind, placebo-controlled trials that began with a 1-week, open-label lead-in period in which patients received either loratadine 10 mg qd (study no. 1) or fexofenadine 60 mg bid (study no.2). patients who improved <25%-33% with loratadine were randomized to treatment with: (1) azelastine nasal spray 2 sprays/nostril bid, (2) azelastine nasal spray 2 sprays/nostril bid plus loratadine 10 mg qd, (3) desloratadine 5 mg qd, or (4) placebo. patients who improved <25%-33% with fexofenadine were randomized to treatment with: (1) azelastine nasal spray 2 sprays/nostril bid, (2) azelastine nasal spray 2 sprays/nostril bid plus fexofenadine 60 mg bid, or (3) placebo. the primary efficacy variable was the change from baseline to day 14 in the total nasal symptom score (tnss), consisting of runny nose, sneezing, itchy nose, and nasal congestion. symptom severity was recordedam and pm in diary cards on a 4-point scale (0=none; 1=mild; 2=moderate; 3=severe). results: in both studies, patients treated with azelastine nasal spray experienced increasing improvement intnss over 14 days of treatment.the improvements were approximately 2-fold greater than placebo at each day of the study, and the differences from placebo were statistically significant (p<.05) at days 2, 7, 14, and overall. in study no. 1, 33% of patients treated with azelastine had >30% improvement in tnss compared to 17% in the placebo group. in study no. 2, 29% of patients treated with azelastine had >30% improvement in tnss compared to 12% in the placebo group. conclusions: azelastine nasal spray was effective in treating patients with moderate-to-severe sar who remained symptomatic after treatment with either loratadine or fexofenadine. azelastine demonstrated first-day effectiveness, and patients treated with azelastine experienced increasing improvements in rhinitis symptoms over the 14-day study periods.azelastine nasal spray is an effective treatment alternative to oral loratadine or fexofenadine and an appropriate first-line therapy in the management of sar. introduction: a large, open-label, azelastine (astelin) nasal spray patient experience trial was conducted in patients with sar, vmr, or mixed rhinitis (allergic rhinitis with nonallergic triggers). this analysis evaluated the effect of azelastine nasal spray in treating rhinitis symptoms in a subset of patients with a history of asthma or sinusitis. methods: patients were entered into an open-label protocol and treated for 2 weeks with azelastine nasal spray at a dosage of 2 sprays per nostril bid. after 2 weeks, the patients completed a questionnaire that assessed onset of action, symptom improvement, satisfaction with therapy, and quality of life. results: from a total of 4364 rhinitis patients who received azelastine monotherapy during the 2-week study period, data were analyzed for patients with asthma (n=260) or sinusitis (n=346). a greater percentage of these patients had severe rhinitis compared to the overall population. nasal congestion and postnasal drip were reported as the most bothersome rhinitis symptoms. after 2 weeks of treatment with azelastine nasal spray, >80% of patients with asthma and >85% of patients with sinusitis reported some or complete control of congestion and postnasal drip. in addition, >62% of patients with asthma reported chest tightness, shortness of breath, and wheezing were somewhat or completely controlled, and >77% of patients with sinusitis reported that headache and facial pain were somewhat or completely controlled during treatment with azelastine nasal spray. conclusion: azelastine nasal spray provided effective control of rhinitis symptoms, including nasal congestion and postnasal drip, in patients with a history of asthma or sinusitis. introduction: epinastine is an antihistamine with mast cell stabilization and anti-inflammatory properties. epinastine 0.05% ophthalmic solution was evaluated for treatment of allergic signs and symptoms elicited by feline dander in a cat exposure room. methods: participants (n=30) were aged 18 years, with a history of ocular allergy to cats, a positive skin prick reaction to cat dander, and an ocular itching score of 2 (on a 0-4 scale) within 30 minutes of entering the cat room. subjects wore a tb mask while in the cat room to reduce the effects of inhaled allergen. after 30 minutes of exposure, 1 drop of epinastine hcl 0.05% was instilled in one eye, and olopatadine 0.1% was instilled in the fellow eye. environmental exposure to cat dander continued for another 60 minutes. prior to instillation, and at 5, 15, 30, 45 and 60 minutes after instillation, conjunctival hyperemia and chemosis (scales of 0-3), and ocular itching, tearing, ocular burning, nasal itching and rhinorrhea (scales 0-4) were assessed. results: instillation of a single drop of ophthalmic epinastine significantly reduced ocular itching from a mean pre-instillation score of 2.27 to a mean score of 0.37 at 60 minutes after instillation (p<.001), despite continuous exposure to cat dander during the entire period. similarly, ocular burning, tearing, and hyperemia were significantly reduced by epinastine treatment (p<.002). chemosis was only weakly induced by cat room exposure, with a mean pre-instillation score of 0.167; however, epinastine treat-ment decreased that to 0 (p=.023). instillation of epinastine also significantly reduced nasal itching and rhinorrhea scores (p<.043). results for olopatadine were not statistically different; however, the change from baseline in itching scores in the epinastine-treated eyes was greater than that seen in the olopatadine-treated eyes at the majority of timepoints. conclusion: ophthalmic epinastine is indicated for the prevention of itch associated with allergic conjunctivitis.this study shows that treatment of cat-sensitive subjects with ophthalmic epinastine following environmental exposure to cat dander significantly reduced ocular itching and other signs and symptoms of allergic conjunctivitis. objective: the objective of this study was to evaluate azelastine (astelinâ®) nasal spray, cetirizine (zyrtecâ®), fluticasone (flonaseâ®), and placebo in the treatment of patients with symptomatic seasonal allergic rhinitis. methods: this was a double-blind placebo-controlled pilot trial in 60 patients with seasonal allergic rhinitis. the study began with a 1-week, placebo lead-in period, followed by a 1-week blinded treatment period (day 1 to day 7). efficacy variables were: (1) change from baseline to day 7 in the total nasal symptom score (tnss; consisting of rhinorrhea, sneezing, itchy nose, and nasal congestion); (2) onset of action based on tnss over the 4 hours following initial administration of study drugs; and (3) change from baseline to day 2 (24-hour change) in tnss. tnss was scored twice daily (am and pm) on a 4-point rating scale (0=none, 1=mild, 2=moderate, 3=severe). patients recorded a minimum 12-hour tnss of 8 on at least 3 days during the lead-in period, and a congestion score of 3 on at least 3 days to qualify for entry. qualified patients were randomized to treatment with: (1) azelastine nasal spray 2 sprays per nostril bid plus placebo capsules qd; (2) cetirizine 10-mg tablets qd plus placebo nasal spray; (3) fluticasone 2 sprays per nostril qd plus placebo capsules qd; or (4) placebo nasal spray plus placebo capsules. results: azelastine significantly (p<.05) improved the tnss compared to cetirizine, fluticasone, and placebo beginning 30 minutes after initial administration; cetirizine significantly improved tnss versus placebo at 150 minutes; fluticasone showed no significant differences from placebo over the 4-hour evaluation period. azelastine significantly (p<.05) improved the tnss at day 2 (24-hour change from baseline) compared to cetirizine, fluticasone, and placebo. conclusions: azelastine nasal spray improved the tnss in patients with moderate-to-severe seasonal allergic rhinitis. in addition, azelastine nasal spray demonstrated a 30-minute onset of action and significantly improved tnss versus cetirizine, fluticasone, and placebo 24 hours after initial administration. introduction: epinastine, an antihistamine with mast cell stabilization and anti-inflammatory properties, has been developed for the treatment of allergic conjunctivitis. the efficacy and tolerability of epinastine was assessed and compared with levocabastine. methods: eligible patients for this randomized, double-masked, parallel-group, active-controlled environmental clinical trial were 18-65 years old with a recent diagnosis of seasonal allergic conjunctivitis. patients instilled 1 drop epinastine hcl 0.05% or levocabastine 0.05% ophthalmic solution in each eye bid for 6 weeks. patients and investigators assessed efficacy and tolerability at study visits on days 0 (baseline), 7, 14, 28, and 42, and assessed overall efficacy and tolerability at study exit. adverse events were monitored. results: epinastine provided superior itch relief compared with levocabastine (p=.048; see figure) ; mean ocular itch scores over 4 treatment visits were 0.79 for epinastine and 0.97 for levocabastine (0-3 scale; 3=worst; baseline scores were 2.08 for epinastine and 2.06 for levocabastine). the mean summed score (ocular itching, tearing, and foreign body sensation) over 4 treatment visits was significantly better for epinastine than levocabastine (p=.010).at study exit, 53% of epinastine-treated patients rated overall efficacy "very good" (the highest possible rating), versus 34% of levocabastine-treated patients. at 5 minutes postinstillation, 77% of epinastine-treated and 75% of levocabastine-treated patients rated tolerability "very good". at study exit, 80% of epinastine-treated and 75% of levocabastine-treated patients rated overall tolerability "very good", with investigator ratings being similar. treatment-related adverse events occurred in 7.1% of epinastine-treated patients (most frequent: eye pain and skin itching, 1.2% each) and 10.3% of levocabastine-treated patients (most frequent: double vision, 3.4%; influenza-like symptoms, 2.3%); most aes were mild or moderate. conclusion: our results confirm the therapeutic potential for epinastine as an efficacious treatment suitable for long-term use throughout the allergy season. ophthalmic epinastine was superior to levocabastine for relief of ocular symptoms in patients with allergic conjunctivitis and was well-tolerated. since chronic inflammation is the histopathologic landmark of otitis media with effusion, clinical observations have led us to believe that the combination of a cysteinyl leukotriene receptor antagonist montelukast with an oral antibiotic may be more efficacious than monotherapy with an oral antibiotic in the treatment of serous otitis media. we studied twenty pediatric patients (age 3 years to 6 years) in a randomized open labeled 2-week trial to compare the efficacy of the combination montelukast (4 mg or 5 mg chewables tablets qd dosed according to patient's age) with an oral antibiotic amoxicillin/clavulanate potassium (90 mg/kg/day in 2 divided doses every 12 hours) to a monotherapy with an oral antibiotic amoxicillin/clavulanate potassium for the treatment of otitis media with effusion. the efficacy of treatment options was assessed using pneumatic otoscopy, impedance tympanometry, and audiometry to monitor the clinical course of the middle ear effusion in both treatment groups. in the combination group montelukast and antibiotic a resolution of otitis media with effusion occured at the 7th day. in contrast in the group treated with monotherapy with the oral antibiotic the resolution of otitis media with effusion occured on the 14th day. in conclusion, the combination of montelukast plus an oral antibiotic is more effective than monotherapy with an oral antibiotic.the combination of montelukast plus an antibiotic may be a safer and shorter therapy given the safety issues with long term use of systemic antibiotics. introduction: a randomized, double-blind, placebo-controlled study was conducted in an environmental exposure chamber (eec) to compare the efficacy of three doses of olopatadine nasal spray, a topical anti-allergy treatment for seasonal allergic rhinitis (sar), versus placebo spray. methods: patients aged 17-65 years old with a history of sar were screened, consented, evaluated for a positive skin test to ragweed allergen, and enrolled in this irbapproved study. a total of 320 "primed" patients were exposed to ragweed allergen in the eec and randomized to olopatadine 0.2% (n=80), olopatadine 0.4% (n=80), olopatadine 0.6% (n=80), or placebo (vehicle) (n=80) spray, 2 sprays/nostril once in the morning. symptoms were self-assessed using a 4point scale (total nasal symptom score, tnss, comprised of sneezing, runny, itchy and stuffy nose) via diaries at periodic intervals during the 12-hour study period. safety was also assessed. results: obvious trends indicated a dosedependent response to olopatadine 0.2%, 0.4% and 0.6%, though concentrations were not statistically different from each other. all three concentrations of olopatadine were clearly more efficacious than placebo spray at the first time point, 30 minutes, continuing to the end of the 12-hour session. olopatadine exhibited a safety profile comparable to placebo. conclusions: olopatadine nasal spray 0.2%, 0.4% and 0.6% exhibited dose-dependent responses. onset of action for all three concentrations of olopatadine was apparent at the first post-dose timepoint, 30 minutes, and efficacy was maintained throughout the next 12 hours. olopatadine nasal spray was safe, well-tolerated, and effective for the treatment of sar in the eec chamber. c. slonim * , tampa, fl. objective: to assess patient subjective responses to the treatment of allergic conjunctivitis using azelastine hydrochloride ophthalmic solution. methods: participating physicians selected 20 patients from their practice to receive azelastine hydrochloride 0.05% ophthalmic solution 1 drop per affected eye twice daily for 5 days. patients on prior ocular allergy medications were allowed to participate. after 5 days of treatment with azelastine hydrochloride, patients (n=2, 887) rated their experiences with azelastine hydrochloride via a self-administered survey. not all questions were answered by each patient. results: at baseline, 88% of patients reported that their ocular itching affected their work, school, and/or leisure activities at least "somewhat". after using azelastine hydrochloride, 70% of patients achieved either "moderate" or "complete" relief from ocular itching, including 30% who reported "complete" relief from itching. seventy-one percent (71%) of patients had been treated previously with a topical prescription anti-allergy medication for their ocular itching. seventy percent (70%) of patients (n=836) who had not been previously treated with a topical prescription anti-allergy medication treatment and 71% of previous medication users (n=2, 192) experienced at least "moderate" relief of itching when treated with azelastine hydrochloride. sixty-five percent (65%) of the previously-treated patients rated azelastine hydrochloride as "somewhat better" or "much better" than their previous medication. conclusions: results suggest that azelastine hydrochloride ophthalmic solution is an effective treatment for the ocular itching associated with allergic conjunctivitis as rated by the patient, regardless of whether they had been treated previously with a topical prescription anti-allergy medication. objective: to determine an association between food allergy and acid reflux in adults. method: we conducted a retrospective chart review of 60 atopic adult patients in an academic otolaryngic allergy practice. 30 adults who tested positive and 30 adults who tested negative for food allergy were included in the study. charts were reviewed for a diagnosis of gastroesophageal reflux disorders (gerd). this included a history of laryngopharyngeal reflux (lpr) and peptic ulcer disease (pud). population prevalence (19.8%; ci 17.7-21.9) of acid reflux was estimated from a historical study (locke gr et al. prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in olmstead county, minnesota. gastroenterology 1997; 112:1448-56) that had a similar subject population. the prevalence of gerd in each study arm, as well as in the total study group of atopic adults, was compared to the historical control. results: subjects testing positive for food allergy had a diagnosis of gerd in 26.7% (95% ci 11.8-41.6) of cases. those subjects who did not demonstrate a food allergy were positive for gerd in 40% (95% ci 25.1-54) of cases. in the total study group, the prevalence of gerd was 33.34% (95% ci 22.8-43.8). on chi square analysis, the prevalence of gerd was significantly higher in the total study group when compared with the historical control (p=0.013). those subjects who tested negative for food allergy had a statistically significant higher prevalence of gerd than the control population (p=0.003). the prevalence of gerd between the group testing positive and the historical control did not show a significant difference (p=0.41). when comparing the study arms to each other, there was no significant difference in the prevalence of gerd (p=0.27). conclusions: the prevalence of acid reflux disorders was not higher in subjects with food allergy when compared to a historical control. although a statistical significance was noted between adults who tested negative for food allergy and the control population with regards to the prevalence of gerd, this may reflect the fact that individuals examined in an otolaryngologist's office are more likely to have acid reflux disorders than the general population. overall, the atopic subjects did have a higher incidence of acid reflux disorders, but there was no statistical significance between subjects with and without food allergy. a. suryadevara * , d.l. hamilos, boston, ma. introduction: recent studies suggest that crs without nasal polyposis (crssnp) and crs with nasal polyposis (crscnp) represent distinct pathologic entities. we wished to determine whether these conditions differed in their clinical presentation. methods: over a two-year period, new patients coming to a university based specialty clinic meeting criteria for crs were enrolled in an outcomes study. patients indicated which of four major (facial pain/pressure/headache, nasal obstruction, nasal purulence/discharge, and hyposmia/anosmia) and four minor (fever, halitosis, dental pain, cough) criteria for crs they were experiencing. rhinoscopy was performed to look for nasal polyps or polypoid tissue in any sinus area. the prevalence of each symptom was compared in the groups by chi square analysis. results: the population (n=126) had a mean age of 46 +/-13.6 and was 59% female, 86% caucasian, 8.7% african-american, 1.6% asian and 1.6% hispanic. most patients (87%) were non-smokers. all had at least 2 major criteria or 1 major + 1 minor criteria for crs at enrollment. forty-one patients (32.5%) had crscnp. the mean number of major criteria was greater in the crscnp than crssnp (3.27 vs 2.91, p=0.017). nasal obstruction and hyposmia/anosmia were more prevalent in crscnp (p= 0.05, 0.025 respectively). facial pain/pressure/headache was more prevalent in crssnp (p=).025). the most prevalent symptoms in crscnp were: nasal purulence/discharge (97.6%)>hyposmia/anosmia (85.4%)>facial pain/pressure/headache (82.9%)>nasal obstruction (61%). in contrast, the most prevalent symptoms in crssnp were: facial pain/pressure/headache (95.3%)>nasal purulence/discharge (88.2%)>hyposmia/anosmia (64.7%)>nasal obstruction (42.4%). none of the symptoms were absolutely distinguishing of these conditions. no differences were found between the two groups for fever, halitosis, dental pain or cough. conclusion: we conclude that patients with crscnp have a greater burden of symptoms of crs and a much higher prevalence of hyposmia/anomsia. these findings are consistent with other studies showing that, in comparison to crssnp, crscnp tends to be more difficult to treat and have a higher rate of relapse after intensive medical therapy (subramanian et al, am j rhinology 2002;16:303). l.e. mansfield 1* , e.e. philpot 2 , c. posey 1 , 1. el paso, tx; 2. research triangle park, nc. daytime sleepiness is a common complaint in sar. patients often complain of mental slowness, difficulty in concentrating, and thinking. the present study evaluated whether effective therapy of sar would decrease dss and improve an objective measure of cp. dss was measured using the epworth sleep scale (ess). objective cp was measured using the test of variables of attention (tova), a validated test. thirty two adults (15 males, 17 females with a 2 year history of sar, a compatible physical exam, and corresponding positive allergy testing) volunteered for this 3 week randomized double blind placebo controlled study. after a one week inf placebo (pl) baseline, the subjects received either active inf or continued pl. they maintained daily nasal symptom dairies and ess. the subjects took the tova test at the end of week1 and week3. weekly nasal symptom scores significantly improved with the inf, but not the pl. w1 vs. w3 nasal congestion inf 29, 24 p=.03, pl 29, 26 p=ns; runny nose inf 22.5, 19.9 p=ns; pl 21.75, 21.38 p=ns; sneezing inf 26.5, 19 p=.01; pl 24.9, 21.1 p=ns. total weekly ess was abnormal and decreased significantly in the inf group, but not in pl group. w1 vs. w3 inf 60.5, 46.5 p=.001, pl 52.6, 46.8 p=ns. response time of the tova testing, initially somewhat slow, significantly decreased in inf but not pl treatment. w1 vs. w3 inf 435 msec, 385 msec p=.02; pl 360 msec, 359 msec p=ns. these results demonstrate that sar is associated with dss and cp problems. the mechanism is likely to be sleeping disordered breathing associated with nasal congestion and obstruction. effective treatment of nasal congestion with inf led to decreased dss and improved cognitive performance. l.e. mansfield 1* , c. graham 2 , 1. el paso, tx; 2. new york, ny. there is increasing recognition that sleep disturbance and daytime tiredness occur during active ar. the mechanism appears to be nasal congestion and obstruction leading to sleep disordered breathing and resultant poor quality of sleep. in our practice, as part of the initial history, questions regarding fatigue, snoring, sleep problems, and tiredness are addressed. sleep problems and tiredness are graded according to the following scale: effect on daily activity ; 0=not troubled;1= a little trouble; 2=somewhat troubled ;3= trou-bled a lot ; 4= total disruption. we reviewed 272 consecutive charts of patients with allergic rhinitis documented by history, physical examination and allergy testing. there were 169 females and 103 males; age range 5y to 84y. 127 (47%) of patients or parents recognized they commonly snored. 40 (15%) stated they were chronically fatigued. the graded answers concerning sleep problems and tiredness were even more revealing of ar patient's perception of their problems see table in general, the higher sleep problem responses were associated with higher tiredness scores. national surveys of unselected populations suggest that about 10 percent of adults consider themselves to have sleep problems. the high frequency of sleep related problems and tiredness in our sample has prompted us to add more detailed questions regarding sleep related events to our intake history. it is our opinion that questions specifically related to sleep and daytime tiredness should be included in all evaluations for allergic rhinitis. we conclude that sleep related problems and tiredness may be more common in patients with allergic rhinitis than previous reported. r.w. weber 1* , j. garcia 2 , r. faruqi 2 , d. banerji 2 , g. georges 2 , the study 405 investigator group 3 , 1. denver, co; 2. bridgewater, nj; nj. introduction: the intranasal glucocorticosteroid triamcinolone acetonide (taa) is a safe and effective treatment for persistent allergic rhinitis (par). a new hydrofluroalkane-134a (hfa) propellant delivery system (taa-hfa) has recently been developed. this study primarily assessed the long-term safety of taa delivered via this new device, as well as its long-term efficacy. methods: 396 patients aged 12-69 yrs (mean=32) with par enrolled in this 1-yr, open-label study at 10 centers in the us. patients received taa-hfa 220 î¼g once daily for a 2-week run-in period before adjusting the dose to 440 î¼g or 110 î¼g once daily based on symptom severity. doses were standardized to 440 î¼g once daily across all patients at ~4 months to ensure sufficient long-term safety data at the maximum dose. physical exams, including measurement of vital signs and laboratory measurements were taken at baseline, 6 months and study end. independent patient and physician global symptom evaluations were performed at baseline, week 2 and months 1-12 thereafter. patients recorded any adverse events (aes) on daily diary cards. results: of the 396 patients included in the study, 349 (88.1%) reported aes. the incidence of aes was similar to that of other comparable allergic rhinitis long-term studies. the most frequently reported aes were pharyngitis, rhinitis, local reactions, headache, epistaxis and sinusitis (table 1) . most aes were mild-to-moderate in intensity; 34 patients withdrew from the study due to aes. there were no clinically relevant changes in physical exams, vital signs or laboratory measurements. a total of 4 serious aes (saes) were reported; breast carcinoma (n=1), depression (n=1), post-operative spinal fluid leak (n=1) and staphylococcal infection (n=1). saes were thought to be not related to the study drug. at final visit, 83% of patients had either moderate or marked/complete relief of symptoms using global symptom scores. similarly, 86% of physicians rated their patients as having either moderate or marked/complete relief. conclusions: long-term administration of taa-hfa 440 î¼g exhibited a good safety and tolerability profile, while providing moderate-to-complete symptom relief in more than 80% of patients treated for par. introduction: second-generation, 'non-sedating' antihistamines (ahs) have lower tendency to cross the blood-brain barrier and cause central nervous system side effects than first-generation agents. however, studies have suggested differences between second-generation ahs regarding cognitive function impairment. methods: a medline literature search was performed using the search terms 'antihistamine and impairment', 'antihistamine and psychomotor' and 'antihistamine and central effects', as well as with individual ah names (acrivastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mequitazine and mizolastine). the findings for second-generation ahs were reviewed and well-designed, placebo-and positive-controlled studies in humans using objective measures of cognitive impairment were included. results: 43 publications were identified as the inclusion criteria. all included objective assessments such as driving performance, critical flicker fusion and divided attention tasks. there was a large variation in the numbers of available well-designed studies; the most rigorously assessed agents were fexofenadine and cetirizine. a number of the ahs (ebastine, acrivastine, loratadine, mequitazine and mizolastine) were not impairing at recommended doses, but were at higher doses. in a small number of available studies, the newer ahs desloratadine and levocetirizine produced no impairment at recommended doses (5 mg); however, higher doses were not investigated. cetirizine studies were variable; impairment at the recommended 10 mg dose or higher was seen in a number of studies. in contrast, fexofenadine hcl, up to a dose of 360 mg, was non-impairing in a large number of studies. only one study indicated impairment in one task (critical tracking) and this was only observed with the first doses of fexofenadine hcl (120 and 180 mg) and not subsequent doses; however, the authors concluded that doses up to 240 mg/day should be safe for patients who drive. conclusion: while second-generation ahs are less impairing than the first-generation, some newer ahs produce impairment at or above the recommended dose. these differences become important to the patient when agents cause sedation or if patients over use beyond the recommended dose. in conclusion, fexofenadine was the only ah found to be non-impairing in all studies, even at double the recommended us dose. s. shaver 1 , r.b. berkowitz 1* , c. lutz 1 , p. jones 1 , c. qiu 2 , s. meeves 2 , s.t. varghese 2 , g. georges 2 , 1. woodstock, ga; 2. bridgewater, nj. introduction: fexofenadine (fex) is a h1-receptor antagonist, with proven efficacy in the treatment of allergic rhinitis (ar). to date, no live cat-room challenge studies have assessed the efficacy of fex in cat-allergen induced ar. this study assessed the efficacy of a single dose of fex hci 180 mg in preventing and controlling cat-allergen induced ar using the cat-room challenge model. methods: this single-center, prospective, randomized, doubleblind, placebo-controlled, two-way crossover study consisted of a screening visit, one or two priming visits and two treatment periods, separated by a 14 (â±3)-day wash-out. qualifying subjects were randomized to treatment sequence 1 (placebo followed by fex) or 2 (fex followed by placebo). baseline endpoints were obtained prior to study drug administration, and 5 minutes before entering the cat challenge room for allergen challenge. allergen challenges were initiated 1.5 hours post-dose, for both treatment periods. the primary endpoint was the change from baseline in total symptom score (tss; sum of rhinorrhea, itchy nose/palate/throat, sneezing and itchy/watery/red eyes) after 30 minutes of allergen exposure at 2 hours post-dose, compared with placebo. other endpoints included changes in individual symptom scores, including nasal congestion. levels of airborne felis domesticus allergen 1 (fel d 1) were determined. results: of 211 subjects screened, 66 were randomized and 63 completed the study; 32 and 31 in sequence 1 and 2, respectively. mean change in tss from baseline was significantly less with fex compared with placebo at 30 minutes after initiation of the cat allergen challenge (p=0.0327). significantly greater percentage reductions in the individual symptom scores for sneezing (p=0.0037) and nasal congestion (p=0.0455) were observed with fex compared with placebo, 30 minutes after challenge. although levels of fel d 1 varied widely, they were balanced between treatment groups. the overall incidence of treatment-emergent adverse events (aes) was low and comparable between groups; no serious aes occurred. conclusion: this study demonstrated that a single dose of fex hci 180 mg is effective and well tolerated as a prophylactic agent for alleviating the ar symptoms induced by exposure to cat allergen. further large-scale clinical trials are warranted to confirm these findings. rationale: allergic rhinitis in children is thought to be associated with several co-morbid disorders. we conducted the following study to assess whether children with diagnosed hypertrophy of tonsils and/or adenoids evaluated by an allergist were more likely to demonstrate objective evidence of allergen sensitization than children similarly evaluated without evidence of these upper airway obstructions. methods: records from the past ten years were identified in the hospital database by presence of an allergy clinic visit and an icd-9 code for hypertrophy of adenoids and/or tonsils. we reviewed these records to confirm that the diagnosis was accurate. we included subjects if reliable skin prick or in vitro testing for specific ige to aeroallergens was performed. for comparison, we randomly obtained an age and testing-type similar sample. first group subjects were excluded from the second group. skin testing was performed with commercial allergen extracts applied with a dermapikâ©. in vitro testing was by unicapâ© feia. positive skin testing had at least a wheal 3 mm or flare 10 mm greater than the negative control. positive in vitro values were 0.7 ku/l or greater or a positive pollen mix. additionally, we performed a search in an insurance database to determine how many local children had a code for allergic rhinitis. results: of 202 pediatric allergy patients with adenoid/tonsillar hypertrophy tested, 41.6% (95% ci +/-6.8%) had at least one positive test. in 802 without adenoid/tonsillar hypertrophy, 50.7% (95% ci +/-3.5%) had at least one positive test. the observed difference was 9.1 % (95% ci +/-7.6%). the standard error of the difference in percentage was 3.94; the z score was 2.3. the corresponding p value is 0.02. the percentage of 70, 356 children with an allergic rhinitis icd-9 was 15.6% (95% ci +/-0.3%). conclusion: the number of allergist-referred children with adenoid and/or tonsillar hypertrophy testing positive for an aeroallergen is slightly less than the number of similar children without these diagnoses testing positive. it is not clear that adenoid/tonsillar hypertrophy is associated with a higher risk of allergic rhinitis. a prospective study with allergy testing of all children with adenoid and/or tonsillar hypertrophy might provide information that could alter referral patterns. w.e. berger 1* , w. storms 2 , s. kimura 3 , m. beck 4 , s. galant 5 , t. westbrook 3 , 1. mission viejo, ca; 2. colorado springs, co; 3. pensacola, fl; 4. miami, fl; 5. orange, ca. background: patients having allergic rhinoconjunctivitis are often treated with nasal spray or systemic allergy therapy, forgoing therapy specifically targeting ocular symptoms. the rhinitis quality of life questionnaire (rqlq) and allergic conjunctivitis quality of life questionnaire (acqlq) instruments can be used to quantify the relative benefit of varying medication regimens. objective: to determine the extent of benefit gained in quality of life when an eye drop treatment for ocular allergy (olopatadine) was added to rhinitis patients' preexisting regimen of nasal or systemic allergic treatment. methods: this was a four week prospective, multi-center, open-label crossover, quality of life study occurring during allergy season. at visit 1, patients completed the rqlq and acqlq questionnaires to assess baseline quality of life. patients were randomized to receive ocular allergy therapy (olopatadine, patanol bid) concomitant with their systemic or nasal rhinitis treatment(s) for 2 weeks between either visit 1 and visit 2 (group a) or between visit 2 and visit 3 (group b). at visit 2 and visit 3, patients completed the rqlq and acqlq. results: a total of 200 patients completed this study: 97 in group a, 103 in group b. of these, 181 (90.5%) experienced eye allergy symptoms at least 1 day during the previous week as reported in the baseline acqlq. baseline scores of the rqlq and acqlq for both groups were comparable. clinically significant improvement from baseline in global rqlq and acqlq was seen following addition of ocular therapy for both groups (rqlq: -1.07, -0.94; acqlq: -1.2, -1.2). similar improvement was seen across all domains of both questionnaires. the acqlq correlated with the rqlq in the applicable domains. conclusion: many allergic rhinitis patients using nasal or systemic medication also suffer from ocular allergic symptoms. for these patients, quality of life improvement is not maximized; the addition of a topical antiallergy eye drop can result in beneficial effects on quality of life. in this study, the addition of olopatadine eye drops to these patients' medication regimens resulted in significant improvement in not only eye symptom related quality of life domains but in overall quality of life. h. milgrom 1* , r. lanier 2 , f.c. hampel 3 , b. kittner 4 , 1. denver, co; 2. fort worth, tx; 3. new braunfels, tx; 4. bridgewater, nj. introduction: fexofenadine, a non-sedating, selective h1-receptor antagonist, is currently indicated for use in children aged 6-11 years with seasonal allergic rhinitis in a number of countries, including the us, and has an excellent safety profile in this age group. this study was designed to assess the safety and tolerability of fexofenadine in children aged 2-5 years with allergic rhinitis (ar). methods: the study had a multicenter, double-blind, randomized, placebo-controlled, parallel-group design. children aged 2-5 years (n=453) with ar were randomized 1:1 to either placebo twice daily (bid; n=231) or fexofenadine hcl 30 mg bid (n=222), for 2 weeks. both treatments were given orally as granulated powders (capsule content) mixed with two teaspoons of apple sauce. treatment-emergent adverse events (teaes) were recorded for all subjects by parents/caregivers and assessed by investigators. clinical laboratory variables, physical examinations, vital signs and ecg evaluations were also assessed in a subgroup of children (placebo, n=79; fexofenadine, n=71). results: baseline demographics were similar in both treatment groups. while approximately 50% of children in both groups experienced at least one teae, no unusual or unexpected teaes were observed in the fexofenadine group. when the total group was analyzed for teaes by body system, or assessed separately by age groups of 2-, 3-, 4-and 5-year-olds, no clinically meaningful differences were observed between the two treatment groups. in both treatment groups, the majority of subjects overall and in each age group experienced teaes rated as mild or moderate in intensity. few subjects experienced teaes considered possibly related to study medication (placebo: 8.2% [19/231]; fexofenadine: 9.5% [21/222]). the percentage of discontinuations due to teaes was also comparable between treatment groups (placebo: 6.9% [16/231]; fexofenadine: 5.0% [11/222] ). in the subgroup assessment, no clinically relevant changes were seen from baseline for laboratory variables, vital signs, ecgs or physical examinations in either treatment group. introduction: the efficacy and safety of fexofenadine hcl 30 mg bid has been proven in two large phase iii studies in pediatric subjects aged 6 to 11 years with seasonal allergic rhinitis. in addition, the safety of fexofenadine has been demonstrated in pediatric subjects 2 to 5 years of age with allergic rhinitis (ar). subsequently, two studies (t/3001; t/3002) have assessed the pharmacokinetics, safety and tolerability of fexofenadine 15 and 30 mg bid in pediatric subjects 6 months to 2 years of age. methods: both studies were of multicenter, randomized, double-blind, placebo-controlled, parallelgroup design and enrolled pediatric subjects aged 6 months to <1 year weighing 10.5 kg and aged â±1 year to <2 years weighing >10.5 kg. all subjects had a diagnosis of ar as assessed by previous medical history, pattern, or suggestive physical findings. subjects were randomized to receive fexofenadine hcl 15 mg (t/3001), or 30 mg (t/3002) granulation powder twice-daily, or placebo for a minimum of 7 days. safety was evaluated based on adverse events (aes), vital signs, 12-lead electrocardiograms (ecgs), and physical examinations. results: a total of 174 and 218 subjects were randomized in studies t/3001 (fexofenadine hcl 15 mg bid: n=85, placebo: n=89) and t/3002 (fexofenadine hcl 30 mg bid: n=108, placebo: n=110), respectively. in t/3001, 40.0% (34/85) of children receiving fexofenadine and 42.7% (38/89) receiving placebo experienced at least one treatment-emergent ae (teae). in t/3002, the incidences of teaes were 35.2% (38/108) and 52.7% (58/110), respectively. in both studies, most of the teaes experienced were mild or moderate in intensity. the incidence of possibly-related teaes was also similar for both treatments in each study. no clinically relevant changes from baseline to study end were observed for vital signs, ecgs and physical examinations. conclusions: the findings of this study show that fexofenadine 15 mg and 30 mg bid are well tolerated and have a safety profile comparable to placebo in pediatric subjects aged 6 months to 2 years. for seasonal allergic rhinitis (sar) patients that remain symptomatic on an h1-receptor antagonist, cetirizine, and a nasal glucocorticosteroid, mometasone furoate, the addition of omalizumab, a recombinant, humanized, chimeric, anti-ige monoclonal antibody, may provide additional efficacy in sub-optimally controlled seasonal allergic rhinitis patients. in this open labeled 12week trial, 20 patients with symptomatic sar currently using cetirizine, 10 mg qd, + mometasone furoate, 100 mcg/nostril qd, were randomized to continue the existing therapy cetirizine + mometasone or to add-on omalizumab subcutaneously (every 2 weeks to 4 weeks) dosed according to patient's weight, and baseline ige levels to the existing therapy cetirizine + mometasone furoate. the endpoints of the trial include: rhinomanometry, nasal symptom score (composite score of nasal congestion, rhinorrhea, sneezing, post nasal drip and itching) and flexible rhinopharyngolaryngoscopy examination. mean efficacy measurements at the end of the 12-week trial revealed a significant improvements in all parameters examined in the treatment group receiving omalizumab (as add-on to the existing therapy), compared to the other group. in conclusion, the addition of omalizumab to the combination of cetirizine plus mometasone furoate, is more effective than the combination of cetirizine plus mometasone furoate, for the treament of seasonal allergic rhinitis patients. it appears that when omalizumab is added to the combination h1receptor antagonist, cetirizine, and nasal corticosteroid, mometasone furoate, the primary end points (rhinomanometry and symptom scores) are significantly improved. background: based on the official statistic data, the prevalence of allergic diseases in russia has increased more than 3 times during the past 10-15 years, but still the lowest of all european countries. in some studies done in some regions of russia based on isaac program, it has been shown that the prevalence allergies is significantly higher than indicated in official statistics of health departments. the goal of this investigation was to study the prevalence of allergic diseases, in children of south russian region. meth-ods: this study was done in two steps according to isaac program guidelines. in the first step a questionnaire was given to a total of 6558 school children, ages 7 to 8 (group a) and 13 to14 years old (group b), from the two cities of krasnodar and novorossiysk in southern russia. in the second step a physical exam, skin prick tests with different allergens (pollens, molds, cat, dust mites, foods etc.), and pulmonary function tests were performed. results: wheezing was reported in 12.9% of group a and 15.3% of group b children within the past 12 months. the severity of asthma reported was mild in 72% (group a)-84% (group b); moderate in 16.7% (group a)-10.7% (group b) and severe in 3.4% (group a)-5.8% (group b) in studied children). majority of the cases of asthma was noted to be allergic asthma. in both groups of children there was a high incidence of allergies to perennial allergens such as dust mites, cats, molds and other indoor allergens, 18.7% (group a) and 77.3% (group b). the percentage of allergies to pollens was 19.1% and 33.0%, accordingly. allergic rhinitis symptoms were noted in 26.6% (group a) and in 38, 6% (group b). atopic dermatitis symptoms with skin itching observed in 8.3% (7-8 years old)and 5.3% (13-14 years old). family history of atopy was noticed in 34.6% of group a and 41.6% of group b children. conclusions: the prevalence of allergic diseases in south russia is similar to the ones in most of the european countries. the prevalence of asthma has been associated with increased incidence of allergies, due to indoor and pollen allergens. the prevalence in rhinitis and atopic dermatitis in south russia is parallel to asthma. acknowledgement: we would like to thank hollister-stier lab., greer and antigen lab. for allergen samples. objective: to examine the cost and effectiveness of telithromcyin vs. azithromycin for treatment of mild acute sinusitis under current levels of antimicrobial resistance. methods: we considered an adult with mild acute sinusitis, and symptom duration of 7 days. a decision analytic model was created to compare 2 strategies of 1st-, 2nd-and 3rd-line therapies: azithromycin/amoxicillin-clavulanate/levofloxacin (azi/amc/lev), and telithromycin/amoxicillin-clavulanate/levofloxacin (tel/amc/lev). we considered 3 outcomes: response to initial therapy, cost, and time to completion of all antibiotic therapy. clinical resolution was due to response to antibiotic, or to spontaneous resolution. we assumed bacteria that were resistant in vitro would only be resistant in vivo 50% of the time. resistance levels were based on the 2000-2001 us protekt surveillance study. model parameters, such as prevalence of bacterial infection, frequency of causative pathogens, and rates of spontaneous resolution, were based on the published literature. those failing to improve after 5 days were switched to next line therapy. we analyzed claims data from 8 managed care organizations to estimate non-drug charges for initial and follow-up care, and applied a 60% cost-to-charge ratio. drug costs were estimated using the wholesale acquisition cost plus $8 for overhead and dispensing. all costs were adjusted to year 2004 $us. results: the model predicted the tel/amc/lev strategy would result in 71.8% improving by 5 days compared to 65.4% for azi/amc/lev. the telithromycin strategy had lower mean cost, $172 vs. $176. although telithromycin cost more than azithromycin, the tel/amc/lev strategy had slightly lower total drug costs ($95 vs $96) due to less need for additional antibiotic courses. mean time to completion of therapy was 8.4 days for tel/amc/lev and 9.1 days for azi/amc/lev. sensitivity analyses showed that tel/amc/lev had superior health outcomes even when only 5% of in vitro resistant organisms were also resistant in vivo. tel/amc/lev also had lower cost if at least 30% of cases were bacterial, or if in vitro resistant organisms were at least 30% resistant in vivo. conclusion: based on results obtained using this decision analytic model, initial treatment of mild acute rhinosinusitis with telithromycin may result in improved outcomes and lower cost than initial treatment with azithromycin. rationale: "delta crud" is the term used to describe rhinosinusitis syndromes in the mississippi delta region. local perception is that it is associated with chemical crop dusting, regional produce, especially cotton, or high rates of mold allergy. the climate is extreme with mild winters, hot humid summers, and large volume rain. thirty-five percent of inhabitants live below the poverty level, 62% are african american. patients from the agriculturally intensive delta suffer from asthma at almost twice the rate of those in the neighboring hills. rates of pesticide use are among the highest in the nation. there are no prevalence estimates for rhinosinusitis in this region. "delta crud" is chronic in many patients with exacerbations occurring in the summer and fall, especially during chemical spraying and defoliation. we conducted this cross-sectional questionnaire based pilot study to begin characterization of rhinosinusitis in this population. method: the sinusitis treatment outcome questionnaire, with two modifications, was given to consecutive patients presenting to the north sunflower regional hospital er and the sunflower outpatient clinic one month prior to the beginning of summer crop dusting. the question, "do you have delta crud?" was added. the survey was anonymous, allowing irb exemption. results: 91 consecutive patients returned completed questionnaires. 46(50%) admitted to having "delta crud". patients who claimed to have delta crud had significantly more sinus headache, nasal pruritus, conjunctivitis, and chest symptoms (see table) . there was no significant difference in antibiotic prescriptions, er visits, and missed work. six patients with delta crud had been hospitalized for "allergy reasons" compared with three patients without delta crud. despite severe symptoms just 4 patients received sinus ct scans. only 10/46 patients were prescribed intranasal corticosteroids. conclusion: in our pilot study, the prevalence of chronic rhinosinusitis symptoms (delta crud) is 50%, with severe sinus, pulmonary and ocular symptoms. evaluation and treatment may be suboptimal in this economically disadvantaged rural region. further characterization of "delta crud", pollen counts, ige mediated disease, environmental contributions and comparative studies of related regions are needed. introduction: patients with rhinitis commonly experience sinus pain and pressure (sp+p). many patients with recurrent acute bacterial sinusitis (rabs) base the presence of a recurrence on the severity of sp+p and other nasal symptoms. the ability of patients to differentiate between rhinitis and rabs was evaluated by reviewing the subject screening logs of 4 previously reported clinical trials of flonase (fluticasone propionate) nasal spray, 50 mcg (fp). methods: the efficacy of fp was studied in two trials in subjects with sp+p due to allergic rhinitis and in two trials of subjects receiving cefuroxime axetil to treat an acute episode of rabs. sp+p screening logs were examined to determine how many subjects who thought they had sp+p were excluded from the study for an upper respiratory or sinus infection. rabs screening logs were examined to determine how many subjects with symptoms of an acute episode of rabs were excluded from the study for a negative sinus x-ray or ct scan. rabs symptoms experienced at the screening visit by subjects who qualified for the study were also evaluated. results: of 505 subjects screened in the sp+p studies, only 4 (0.8%) were excluded for evidence of sinus or upper respiratory tract infections, as clinically diagnosed by the investigator. out of 1502 subjects with screening log data in the rabs studies, 649 (43.2%) were excluded for a negative sinus x-ray or ct scan. of the 704 subjects who qualified for the rabs study, the most prevalent symptoms included nasal congestion (100%), mucopurulent discharge (97%), facial pain or tenderness in the sinus area (93%), sinus headache (90%) and malaise (90%). only 15% of subjects had a fever. only one symptom, nasal congestion, was rated by clinicians as severe for greater than 40% of subjects in either study (46% and 43%). conclusions: while most subjects can determine when sp+p is due to allergic rhinitis, many cannot determine when symptoms progress to a sinus infection. symptoms experienced by subjects with rabs were consistent with inflammation, but did not include fever as may be expected with an untreated bacterial sinus infection. under appreciation by patients for the role of inflammation in sinus disease may result in over self-diagnosis of sinus infection and the demand for antibiotics. liposomes are small particles consisting of lipid bilayer membranes, which are used to deliver drugs including amphotericin b, more efficiently and with less toxicity. very few cases of allergy to liposomal amphotericin b (lab) have been reported to date. although there is a report on conventional amphotericin b (cab) desensitization, to our knowledge no case of lab desensitization has been described yet. a 75 y/o patient with lymphoma was treated with lab for pulmonary aspergillosis. within 30 minutes of infusion he developed urticaria, hypotension and tachycardia for which he was treated with the appropriate drugs for anaphylaxis. a second attempt to re administer lab resulted in a similar anaphylactic reaction. desensitization to lab was then successfully completed using a modified protocol based on desensitization to cab (jaci 1995; 96:425-7) : 0.0005 mg infusion over 10 minutes 0.005 mg infusion over 10 minutes 0.05 mg infusion over 10 minutes 0.5 mg infusion over 30 minutes 5 mg infusion over 30 minutes 50 mg infusion over 30 minutes 100 mg infusion over 30 minutes 200 mg infusion over 120 minutes conclusion: desensitization to lab, a lifesaving drug for invasive fungal diseases, can be performed successfully. adverse events (aes) were recorded throughout the study. therapeutic comparability was defined a priori as a clinical response within 30% for hfa vs cfc for the primary efficacy measures. results: baseline demographics were similar between treatments for the intent-to-treat population. mean 24-h baseline symptom scores for nasal stuffiness, nasal discharge and sneezing were 2.4, 2.3 and 2.1, respectively, out of a possible score of 3. all taa-cfc and taa-hfa doses significantly (p<0.05) reduced 24-h, and am and pm 12-h reflective scores for nasal stuffiness, nasal discharge, sneezing and ni vs placebo (except cfc 14 î¼g for sneezing). taa-hfa and taa-cfc were statistically comparable (within 0.70 and 1.3 for the 2 one-sided 90% confidence interval) at doses of 110 î¼g and 440 î¼g for the primary variables of nasal discharge, sneezing and ni for the 24-h, as well as the am and pm 12-h reflective assessment, over the 2-wk period 36 * , 66 * agrawal p27, p35, 41, p58, p105, p106, p110, p180 41 * , p21, p27, p58 * p105, p106, p110, p180 p7 * finegold, i. 42 * fink p21 * 26 * sienra monge 45 * , 55, 62 * so, c. p52 * soane 70 * , p143 * staveren, a.m rates of cardiovascular mortality are higher during peak pollen times. (brunkreef, lancet 2000) . for this reason, mast cell stabilizing agents and leukotriene antagonists are under development for the treatment of myocardial infarction. conversely, ige mediated disease may be protective against sudden cardiac death.(szczeklik, coron art dis 1993) ar has not been studied in this context. we conducted a retrospective case control pilot study of va patients who were diagnosed with allergic rhinitis and had an acute myocardial infarction. methods:the electronic medical record of a large va hospital was queried for patients diagnosed with an acute myocardial infarction (ami) in the past six years. patients were divided into groups with and without ar. patients with chronic urticaria, asthma, and eczema were excluded from this study. primary outcome was all-cause mortality. secondary outcomes included lv systolic function and peak troponin levels. results: 424 patients were diagnosed with ami, 63 (15%) of which were also diagnosed with ar. patients with and without ar did not differ in terms of age, ethnicity, tobacco status, hypertension, diabetes, or lipid levels. 14/63 (22%) patients with ar died, compared to 152/361 (42%) control patients, (p-value: 0.0028). ar patients had lower mean peak troponin values (7.7 vs. 11.8), but these were not significant. both groups had similar lv function. conclusion: this pilot study suggests an association between allergic rhinitis and a decrease in ami allcause mortality independent of other factors. atopic patients have been shown to have prolonged bleeding times, reduced platelet aggregation, and delayed thrombin generation which can result in delayed clot production. (szczeklik, thromb haem 1986) possibly, patients in our study diagnosed with allergic rhinitis were more likely to monitor their health symptoms or had physicians who carefully addressed multiple issues. rigorous prospective studies are needed to determine the role of ar in myocardial infarction. purpose and methods. a formulation of olopatadine hydrochloride ophthalmic solution (olopatadine 0.2%) was evaluated in a randomized, placebocontrolled, double-masked, hybrid environmental study intended to determine efficacy and safety in 240 subjects with histories of seasonal allergic conjunctivitis or rhinoconjunctivitis. in this 12-week trial, subjects regularly assessed their ocular signs and symptoms. additionally, subjects evaluated both the frequency and severity of their nasal symptoms. daily throughout the study, ragweed pollen counts were obtained from each investigative center. repeated measures analysis of variance was used to compare treatment differences in the slopes for nasal symptoms as a function of pollen counts. results. the nasal results are presented herein. specifically, relative to placebo, olopatadine 0.2% significantly reduced the frequency of pollen effects on sneezing (p=0.0355) and itchy nose (p=0.0032), and reduced the severity of pollen effects on sneezing (p=0.0451), itchy nose (p=0.0178), and runny nose (p=0.0327). in this study, the most frequent ocular adverse event that was related to therapy with olopatadine 0.2% was ocular dryness, occurring at an incidence of 1.7%. no treatment-related, clinically relevant changes were observed for visual acuity, intraocular pressure, ocular signs, or fundus parameters. conclusion. olopatadine ophthalmic solution, 0.2% is safe, well-tolerated, and effective in reducing some effects of pollen on the nasal symptoms associated with allergic rhinoconjunctivitis. author index key: cord-022650-phsr10jp authors: nan title: abstracts tps date: 2018-08-14 journal: allergy doi: 10.1111/all.13539 sha: doc_id: 22650 cord_uid: phsr10jp nan (either in men or women) between metabolic syndrome and incident asthma. conclusion: this study confirmed the significance of obesity as a risk factor for incident asthma. moreover, obesity appeared to be a stronger risk factor than metabolic syndrome. 0638 | relationship between helminth infection, blood eosinophils and asthma symptoms in a rural community from the tropics peñaranda d; alvarez l; sierra n; lopez j; zakzuk j; caraballo l institute for immunological research. university of cartagena, cartagena, colombia background: immune response to helminths shares many features with the allergic response. in tropical regions where helminths are highly prevalent, asthma is still a major public health burden. large clinical cohorts suggest that high blood eosinophils (hbe=>400 cells/ mm 3 ) are associated with asthma exacerbations. however, the association between hbe and asthma severity in rural communities with prevalent helminthic infections is unclear. method: patients with wheezing symptoms in the last year living in a rural tropical community (santa catalina, colombia) where helminths are highly prevalent, were recruited for this study. blood eosinophils were assessed by complete blood count. parasitic infection was evaluated with two serial coprological exams (kato-katz method) and skin prick tests were conducted to determine reactivity to ascaris. results: seventy-three patients (mean age: 21; range: 2-64 years old) were recruited in this study. a. lumbricoides and t. trichuria active infection (47.9% and 16.4%, respectively) were not related to age or gender. a positive spt to ascaris extract, aba-1 and d. pteronyssinus was observed in 23%, 18.4% and 34.2%, respectively. mean eosinophil count was 621 cells/mm 3 ; 43.9% had hbe. rate of patients with at least one emergency department visit was 61.9% and hospitalization, 21.9%. blood eosinophil counts (as a continuous variable) were inversely associated with age (p = 0.03) and higher in helminth infection (p = 0.002). in crude univariate analysis, exacerbations (er and/or hospitalization) were associated with age (or: 0.96; 95% ci: 0.93-0.99, p < 0.01) and hbe (or: 2.9; 95%ci: 1.1-7.8, p = 0.04), but not with helminth infection. for a better definition of asthma, multivariate analysis done in those >7 years old indicated that hbe, helminth infection and positive ascaris spt were not associated with asthma exacerbations. conclusion: uncontrolled asthma is common in rural places of the tropics. since helminth infection influences eosinophilia, the clinical value of hbe to predict exacerbations is limited in helminth-endemic populations. castro mc 1 ; ferreira j 2 ; sarmento d 2 ; carvalho c 2 ; matos a 2 ; bicho m 2 1 chln-immunoallergy; lisbon medical school-genetic department, lisboa, portugal; 2 lisbon medical school-genetic department, lisboa, portugal background: the bioavailability of no and endothelial homeostasis depends on the functional polymorphism of 19-bp del/ins within intron-1 of dhfr (dihydrofolate reductase enzyme) (rs70991108) that could interfere in the regeneration of bh4 (tetrahydrobiopterin) from bh2 (7,8-dihydrobiopterin) and contributes to endothelial dysfunction in asthma. method: asthmatics (n = 123) compared with control group (n = 50).the polymorphism was analyzed by pcr. control of asthma assessed by (acq7 and paqlq). statistical analysis with spss 23.0 establishing a significance level of p < 0.05. results: there are 80 women and 43 males in asthmatics and 39 women and 11 males in controls (p = 0.137). in asthmatics: age ( x ± sd): 38.26 ± 19.24 ; and in control group: age ( x ± sd): 51.50 ± 13.34. the genotype frequencies in asthmatics are: dd (6.5%); id (66.7%); ii (26.8%); in control group: dd (12.0%); id (64.0%); ii (24.0%); there is no statistical difference between groups (p = 0.478). the allelic frequencies in asthmatics are: allele d (39.8%); allele i (60.2%); in control group: allele d (44%); allele i (56%); there is no statistical difference between groups (p = 0.476). the genotype frequencies in the uncontrolled asthmatics are: dd (0.0%); id (61.1%); ii (38.9%) ; in the controlled asthmatics are: dd (9.4%); id (68.2%); ii (22.4%); there is statistical difference between groups (p = 0.047). genotypes id and ii are more frequent in the uncontrolled asthmatics. the allelic frequencies in the uncontrolled asthmatics are: allele d (30.6%); allele i (69.4%); in the controlled asthmatics are: allele d (43.5%); allele i (56.5%); there is a trend to have differences between groups (p = 0.059). allele i is more frequent among uncontrolled asthmatics. the uncontrolled asthmatics are older than the controlled asthmatics (p < 0.001). there is no differences in gender distribution (p = 0.903). the genotype ii confers a risk of being uncontrolled asthmatic of 2.950 times when compared with controlled asthmatics and adjusted for age: or b : 2.950 [1.117-7.789 ]; p = 0.029. physiopathology and the emergence of evidence-based clinical guidelines. however, variation still exists among some diagnostic aspects of asthma in real life. it is unknown to what degree diagnosis is affected by the treating physician's medical specialty. results: a total of 62 gps, 239 pediatricians, 364 allergists, 161 pulmonologists and 34 otolaryngologists (orls) replied. although for general application of diagnostic clinical criteria all physicians rated similarly, in general accordance with the mag suggestions, a third of non-pulmonologist practitioners don't recognize chest discomfort as one of the clue symptoms of asthma, but they erroneously believe crackles are (p = 0.01). we found agreement in almost half of all physicians to erroneously believe that viral illness' induced wheezing in non atopic children predisposes asthma. conversely, 75-85% are aware that allergic sensitization predisposes to asthma. most specialists -except pulmonologists (p = 0.02)-incorrectly listed fev1 as the best parameter to identify airflow obstruction (ao) and fev1/fvc to assess ao severity. 20% of gps do not know peak expiratory flow (pef) measurements could be valuable, and 75% of all specialists are not aware that changes in pef can also be used to confirm ao reversibility. to classify asthma, only pulmonologists adequately considered the level of control in similar proportion than severity (81% and 83%, respectively), which is uniformly the preferred method by most other specialists. conclusion: although in general many clinical aspects of asthma diagnosis seem to be accurately assessed, there is a wide specialityspecific variation regarding some aspects of phenotyping and classification, diverging from mag's recommendations. as such, our results can help to detect knowledge-gaps and to guide the development of more focused specialty-specific learning tools to improve clinical impressions, process medical evidence, and apply it to patient care. 0652 | issues, continuous medical education on treatment of acute asthma, exercise induced asthma and asthma in pregnancy should include, per medical specialty background: to unify and improve the management of asthma, including asthma exacerbations, the mexican guideline on asthma (25.5%) of 51 employees who stated increased symptoms with flour exposure. among all workers 9 (5.5%) employees were diagnosed as asthma and 7 (4.3%) workers were diagnosed as ba. conclusion: wheat flour sensitivity is high among workers who are exposed to wheat flour, however the prevalence of ba is similar to the previous data in the literature. johnsen cr 1 ; callesen kt 2 ; jensen bm 2 ; poulsen lk 2 1 clinic of allergy, dept. of dermato-allergology, gentofte hospital, copenhagen, denmark; 2 laboratory of allergy, gentofte hospital, copenhagen, denmark background: enzymes are well known as sensitizers and causes of occupational allergy primarily in the industries producing and using the products. we present a case of occupational contact urticaria, rhino-conjunctivitis and asthma in a 32 year male chef who was using a transglutaminase enzyme powder obtained from fermentation of streptomyces mobaraense as meat glue in processing of fine culinary dishes. this transglutaminase has been used for protein food preparation in industrial settings since 1992 to improve the texture of protein rich foods such as surimi or ham. in this case it was used in small scale in a gastronomy restaurant kitchen spraying enzyme powder with a sieve over raw meat without any protective equipment in contrast to the producer's recommendation. the chef was also found allergic to dried, edible mushrooms also forming part of the meat dish prepared with the transglutaminase enzyme powder. in one occasion he experienced an oral reaction with itching and swelling of the mucosa in the mouth, stridor, angioedema of the face, and urticaria after ingestion of beef meat treated with transglutaminase and rolled in horn of plenty dried mushroom powder. no other symptoms of food allergy were reported but a known cat allergy was. background: formaldehyde and xylene are occupational skin and respiratory irritant and/or sensitizer, exposure to those may be associated with dermatitis, rhinitis and asthma. health care workers, as nurses, laboratory technicians, doctors could be exposed in different tasks in operating rooms, endoscopy and in pathology laboratory. we describe three cases of work-related rhinitis in technicians employed in the same unit of hospital pathology . first case: a woman of 38 years old underwent medical examination in our occupational allergy unit because allergy respiratory symptoms. she has been working for 8 years in pathology laboratory and was exposed to xylene and formaldehyde. she developed rhinitis, rhinosinusitis, hyposmia and cough with sputum after 5 years started work. she had negative skin prick test for common aeroallergens. lung function was normal with a fev1/fvc ratio of 80% of predict. blood cells count reveled 15% of eosinophils (980/mmc) with 6550 total leucocytes. second case: a woman of 40 years old was affected by moderate persistent allergic rhinitis with positive skin prick tests to house dust mite, dog and cat. in the last year rhinitis symptoms worsened in relation to work and improved during vacation. when she was exposed mostly to formaldehyde during shift at the end of it she usually experienced face skin and conjunctival erythema. she developed work-related symptoms after 14 years of exposure in the pathology unit. third case: a woman of 38 years old, who has been working for 14 years in the pathology unit and was exposed to formaldehyde and xylene, in the last year developed moderate-severe persistent rhinitis with hyposmia and chronic cough. she referred to otorhinolaryngologist and an irritant induced rhinitis was diagnosed. she had negative skin prick test for common allergens and normal lung function. results and conclusion: the workers experienced respiratory symptoms in relation to work exposure to formaldehyde and xylene. the suspected causal agents were monitored in the work environment and an exceeding of the recommended limit values was found. preventive measure were adopted with a reduction of exposure and symptoms improve only in the second and third case. challenge test with mannitol is considered to be more specific than test with methacholine. also, duration of procedure is shorter and safer. therefore the study aim was to compare the usefulness of these two tests in monitoring of sict. method: four bakery workers with suspicion of oa underwent single-blind, placebo-controlled sict with workplace allergens accompanied by evaluation of nsbhr with mannitol and methacholine before and after sict. clinical examination, spirometry, skin prick tests (spts) to common aeroallergens and occupational allergens, serum specific ige antibodies to occupational aeroallergens were also performed. results: positive spts results to occupational aeroallergens were found in all bakery workers, specific ige to flours were detected only in two subjects. three out of the four patients displayed positive sict reaction (in two cases early spirometric response). in all of these 3 patients, airway response to methacholine increased significantly. in the first two patients also airway reaction to mannitol was significant, whereas in one subject with early reaction there was no increase in nsbr after mannitol inhalation. the patient with negative sict results did not reveal any changes in nsbr before and after the test, neither to methacholine nor mannitol. 0668 | rice-induced occupational anaphylaxis and socio-economic impact-case report method: in this prospective study, a total of 240 students completed a self-administrated questionnaire that comprised different questions and gave information about the participants and their glove use, working habits, signs and symptoms related to these gloves, precautions taken to minimize it, etc. skin prick test is performed through commercial extract latex gloves (stallergenes), while patch test is prepared through latex gloves and adhesives. two types of gloves are used: gloves that contain latex and gloves without latex (vinyl gloves), which are used also as e negative control. results: questionnaire items and diagnostic tests revealed that one-fourth of subjects were suspicious for latex gloves hypersensitivity. their mean value for skin reactions like irritant or allergic dermatitis or contact urticaria was between 10% and 14%, while for other symptoms the mean value was under 5%. logistic regression analysis revealed an association between different questionnaire items and positive allergy tests among suspected cases and diagnosed cases of latex allergy. approximately 20% of people who work with laboratory animals experience some allergic symptoms and about 10% of animal technicians go on to develop serious symptoms of asthma. uk government guidelines state that employers must prevent or adequately control exposure of employees to animal allergens and should undertake monitoring to ensure that suitable controls remain effective. the most widely used monitoring method is personal iom filters. however, these need to be attached to a pump and carried by the technician which can be cumbersome and awkward. previous data has demonstrated that allergens from dust mite, cat, dog and pollen could be captured and quantified by a novel type of nasal filter. in this current study, we sought to assess the feasibility of using the nasal filters for the assessment of exposure to mouse allergen in a laboratory facility. method: technicians working in a laboratory animal facility were asked to wear the filters during normal routine work. for comparison, they were also asked to wear an iom filter for the same duration. allergen was extracted from nasal and iom filters by gentle rocking in pbs-tween for two hours. levels of the major mouse urinary protein (mus m 1) were quantified using our multiplex array technology, which is highly sensitive and allows for quantification of mus m 1 down to 0.01 ng/ml. results: significant levels of mus m 1 were detected in the nasal filter extracts and these levels correlated with the type of activity that was being performed by the technician, as well as the housing environment of the mice. levels were compared to the suggested 'safe' limit of allergen exposure of 5 ng/m 3 . we also found that the technicians grew accustomed to the nasal filters quickly and found them far more practical for every day monitoring that wearing the iom filter and pump. conclusion: these data indicate that nasal filters may be considered a simple and easily wearable method for monitoring laboratory animal allergen exposure. future studies are planned to assess the feasibility of wearing the filters for analysing exposure to other laboratory animal allergens from rat and guinea pig. havana university lower co 2 emission, water and feed consumption and limited waste production. insects are currently allowed both for human and animal feeding in some eu countries, including italy and the risk profile related to production and consumption of insects as food and feed, including risk of allergenicity, is currently under evaluation by efsa. both food and feed products derived from insects require multiple manipulations by the breeder and/or by the workers who transform the insect into the commercial products, thus the occupational exposure have to be considered too. the aim of this work is to evaluate the allergenicity of tenebrio molitor, one most used species for animal feeding. method: t. molitor proteins were extracted from intact dried larvae and from flour of dried larvae. the protein extracts were separated in one-dimensional electrophoresis conclusion: according to these results, the larva flour seems to be less immunoreactive than the intact counterpart, probably due to the processing that causes the degradation of protein bands over 50 kda. working in gastronomy is associated with exposure to many factors with an irritating and allergic potential influencing respiratory system. food products and organic dust are the source of inhaled allergens which may cause sensitization during apprenticeship. the study aim is a prospective observation of incidence of sensitization to selected environmental and occupational allergens among culinary school apprentices and identification of work-related allergic diseases in this group. method: the cohort comprised 374 apprentices. they were examined in the first and the second year of education. questionnaire and allergological tests [(skin prick test) spt to common and occupational allergens, ige level evaluation (total and specific for occupational allergens) and pulmonary tests] were performed]. results: the most frequent symptoms reported by examined apprentices were rhinitis (12.8%), conjunctivitis (7%), skin symptoms (6.7%), dyspnea (5.6%) and cough (2.7%). 10 subjects developed nasal symptoms during the second year of education, while in 6 cases the skin symptoms and in 4 subjects conjunctivitis appeared. in 7 cases the work-related symptoms were reported. the most frequent positive results of spts were obtained with dermatophagoides pteronyssinus 24.4%, dermatophagoides farinae 21.6%, grass pollens 18.6%. positive spt to rye and barley flour were found in respectively 2.2% and 1.4% apprentices. 4.1% of apprentices had specific ige to flours. the preliminary results indicate that work-related allergy symptoms and hypersensitivity to occupational allergens are rarely found among culinary school apprentices in the first years of education. the further observation will allow to evaluate the trends in incidence of allergy to occupational allergens, as well as the clinical presentation of allergy in that group. 0677 | how multifaceted the clinical presentation and etiology of allergic diseases could be? method: the study was done in children from west georgia randomly and on based of questionnaire of representative cohort. (2014) (2015) (2016) . the cohort was 1500 children, 1-16 years old, risk factors were studied by way of interviewing, clinical-laboratory dates. for assessing the risk factors, was used 'case control' method. the statistical processing of material was done with computer program sps/sv12. inclusion criteria for enrolment were: collectors of dust, gender, existence of moisture and mold consuming of tabasco, atopic dermatitis and seasonality. results: the groups, which we have studied, prevalence of acute respiratory viral infection was 61%, bronchitis −29.3%, allergic rhinitis 33.9%, atopic dermatitis 9.1%, food allergy 5.4%. the reliability was high (p < 0.05) in families with bronchial asthma compared with healthy population. bronchial asthma was detected in 5.7% of population. the hereditary load of allergic diseases in patients with bronchial asthma was 9.7% and in healthy cohort it was 5.7% (p < 0.001). conclusion: based on the results, we can conclude that, ecological factors and genetic predisposition significantly influences on prevalence of sensibilisation of house dust mite, molds and formation of bronchial asthma. as the genetic and environmental factors that act on an immune system are better elucidated and their roles established, the implementation of more enduring preventive efforts will be developed. however, at present, the best approach to the child at high risk for the development of allergies is to institute dietary and environmental control measures early to decrease sensitization, and to recognize and appropriately treat the evolving signs and symptoms of allergic disease. background: plantation of road-side avenue trees has become a major part of the urbanization programme in kolkata metropolis of india for megacity beautification and environmental management. due to evergreen habits, gulmohor (delonix regia) and chhatim (alstonia scholaris) are frequently selected for plantation programme to generate green belts. however, an increasing incidence of seasonal pollinosis was observed among the inhabitants living in close vicinity to these trees suggesting a possible link between the airborne pollen load and the concomitant respiratory hazards. this prompted us to investigate the allergens in the pollen of these two dominant avenue trees. method: aerobiological surveys were conducted at multiple sites of kolkata for a period of two years using seven-day volumetric burkard sampler to record the pollen concentration in the outdoor ambient air. clinical data and residual blood of pollinosis patients were collected from a public hospital. allergens were detected in the pollen proteome fractionated in 2d gel by ige-serology. the major igereactive proteins were partially purified by ammonium sulphate fractionation followed by ion-exchange chromatography. the allergenic activity of the fractions was tested by histamine release assay. results: a clear correlation was observed between the pollinosis related morbidity and the aeropollen load especially during the peak flowering period of these two trees. about 41% and 52% of the patients displayed positive spt response and ige-reactivity using pollen extracts of gulmohor and chhatim respectively. immunoproteomic analyses revealed the presence of 7-8 ige-reactive components in the 2d pollen proteome of these species. hierarchical cluster analysis with patient immunoblot data identified a 31 kda and a 25 kda protein as major allergens of gulmohor and chhatim respectively. the purified fractions containing each of these two major allergens induced histamine release from granulocytes within a range between 42 and 77%. method: immortalized human keratinocyte cell line (hacat) and primary normal human epidermal keratinocytes (nheks) were differentiated with calcium chloride for 1 and 3 days, respectively. following the differentiation, the cells were treated with il-4 (100 ng/ml), il-13 (100 ng/ml), and/or hcho (4 × 10^-4%) for 2 hours. the mrna expression of flg, ivl, lor, dsg1, dsg3, dsc1, dsc3, as well as tslp was analyzed using quantitative real-time pcr. results: hcho exposure decreased the mrna expressions of structural components (flg, ivl, and lor) and cell adhesion molecules (dsg1, dsg3, dsc1, and dsc3) in a short-period time of exposure (2 hours). we also found that hcho exposure significantly enhanced il-4-and/or il-13-induced tslp production in nheks as well as hacat. interestingly, exposure to hcho alone is enough to increase the tslp mrna expression in both cells. conclusion: our results suggest that hcho exposure might synergistically damage the skin barrier function with il-4 and il-13 by increasing tslp expression and decreasing structural components as well as cell adhesion molecules. 0685 | skin prick test reactivity to aeroallergens in adult allergy clinic in a tertiary hospital: a 12-year retrospective study results: five different human sera were screened for specific ige level against 29 different allergen sources using test methods of three different suppliers. the sensitivity of the three different methods can be arranged in the ascending order manufacturer a < manufacturer c < manufacturer b. with the test of manufacturer a, 45% of the measurements were below the detection limit (0.35 ku/l), with the test of manufacturer c, 16% of the measurements were below the detection limit, whereas the test of manufacturer b leads to values below the detection limit in 10% of the cases. in terms of variation coefficient, the test system of manufacturer c had the best performance. test systems of manufacturers a and b exhibited comparable variation coefficients, which were considerably higher than that of manufacturer c. conclusion: based on these test results, only the test of supplier c is recommendable for determination of levels of specific ige for diagnostics of allergic patients. with the test of manufacturer a, elevated levels of specific ige antibodies for many allergens cannot be detected due to the poor sensitivity of the test system. the test system of supplier b exhibits a good sensitivity but the coefficient of variation is rather high for a diagnostic test. this drawback could be circumvented by multiple determination of one test parameter. although this is an advisable strategy in general, the routine in diagnostic laboratories is incompatible with this approach, since throughput would decrease while costs would increase. this study is another good example for the need of the implementation of a characterized standard material with known values of sige, as demanded by wojtalewicz et al. method: cd203c and cd63 expression on basophils were monitored upon exposure of whole blood samples (<24 hours) to anti-ige and/or allergenic extracts. staining was conducted on exposed samples using dry room temperature stable antibody panels (dura innovations format) coated in 96 well plates, eliminating all antibody pipetting steps from the workflow. red blood cells were lysed and data was acquired (without further wash steps) on a cytoflex flow cytometer (beckman coulter). staining and lysing were automated using a biomek (beckman coulter). results: the described no-wash preparation protocol, already established for manual preparation mode in tubes, could be transconclusion: the hr-test was significantly less likely to be positive, if a patient suffered from monosymptomatic ae than in ae patients with concomitant urticaria. this could signify a higher likelihood of treatment response to antihistamine and other anti-allergic medication in the latter group. background: pathogenetic mechanisms of allergy are polymorphic. they include ige-dependent and ige-independent, allergen-specific granulocyte-mediated and lymphocytic reactions, as well as nonspecific hypersensitivity, which are realized through a variety of mediators: histamine, tryptase, etc. allergen bucal challenge mimics the natural situation and is useful for understanding the mechanisms of allergic airway inflammation and airway hyperresponsiveness (ahr).saliva used as a non-invasive readily available bio-sample for diagnosis instead of blood. biomarkers in saliva are associated with the pathogenesis and clinical outcome of allergic diseases method: aim: to examine mediators for ahr with buccal(mucosal) challenge tests. we examined 14 patients with allergic asthma(the history, positive skin prick test, serum specific ige) and 12 healthy volunteers. saliva were collected. then, both groups were subjected to buccal(mucosal) allergen challenge by a water-salt solution of the mite allergen dermatophagoides pteronyssinus. saliva was recollected in 30 minutes and 24 hours after the provocation. the level of myeloperoxidase, elastase, tryptase in saliva were determined by the elisa. that provocative test did not cause clinical symptoms development or reduction in nasal bronchial patency in any patient. results: in patients with allergopathology, an initially increased level of myeloperoxidase and tryptase in 30 minutes after the provocation, elastase increased in 24 hours (table 1) . tryptase in saliva after 30 minutes increased till 0.07 (0.04; 0.19) (me, pg/ml (lq;uq)), p = 0.0006. increased tryptase is presence of increased cellular inflammation, e.g. mast cells. its ige-dependent hypersensitivity, because there was the correlation between the elevated level of tryptase and positive prick tests. elevated levels of myeloperoxidase and elastase in saliva may be the criteria for the neutrophil hypersensitivity and ige-independent reactions. in healthy volunteers this increase was not observed. the identification of tryptase, myeloperoxidase, elastase can be used for diagnosis of types of ahr. tryptase is a mediator of early (immediate) response to allergen. increased myeloperoxidase and elastase indicates the involvement of the eosinophils and neutrophils in the oral mucous membrane in the allergic process. these mediators have additional roles in the late phase response. elevated levels of myeloperoxidase and elastase in saliva may be the criteria for the neutrophil hypersensitivity. conclusion: safe and acute in vitro methods allow to conduct early etiological diagnosis of allergy, which contributes to the effectiveness of therapy; the detection of polyvalent sensitization dictates the need for molecular diagnostics to single allergens, which has a higher prognostic level and the clinical significance of predicting the appropriateness and effectiveness of allergen-specific therapy; laboratory diagnostics of the allergy allows to reveal sensitization at the 0 (0, 0) 0 (0, 0) 0 (0, 7.28) *p = 0.002; **p = 0.008; ***p = 0.038. subclinical level, which increases early diagnosis and identify persons with a predisposition to allergy; the establishment of causal allerbackground: antibacterial chemicals like parabens and triclosan have been associated with allergic disease in children. parabens are also suspected to affect metabolic functions, possibly due to their weak endocrine disrupting properties. furthermore, a possible link has been suggested for eczema and adiposity, and thus, how body burden of chemical exposures affect both of these outcomes are of interest. we aimed to describe the association between exposure to parabens and eczema and body mass index (bmi) in an adult population in norway. method: urine biomarkers of butyl-, ethyl-, methyl-and propylparabens were quantified by mass-spectrometry in 496 adult participants (median age=29 years) from the rhinessa study in bergen, norway. linear regression models adjusted for gender, age and bmi (for eczema outcomes) and with clustering for siblings, were applied to model possible association between specific gravity standardized urine biomarker concentrations of parabens with bmi and eczema. results: propyl-(ppb) and methyl-parabens (mpb) were detected in 95% of the urine samples; ethyl (epb) in 62% and butyl (bpb) in 38% of the samples. in women, epb and bpb were detectable in 73% and 61%, respectively. participants with current eczema (15%) had lower level of several parabens compared to those without eczema (bpb for both genders; epb in women only and sum of all parabens in men only). body burden of epb (geometric mean (gm)) was 6.7 μg/l in women with current eczema compared to 22.3 μg/l in women without eczema (p = 0.03). body burden of parabens (mpb and epb) were inversely associated with obesity (bmi>30, (11.4%) ), as compared to normal range bmi (bmi=18. 5-25 (56.4%)) in both men and women. the concentration of mpb for obese women was gm=2213 μg/l compared to 11503 μg/l in women with normal range bmi. for men, the gm for mpb was 35.3 μg/l in obese compared to 134.4 μg/l in normal weight men (p = 0.03). conclusion: person with eczema or obesity had lower paraben levels in urine. we speculate that these chemicals might be stored in adipose tissue, and therefore excreted in urine in lower levels among the obese. eczema and obesity was not strongly associated in the current study. method: we retrospectively analysed medical records of 75 patients who were patch-tested with our dental screening series of 23 substances. adverse reactions to dental materials were suspected based on subjective complaints in the oral cavity and/or objective conditions of the oral mucosa. square plastic chambers on hypoallergenic tape were used. patch tests were applied to the upper back and removed by the patient after 48 hours. readings were performed 3 and 7 days after application (d3 and d7). results were evaluated according to the international contact dermatitis research group guidelines. positive patch test reactions fulfilled the criteria of at least a one plus (+) reaction on d3 and/or d7. the term »contact allergy« is usually used for such reactions. we prefer the term »contact sensitization«. clinical relevance of positive reactions to dental materials was not systematically assessed in this analysis. conclusion: we report a high frequency of positive reactions on d7 that were not seen on d3. this finding demonstrates the importance of an additional late patch test reading in patients with suspected contact allergy to dental materials. background: psoriasis is a chronic inflammatory skin disease. its etiopathogenesis is not exactly known. it is believed that the disease occurs in people with genetic tendency with the effect of a triggering factor. in some studies it is observed that contact dermatitis in psoriasis is increased with respect to normal population. for this reason it is proposed that allergen materials could trigger psoriasis. in this study it is aimed to determine contact allergy frequency in psoriasis cases using patch test. results: 62 of the cases were plaque, 5 of them were guttate, 10 of them were palmoplantar and 3 of them were inverse type. more positivity rate is observed in psoriasis cases (26.25%) than control (12%). the positively responsed materials with respect to decreasing number of patients are found as follows: nickel sulphate (16.25%), thimerosal (7.5%), peru balsam(5%), p-phenylenediamine(2.5%), colophony(2.5%), n-isopropyl-n-fenil-4-fenilendiamin(2.5%), mercaptobenzothiazole(2.5%), benzocaine(2.5%), most frequently plaque type and following guttate type positive responses are observed in evaluations with respect to clinical types. no statistical significance is found between patch test results and pasi values in psoriasis cases. conclusion: patients with psoriasis should be carefully evaluated. sometimes some materials may trigger psoriasis. the composition of the pigments that professional tattooists use are varied inorganic salts of metals or organic vegetable pigments. red tattoos, especially those that contain mercury, are the most common cause of late reactions. method: 35 year-old male patient with no previous allergy history known, who gets a tattoo on his right leg and develops within months, cutaneous erythema and pruritus on the same location as the tattoo. true test ® for skin allergy patch epicutaneous testing is performed. results: 48 and 96 hours reading: showed positiveness for mercury ++, with no late positive reactions after that. conclusion: as allergists we should be familiar with the different types of tattoos available, and know the possible cutaneous complications that each of these decorative techniques can present. it is our responsibility to be able to diagnose any complications at an early stage, establish the most appropriate treatment and, if possible, prevent them by informing the possible users. background: within otorhinolaryngological pathology chronic eczematous otitis externa is one of the most common, usually treated with topical medication successfully; however, there are cases in which the poor response to treatment, or the recurrence thereof, may be due to causes secondary to the medication itself, as observed in cases of allergic contact dermatitis caused by these drugs. case report: we present a 68-year-old male patient without relevant pathological antecedents or known allergies, who consulted the otorhinolaryngology service of our center for otorrhea of 15 days of evolution, bilateral external otitis is diagnosed and a topical otological combination is recommended (beclomethasone dipropionate 0.025% and clioquinol 1%, excipient: macrogol) with improvement. however, during the following 3 years the patient presents exacerbations and remissions of the condition, with negative or inconclusive microbiological studies. during all that time he was using the prior topical treatment and other combination treatments of topical antibiotics, corticosteroids and local antiseptics. more aggressive causes of external otitis such as malignant external otitis were ruled out. during the third year of follow-up, a clear relationship of exacerbations was observed with the use of the first combination of topical drugs, so it was decided to investigate allergic sensitization. material and methods: we perform patch tests using true test ® , standard spanish series (geidac -spanish group for investigation of contact allergy dermatitis), topical corticosteroid battery, antiseptic, as well as topical medications used by the patient. results: from the first reading on day two, positivity was observed for: mixture of quinolines ++ patient's otological combination ++ and chlorquinaldol ++; being confirmed in the reading at day four. eczematous external chronic otitis is diagnosed with allergic sensitization to quinolines (clioquinol, chlorquinaldol). we conclude that in the case of chronic external otitis, allergic contact dermatitis should also be investigated as a possible cause, and it is important to perform epicutaneous tests with the patient's own products to evaluate non-common or hidden allergens that may be relevant to their current pathology. most common causes of acd. it is important to distinguish local findings of infection from acd caused by topical antibiotic treatments. here we present a patient with acd with topical use of bacitracin and neomycin combination therapy due to recurrent blepharitis. an 11-year-old male patient presented with the complaints of itching, redness, swelling of the eyelids and facial edema. he had used various topical ophthalmic antibiotherapy and eye shampoo for 7 years due to recurrent blepharitis. five days ago, due to the redness of the eyelids, burning sensation in the eye, itching of the eyes; he was examined by an ophthalmologist. the eyelids and eyelashes were scaly and dry. the patient was treated with warm water soaked cloth dressing, mechanical eyelash cleaning and topical antibiotherapy (neomycin-simple combination therapy). after the second day of treatment, the patient's topical ophthalmic antibiotherapy was discontinued due to an augmentation of the redness in the eye0723 | contact allergy after exposure to ivy (hedera helix l) potent steroid treatment associated with systemic antihistamines, but with no improvement. on dermatological examination a small, well delineated, eczema-like plaque was noticed on a digital finger, as a new finding striking with her old burn scars. she denied any symptoms and was in good health condition. a 4 mm punch biopsy was performed and histological report established the diagnosis of squamous cell carcinoma. the patient was transferred to oncology department for further investigation and treatment. conclusion: early diagnosis and prompt surgical therapy are recommended to all patients with chronic wounds and scars who develop malignant transformation. *written informed consent for the publication of potentially identifiable personal details of patient (gender, age, illness, location) was obtained. **in relation to this presentation, i declare that there are no conflicts of interest. ertugrul a; hizli demirkale z; bostanci i dr sami ulus maternity and children training and research hospital, ankara, turkey introduction: the incidence of contact sensitization among adolescent has been increasing. nickel is one of the important causes of allergic contact dermatitis (acd) in this age group. increased exposure to nickel and deterioration of the skin barrier are among the important risk factors in children. the gold standard for diagnosis is skin patch test. we report here an adolescent patient who has allergic sensitization to nickel and cobalt. case: a 17-year-old female patient admitted in our clinic with a complaint of edema on her face. the patient had applied chickpea water to her face at least once a day for one week because of her acnes. her medical history revealed that she had experienced similar edema on her face after applications of clay mask one year ago. she was diagnosed with cellulitis and she had been treated with antibiotics for five days. on her physical examination, angioedema was observed on her face, especially on the glabellar region. eosinophilia was not found on her laboratory data. c-reactive protein (crp), c4 and c1 esterase inhibitor protein levels were also normal. the skin prick test was performed with aeroallergens, chickpea, lentil, bean and nuts, and no reaction had been observed. the patch test was performed with 'thin-layer-rapid-use-epicutaneous' (t.r.u.e) test and chickpea. the patient had positive reactions to nickel and cobalt. detailed questioning disclosed that the patient was preparing the chickpea water in a metal pot. result: chickpea water and clay mask contain varying amounts of nickel. it was thought that the edema of the patient is due to nickel allergic contact sensitization. an increased exposure to nickel and cobalt raises the frequency of sensitization. nickel allergy can cause different clinics ranging from localized lesions to systemic reactions. we want to emphasize that a detailed medical history and the patch test would enable clinicians to demonstrate hidden allergens and then make a correct diagnosis. case report: autoimmune progesterone dermatitis is a condition of hypersensitivity to progestogens. it is not an easy diagnosis given the variety of clinical presentations it may have, ranging from eczema, urticaria, erythema multiforme, folliculitis, to angioedema or even anaphylaxis. manifestations are cyclical, occurring when the levels of progesterone are higher, this is, at the luteal phase of the menstrual cycle, and disappear during menses, with the physiological decrease of the hormone. it can also be triggered by exposure to exogenous progestins. we report the case of a 49-year-old woman with a cyclical erythematous and violaceous rash related to the menstrual period. the symptoms typically began 4-6 days before the onset of menses and ended 1-2 days before. the diagnosis was based in the clinical history and intradermal skin tests: skin prick testing with levonorgestrel and medroxyprogesterone were negative, but the intradermal skin test with medroxyprogesterone was positive at a concentration of 50 mg/ml. we performed intradermal testing with the same concentration in three other women with no symptoms to exclude an irritative reaction, which were negative. autoimmune progesterone dermatitis is, perhaps, not so rare, but rather poorly recognized and reported, and thus, underdiagnosed. clinicians should be aware and include always this condition in the differential diagnosis, especially in cases of atypical or intractable skin eruptions. case report: a 46 year old male was referred to a community allergy clinic for assessment of chronic urticaria (cu). allergy assessments for foods, inhalant and inducible physical triggers revealed no association. an autoimmune workup followed, with treatment consisting of standard dose antihistamines (h1 and h2). blood work revealed a persistently low hemoglobin with low-normal ferritin. hematology consulted and followed attempted iron replacement to no avail. skin biopsy revealed neutrophilic rich urticaria with the presence of eosinophils. serum protein electrophoresis (spep) revealed a monoclonal gammopathy with elevated igm, felt to be of undetermined significance (mgus). c-reactive protein (crp) was consistently elevated (183, 256) in conjunction with anemia. rheumatology consulted and cleared of any evidence of vasculitis. hematology considered the anemia to be of chronic disease linked to cu. the cu was resistant to treatment including high dose antihistamibackground: isolated head and neck angioedema (ae) can be mediated by bradykinin (bk) or histamin (hi) . the objective of our study was to determine which etiology was most frequent in cases of death by asphyxiating ae in france. we sought all cases of death by isolated asphyxiating ae reported in france between 2000 and 2014 via death certificates and/or the national pharmacovigilance database. results: the overall mortality by asphyxiating ae for all causes was 0.36 / million inhabitants. the death rate of bkae per million inhabitants was 0.14 and lethality of 0.27 per thousand patients per year. the death rate of hiae per million inhabitants was 0.09 and lethality of 0.006 per thousand patients per year. we found a 45 times higher risk of death in case of bkae than hiae. conclusion: consequently, particularly severe episodes must be initially considered as bradykinin mediated and quickly reassess any first-line treatment that is inappropriate. case report: we present the case of a 72-year-old man who suffered recurrent abdominal pain since age of eight, leading to 3 unnecessary emergency surgical interventions and 5 endoscopies before hereditary angioedema due to c1 inhibitor deficiency (c1-inh-hae) was diagnosed at the age of 70. rare subcutaneous swellings were considered allergic reactions preventing proper diagnosis. family history, positive for recurrent abdominal pain and swellings was totally neglected until diagnosis of c1-inh-hae type i was established through appearance of severe oro-facial symptoms in the propositus' grandson. the diagnosis was suggested by the boy's mother, directed by educational materials available in the international hae patients' association website (www.haei.org). this report highlights and emphasizes the importance of accurately evaluated personal and family history to suspect condition that are scarcely known to the majority of physicians. highlights: diagnostic delay in hae and iatrogenic procedures are an underestimated problem, hiding undefined consequences, possibly destructing an entire lifetime. correct, publically available information provided by patients' associations raise awareness about the disease and could put the milestone of establishing correct diagnosis. de luque v 1 ; lara p 1 ; guardia p 1 ; jimenez ar 2 1 virgen macarena hospital, seville, spain; 2 hospital virgen macarena sevilla, seville, spain background: in the protocol for the study of patients who consult for recurrent acute angioedema with facial involvement, the contactant battery is included (epicutaneous test). we review the results in our patients with facial angioedema to evaluate the contactants to which these patients present sensitization, some of them coexisting with contact dermatitis clinic. we reviewed the patients referred to the clinic for recurrent acute angioedema with facial involvement and to whom a standard battery epicutaneous test was requested. in all these patients, other habitual triggers included in the diagnostic protocol (food, medications, autoimmune diseases, bradyinergic aea/complement deficit …) were ruled out. conclusion: it seems to be profitable to continue including in the diagnostic battery of patients who consult for aea with facial affectation, study of epicutaneous with standard battery. it is a small sample, but the data correlate with what has been published, being more frequent the sensitization to contactants in women and the contactant more frequently involved nickel sulphate. 0734 | ace inhibitor-related angioedema-the value of history taking background: angioedema is a well-recognized side effect of angiotensin-converting enzyme (ace) inhibitor therapy. although it occurs in <1% of the patients who take these drugs, it seems to be responsible for 40% of the episodes of angioedema. this entity is underdiagnosed and failure to recognize it leads to recurrence of episodes, with an impact on morbidity and increased risk of serious reactions. our objective is to analyze the clinical, therapeutic and orientation approach of patients diagnosed with ace inhibitor-related angioedema, evaluated at the outpatient consultation (oa) of immunoallergology (ia). a 3-year retrospective study was performed by analyzing the clinical files of all patients diagnosed with angioedema observed in oa of ia. the following variables were analyzed: gender; age; clinical data; evaluation in emergency department (ed); therapy in the episode; evolution and orientation. the chi-square test was used to study the association between categorical variables: "established therapy"/"disease evolution" and "place of reference"/"withdrawal of ace inhibitor". results: review of 62 cases of patients referred for angioedema. only in 29% the final diagnosis was "ace inhibitor-related angioedema". the mean age of the patients was 63.7 years and 67% were male. the location of angioedema occurred in the tongue in 33% and in the remaining sites (lip, hemiface, tongue and hemiface, tongue and lip) appeared in the same frequency, 17%. none of the patients had airway obstruction. during the episode of angioedema, 22% of patients were not referred to ed and the therapeutic approach was done with antihistamines in 75%. in patients who were referred to ed (78%), antihistamines and corticosteroids medications were administered in 85%. regarding the evolution, it was verified that the duration of the episode was independent of the established therapy (p > 0.05). regarding the place of reference, 60% of the patients were referred form hospital (ec or ed) and, in these, the ace inhibitor was suspended in 73%. in patients referred from general practitioners (40%), in none of them the ace inhibitor had been withdrawal. a causal association between the use of ace inhibitors and the episode of angioedema becomes crucial, since drug withdrawal is indicated. a reference for ai oa should be weighed. therapy with antihistamines and corticosteroids has no proven efficacy. hereditary angioedema (hae) seen by physicians belonging to the hae scientific committee of the aaaeic background: patients with c1-inh-hae frequently suffer from anxiety and stress. the impact of prophylactic treatment on anxiety and stress in c1-inh-hae patients is largely unknown. here, we analyzed data from the apex-1 study, a phase ii study that investigated the effects of the oral kallikrein inhibitor bcx7353. method: c1-inh-hae patients with a history of at least 2 hae attacks per month were randomized to receive four different doses (350, 250, 125, 62.5 mg) of bcx7353 or placebo for 28 days. the depression anxiety stress scale (dass) was administered at baseline and at day 29. the dass consists of three self-reported scales designed to measure the negative emotional states of anxiety and stress. subjects used a 4-point severity/frequency scale to rate the extent to which they have experienced each state. results: baseline dass total scores as well as anxiety and stress domain mean (sd) scores for the 125 mg treatment arm (n = 13) were 20.9 (23.7), 5.0 (5.9), and 8.9 (9.1) points respectively. placebo scores were generally similar or slightly lower at baseline than for the 125 mg treatment arm. the dass questionnaire data showed statistically significant improvements in total score vs. placebo at day 29 (−11.4 method: a two-phase mixed methods approach was used to develop the hae-rt tool including: phase 1: delphi study [hae specialists (n = 9) and national patient advocacy group members (n = 3)] was conducted to reach consensus (80% agreement) on predictor variables to include in the tool. phase 2: retrospective chart review was conducted to assess the predictive findings of the decided variables. a convenient patient sample presenting with angioedema (with and without hae) between january 2012-january 2017 were included in the study. results: nine of 12 invited experts (75%) participated in the delphi study. of 8 hae-specific predictive variables, 4 reached consensuses including: (i) recurrent angioedema; (ii) absence of urticaria; (iii) recurrent abdominal pain/swelling; (iv) lack of response to allergic therapy. the retrospective study included 85 patients (n = 46 with hae; n = 39 non-hae; overall 72% female). hae patients were significantly more likely to have a family history of hae (72% vs 0%; p < 0.0001); previous recurrent angioedema (96%; p < 0.009); present with no hives (91%; p < 0.036); previous recurrent abdominal pain (80%; p < 0.0001); and 2% responded to allergy treatments (p < 0.0001). a regression analysis categorized observed frequencies (actual patient outcomes from chart review) versus predicted (by model); plotted on a 2 by 2 table and calculated the sensitivity and specificity of the hae-rt which resulted in one hundred percent for both. conclusion: our study demonstrated that expert involvement led to the identification and prioritization of variables that when included an hae-rt tool, were associated with a high level of sensitivity and specificity when applied to known patients. the next step is to observe the effect of the hae-rt tool on patient care in the ed. method: evaluation of cardiovascular manifestation included morphology, serum level of troponin t, electrocardiography (ecg) and echocardiography. evaluation of pulmonary manifestation included spirometry, diffusing capacity of the lung for carbon monoxide (dlco) and evaluation for mastocytosis included bone marrow biopsy and serum total tryptase measurements. results: in the study there were 55 patients -35 women and 20 men between 21 and 71 years old (the average age was 45). there were 7 (12.73%) patients with mpcm, 4 (7.28%) with bmm, 42 (76.36%) with ism and 2 (3.64%) with ssm. the average level of serum tryptase was 45.1 μg/l (6.9-270) . troponin levels was within the normal range in all patients. one patient had lowered the ejection fraction (eflv=23%). no one patient had restriction. the average value of a forced lung capacity was 3.33 l (104%) and a total here, we describe a case series of twelve mis patients seen at our department over a 3-year period and report how many of these patients have sm. common phenotypical manifestations of acute hae1 episodes in this region, to review therapeutic challenges in a rural setting in comparison with world standards, and lastly to evaluate the socio-economic burden inflicted by the disease. method: a sample of 13 individuals from a total of 28. the exclusion criteria was the inability to attend booked appointments more than 3 times in 1 year (2017). the following methods were used: an interview to formulate a family tree identifying affected individuals in 4 contiguous generations, and review of the acute presentations in the past year (2017) . a questionnaire to obtain the relevant hae1 associated socio-economic burdens. a chart review to identify the therapeutic strategies in this region. c1inh levels, and complement c4 to confirm the diagnosis. results: polygamy as a local culture was found to be an important factor that perpetuated the genetic burden of the disease. c1inh and c4 levels confirmed hae1 in all participants individually. clinical features during acute attacks included swelling of extremities (100%), facial swelling (69%), neck swelling (23%), and laryngeal swelling (8%). therapeutic strategies for acute attacks included fresh frozen plasma or fresh dried plasma. danazol was used for prophylaxis. hae1 has had a significant negative impact upon the socioeconomic status of the affected individuals. conclusion: hae1 is a newly identified disorder in the broad spectrum of allergy medicine in kwazulu-natal. the diagnosis is simple to confirm but requires an initial high index of suspicion, and therapeutic management still poses a challenge in this region due to lack of resources. genetic counselling is of paramount importance during intervention since polygamy forms part of most cultures in this region. a support strategy is highly recommended in order to help alleviate the socio-economic burden posed by the disease in this region. the socio-economic burden secondary to hae1 (10 participants/5 identical questions each) question 1 (0-5 points) 3 question 2 (0-3 points) 2 question 3 (0-3 points) 1 question 4 (0-3 points) 1 question 5 (0-1 point) 1 method: a total of 172 medical faculty senior year students were included to study on a voluntary basis. students are divided into two groups. one group was given visual user guide that has not been modified, and a visual user guide on which we have modified to the other group ( figure 1 ). then they were asked to show how to use the inhaler spacer. results: the mean age of the volunteers was 25.3 ± 126 years and 104 (60.5%) were male. there were 82 students in the group without modification of the visual user guide and 90 students in the other group with modified the visual user guide. sixty-four per cent of the modified user guide group showed correct use of the inhaler spacer, while 15% of the unmodified group showed correct use (p = 0.001). the group that given modified visual user guide was more successful in all of the display steps of the inhaler spacer. conclusion: modification of the currently available visual user guide of inhaler spacer in our country will increase the correct usage rate. results: mean fev1, fvc, fev1/fvc z-score were 1.8 (1.1-3.9), 1.7 (0.9-3.7), 0.9 (0.8-0.9), respectively. restriction had 31 (57.4%) and obturation 3(5.3%) patients. fev1 (p < 0.001, r 2 = 0.37) and fvc (p = 0.001, r 2 = 0.38) decreased with age (%pv and z-score). background: children who were treated for leukemia are known to have developed long term impairment of lung function. the reasons that complication are only partially known. the aim of this study was to asses pulmonary function in children treated the lower dlco is the most frequent abnormality in childhood leukemic survivors. hsct and pulmonary infection (in particular cmv pneumonia) is a strong risk factor for impairment of dlco in children. clinical manifestation of dlco impairment is poor exercise tolerance. a screening for respiratory abnormalities in survivors following treatment for childhood haematologic malignancies, seems to be of significant importance. 0746 | phenotyping allergic respiratory diseases: an unsupervised classification using latent class analysis allergen groups was significantly associated to uawi (aor[95% ci]:2.1 [1.3-3.6] ), compared to uasi. results: 80.8% of br and 49% of py were women, median age was 32 years, 35% br and 52% py reported having more than four years of training. although they recognized the main symptoms of ar, 26% br and 100% py never asked whether the patient had a medical diagnosis of ar; 20.5% br and 100.0% py did not ask whether the symptoms occurred when close to animals or allergens; 55% br and 76% of py did not ask if the patient had a medical diagnosis of asthma; 59% br and 70% py did not ask if rhinitis worsens asthma symptoms and 51.3% br and 84.3% py did not ask whether symptoms of rhinitis interfere with their daily activities. results: there was a predominance of female (br: 73%, py 50.4%, uy: 70%) median age 31 years old, 124/235 worked in the community and 75/127 in the emergency departments, 34% of the br had more than 10 years of education, 67% from py had between 1 and 5 years, and 82% from uy had been graduated for less than 1 year. br/uy recognize the main symptoms of ar, however 67% of those from uy do not ask: if the patient has physician diagnosis of ar, 72% present shortness of breath, and 93% a medical diagnosis of asthma, 94% if rhinitis worsens asthma symptoms and 90% if symptoms of rhinitis interfere with the patient's daily activities. the prescribed treatment varied a lot, the intranasal corticosteroid use rate was: bd: 78%, pd: 92% and ud: 54%. 100% of doctors in py, 73.4% in br and 78% of uy never refer the patient to the specialist. 22.9% of pcd of br, 62% of py and 6.0% of uy are aware of aria guideline. conclusion: although ar is largely attended by pcp, recognition of symptoms and their impact on asthma, as well as the knowledge about aria guide is low and treatment is not always prescribed according to best practice. allergy education programs, with an emphasis on ar and aria guide, need to be directed to pcp in la for the better assistance of ar patients. 0749 | assessing knowledge of allergic rhinitis among final year medical and pharmacy students in croatia-curriculum change necessity? the two factor structured questionnaire was formed by the authors regarding the topics mentioned. t-test was used for statistical analysis. the global results were formed as composites of (1) ar general characteristics, (2) ar treatment approach, and (3) the participants' overall knowledge. of the 201 respondents, 143 (71.1%) were female and 58 (28.9%) were male (p < .0001). medical students had a median score of 6 of 10 correct answers on (1), 4 of 10 on (2), and 10 of 20 on (3), whereas pharmacy students had median score of 7 of 10 correct answers on (1), 4 of 10 on (2), and 10 of 20 on (3). there were no significant differences in knowledge between two student groups. the results indicate an inadequate level of knowledge of ar in both groups, especially regarding the therapy approach. since general practitioners and community pharmacists have a major role in providing treatment to patients suffering from ar, it is important to develop advanced knowledge on this topic during medical and pharmacy degree courses. despite a relatively small study population, it would be advisable to introduce change by improving the core curriculum regarding ar with more emphasis on treatment, but additional research on this topic is necessary. tan r 1 ; cvetkovski b 1 ; kritikos v 1 ; price d 2 ; yan k 3 ; smith p 4 ; bosnic-anticevich s 5 1 woolcock institute of medical research; university of sydney, sydney, australia; 2 observational pragmatic research institute pte ltd, singapore, singapore; 3 royal prince alfred hospital, sydney, australia; 4 clinical medicine, southport, australia; 5 griffith university, sydney, australia background: people with allergic rhinitis symptoms frequently selfselect over-the-counter medications from community pharmacies without seeking advice from a health care professional. this increases the incidence of complications due to delayed diagnosis and suboptimal treatment. this study aims to (i) compare the demographics, clinical characteristics and medication selected, between pharmacy customers who choose to self-select and those who interacted with a pharmacist when purchasing medication for allergic rhinitis symptoms, and (ii) identify the key factors associated with allergic rhinitis patients' medication self-selection behaviour. a cross-sectional observational study was conducted in a convenience sample of community pharmacies from the sydney metropolitan area. data were collected using a researcher administered questionnaire that included: demographics, pattern of allergic rhinitis symptoms, their impact on quality of life, factors triggering allergic rhinitis symptoms and medication(s) selected. logistic regression was used to identify key factors associated with participants' medication self-selection behaviour. results: of the 296 recruited participants, 202 were identified with allergic rhinitis, of which 67.8% were female, 54.5% were aged more than 40 years old, 64.9% had a diagnosis of allergic rhinitis, and 69.3% self-selected medication(s). significant differences were noted in allergic rhinitis symptoms, impact of allergic rhinitis on quality of life and medication(s) selected between participants who chose to self-select and those who interacted with a pharmacist. participants who experienced moderate-severe wheeze were 4 times more likely to self-select allergic rhinitis medication(s), and those who had allergic rhinitis symptoms impacting on their quality of life were 0.4 times less likely to self-select allergic rhinitis medication(s). conclusion: there is a high incidence of self-selection of over-thecounter treatments for allergic rhinitis symptoms in community pharmacy, with the majority of allergic rhinitis sufferers failing to seek pharmacist advice. this research identified predictors of medication self-selection behaviour in community pharmacy among people with allergic rhinitis, which can inform the design of tools/strategies and targeted interventions, aimed at improving pharmacist engagement and future practice in optimising allergic rhinitis management. the weir family health clinic, cork, ireland; 2 university college, cork, ireland background: allergic rhinitis is a common condition that is predominantly managed in primary care. the incidence of allergic rhinitis is increasing. it is frequently under diagnosed, misdiagnosed and mistreated. it has a significant impact on patients' health related quality of life and represents a huge cost both to healthcare systems and society. the aim of this study was to implement appropriate guidelines regarding the management of allergic rhinitis in primary care and evaluate the effect on patients' health related quality of life. method: patients with a history of allergic rhinitis were selected from three general practice bases in west cork, ireland and quality of life of patients was assessed initially in year one and followed up one year later in a general practice setting using the standardised rhinoconjunctivitis quality of life questionnaire (rqlq). allergic rhinitis and its impact on asthma (aria) guidelines and appropriate prescribing were implemented during this year and patient education and structured follow up was arranged in the intervention group. this was compared with the control group who received usual care. results: 93 valid responses were received, 34 from the control group and 59 from the intervention group. the study demonstrated a statistically significant difference in quality of life in the intervention group. in the adult intervention group the quality of life score decreased between 2015 and 2016 representing an improvement in their quality of life, (t = 4.13; df=56; p < 0.01). the difference in the score between the control and intervention groups in 2016 was also statistically significant.(t = 6.11; df=54; p < 0.01). the numbers in the adolescent groups and paediatric group also demonstrated an improvement in quality of life but the sample size was too small to demonstrate a statistically significant difference. conclusion: as the majority of patients rely on their general practitioners for treatment and diagnosis of allergic rhinitis, primary care represents an important area to target in the management of allergic rhinitis to improve patients' quality of life. the implementation of guidelines has been shown to improve patients' quality of life. this study demonstrates this care can be delivered in a primary care setting with an improvement in patients quality of life but substantial investment in education and resources available to primary care physicians is needed. 0752 | the predictive value of allergy tests in the diagnosis of peanut allergy in adults rey-garcia h; gunawardana n; wheeler k; scadding g; durham s; skypala i royal brompton hospital, london, united kingdom background: adults presenting with either new-onset symptoms attributed to peanuts or with early-onset peanut allergy, often wish to know whether they should continue to avoid peanuts. clinical history and standard tests may be sufficient to provide an answer, but for many the tests are inconclusive and an oral food challenge is required. this review was undertaken to determine the most accurate tests. conclusion: these data suggests that peanut spt and ara h 2 provide the most accurate prediction of the outcome of oral food challenge in adults. should components not be available, then spt would be the test of choice being more accurate in all aspects than sige. combining spt and sige improves the sensitivity and negative predictive value of spt alone. however, the best combination is spt and ara h 2, which increases the overall accuracy to 87%. further studies are needed before it can be determined whether peanut diagnostic tests can replace the oral food challenge in adult patients. method: retrospective chart review was carried out in a community allergy clinic. patients with rap, bloating and altered stools who underwent bt were characterized by age, gender and atopic status. a separate study to assess patients' outcome post-dietary counselling was carried out to determine impact on symptom management. results: thirty-four patients were assessed for fi from january 2014 to december 2017. female gender predominated (31/34, 91%) with an average age of 31 years at presentation. results of fi were positive in 15/34 (44%), borderline in 2/34 (6%) and negative in 17/ 34 (50%). the average age of patients with a positive, borderline and negative tests were 30, 20 and 34, respectively. of the patients who tested positive for fi, 5 (33.3%) had comorbid inhalant allergies alone, 1 (6.7%) had comorbid (unrelated) food allergies alone, 2 (13.3%) had inhalant and food (unrelated) allergies, and 7 (46.7%) were non-atopic. of the patients who tested negative for fi, 7 (41.1%) had comorbid inhalant allergies alone, 0 (0%) had comorbid (unrelated) food allergies alone, 1 (5.9%) had inhalant and food (unrelated) allergies, and 9 (53.0%) were non-atopic. conclusion: patients investigated for carbohydrate intolerance with rap, bloating and altered stools were predominantly female (91%). fi was confirmed in half. atopic status did not help differentiate between the fi positive or negative groups. results of a fod-map elimination diet are separately reported. conclusion: post-bt, 88% of patients reported symptom improvement. patients who implemented fructose or fodmap avoidance reported symptom improvement. one patient who tested negative for fi reported symptom improvement with a low fodmap diet. patients suspected as being fructose intolerant may benefit from a fructose restriction or fodmap diet, while awaiting bt confirmation. this form of dietary intervention may assist and shorten the natural history of non-specific chronic gi symptoms. inappropriate referrals to a uk paediatric tertiary allergy clinic demonstrate lack of allergy education and knowledge in primary care marriage de bristol royal hospital for children, bristol, united kingdom background: up to 8% of children have a food allergy. allergy has become an explanation for all manner of nebulous symptoms and self-diagnosis is common. sham allergy tests are easily available giving incorrect results and resulting in unnecessary, potentially harmful abstracts | 423 parentally-imposed dietary exclusions. there are 100 million allergyrelated google searches per year. the rising prevalence of perceived allergic disease has led to an increase in health service utilisation, including increased referrals to secondary care. clinic waiting lists are long and children with severe food allergies have to wait longer than necessary to be seen method: uk paediatric tertiary allergy clinic referrals were prospectively reviewed over three months. five inappropriate referrals deemed most reflective of poor knowledge in primary care were selected as case summaries to highlight this gap in knowledge. results: 1: schoolchild referred for investigation of allergic cause for a red, watery eye after splashing juice in her eye whilst cutting a kiwi, despite having a co-existent dendritic ulcer. 2: schoolchild referred for peanut allergy testing after inhaling a peanut and developing wheeze, with all respiratory symptoms resolving following peanut removal. 3: young child referred for peanut allergy testing after developing a rash on leg following skin contact with faeces 24 hours after ingestion of peanut butter. 4: teenage boy referred for investigation of likely peanut allergy despite eating peanut butter and tree nuts almost every day. the family were concerned he was allergic to peanut butter. 5: toddler referred for milk allergy investigation after developing urticaria lasting 24 hours 15 minutes after drinking a bottle of milk. the child had consumed cow's milk formula since birth, and continued to consume milk daily for a further five months following the episode of urticaria. conclusion: provision of allergy services in the uk is poor and lack of investment in allergy services has led to suboptimal recognition and management of food allergy in primary care. allergy education provision for primary care practitioners is inadequate and fails to empower healthcare professionals to discern between allergy requiring full investigation and management, parentally-diagnosed allergy or symptoms which clearly have no association with allergy. progress to improve primary care training for allergy needs to be optimised to prevent further unnecessary referrals and lengthening clinic waiting lists. background: in case of allergic reactions to food or insect venom, quick and adequate treatment, based on clear instruction for use of emergency medication and calling for help, is necessary. however, daily practice shows that patients do not use the prescribed emergency medication because they are afraid to use the epinephrine auto-injector or they do not know how to use it. information and instruction offered by a reliable app could be a useful aid. we aim to develop an app for adult patients and children older than 12 years with allergy to food or insect venom, which offers a step-wise approach to support patients, their relatives or acquaintances in case of an allergic reaction. method: first, the content of the app, including a step-wise approach to treat the allergic reaction has been determined, based on literature, a survey about needs of patients and on consultations of healthcare professionals. subsequently, a web-based prototype has been developed with an adult profile and children profile. the content and flow of this prototype was tested by the project group, as well as by selected healthcare professionals and patients and improved according to the test results. next, the revised prototype was submitted to representatives of patient and professional organizations for final approval. currently the procedure for ce approval is ongoing. finally, the app will be built and offered to the market for ios and android. results: a web-based prototype of the allergy app is available with two profiles: adult and older children. the app is useful for patients with a doctor's diagnosed allergy to food or insect venom, who received emergency medication and instructions to use prescribed medication in case of an allergic reaction. based on severity of complaints, the user is informed about the steps to treat the allergic reaction. in case of a moderate to severe reaction, the patient is advised to use an epinephrine auto-injector, to call the emergency number and, if prescribed, to use medication such as antihistamines, prednisone or inhaler. besides that, the app provides links to websites of expertise centres and patient organisations and includes instructions how to use the epinephrine auto-injector. conclusion: the allergy app will help patients, their relatives or acquaintances to adequately treat an allergic reaction to food or insect venom. involving patients and professionals in the development of the app will contribute to its acceptability and usability. 0757 | electronic documentation of drug allergies in a tertiary hospital in singapore: are we relying too much on it? choo kjl; garuna murthee k; naing cs singapore general hospital, singapore, singapore background: singapore has 26 hospitals shared between public and private healthcare system. its healthcare system, ranked #6 in the world by who in 2010 serves a multi-racial population of 5.2 million of which 9% are above 65 years old. drug allergy alert cards (medik awas) were started in 1970s by singapore medical association to improve patient safety. work on computerisation of drug allergy and medical alerts started in the 80s, a precursor to today's critical medical information system (cmis). cmis serves as a platform across all public hospitals in singapore. it promotes uniform reporting of drug allergy and notification of adverse drug events to the health science authority. yet, we found that there is a lack of awareness of one's own drug allergies. method: all patients admitted to ward 73 (general medicine ward) at singapore general hospital from 17 july to 31 oct 2017 were screen for any previously documented drug allergies. consenting patients who had previously documented drug allergies on cmis were interviewed to document their demographics, education level, current medications, knowledge of their own drug allergies and possession of a drug medication alert card. the answers were then compared with their electronic documentation of drug allergies for accuracy. we interviewed 192 patients aged 20-94 with documented drug allergies during the recruitment period. 74% had secondary school education or higher. the majority (76%) spoke english and (58.5%) mandarin. almost half had medical problems and are on long term medications (mean 5.17 medications); hypertension and diabetes being the top two common diseases. 48% of the patients could accurately relay their drug allergies; antibiotics and analgesia being the most labelled. only 24% had a drug allergy alert card while the rest both rely on the hospital's electronic documentation and/or their caregivers to record and relay their allergies to future prescribers. about 21% received prescription from multiple healthcare sites in both the public and private healthcare system. we found patients' knowledge of their own drug allergies dismal. the cmis electronic documentation provided a false sense of security. unfortunately, the cmis platform is not available to all private hospitals, increasing the risk of mis-prescription due to the lack of information. unless this is made available nationally, patients with drug allergies should be given some written documentation, either a letter or medik awas. how frequent are they and how are they treated? method: for this cross-sectional study, participants were recruited in the waiting rooms of local doctors in the rural bavarian forest region of southern germany (q1/2017). a paper questionnaire was handed out to the participants, asking for allergies (pollen, animal hair, bee and wasp venom, drugs, food, house dust mites, contact allergies and other allergies) and how or rather by whom (e.g. general practitioner, specialist, self-treatment) these allergies are treated. results: 718 participants with a mean age of 50.61 years (sd=15.15) and 59% women were included in this study. 38.2% indicated to have at least one allergy, including pollen allergy most frequently (17.4%). women had significantly more often at least one allergy than men (rr= 1.552; ci [1.243;1.937] ) and for almost all examined allergies a significant higher risk of disease. younger age groups indicated more often to have at least one allergy (18[.506;1.151 ]) seemed to be affected less. participants indicated most frequently that their allergy was treated by a general practitioner (37.5%), except of the 18-29-yearold young adults who indicated "no treatment" most frequently (28.2%). conclusion: there is a high self-reported prevalence of allergies in the examined rural bavarian region, that increases with decreasing age and is significantly higher among women. moreover, the data on the absence of an appropriated treatment for allergies is alarming. therefore, medical care needs to be improved in rural regions to lower the burden of allergies. 0759 | the prevalence of the burnout syndrome among medical professionals involved in allergology education programmes astafieva n 1 ; kobzev d 2 ; gamova i 1 ; perfilova i 1 ; udovichenko e 1 ; skuchaeva l 1 ; michailova i 1 1 ≥10) and rpa (low ≥0-11, subscales were calculated and analyzed. results: on average students demonstrated: moderate/high ee scores (24-26); moderate/high dp scores (9-12) and moderate rpa scores (17); higher rpa scores were common (41.4%) among junior students, which is also linked with their levels of engagement, and lower (28%) among senior students. junior specialist (starting specialization) had very low scores in all 3 subscales and expressed a very high motivation in their course and new profession. clinical allergologists with significant experience demonstrated moderate / high ee scores (22-26); low dp (1) (2) (3) (4) (5) and rpa (below 10) scores. high ee scores associated with pressures of service were compensated by a substantial loyalty to their profession and positive assessment of the outcomes of their work. clinical academics demonstrated the highest level of ee scores (29 + among 70 + % of the group) with low to moderate dp and rpa scores, the latter being associated with a loyalty to their profession. it was also possible to identify a correlation between engagement in research activities and lower rpa scores. conclusion: burnout is a complex and multifaceted phenomena, which requires further investigation. however, this research identified that students and junior specialists involved in allergology and clinical immunology programmes with higher levels of engagement and motivation to acquire new specialist knowledge had lower levels of ee, while loyalty to the profession and positive assessment of the outcomes of clinical and research work allows to compensate high levels of ee among experienced practitioners and clinical academics and to reduce burnout effects overall. 0760 | appeal (allergy to peanuts impacting emotions and life): the first pan-european study to evaluate the psychosocial burden of living with peanut allergy deutscher allergie-und asthmabund (daab)/german allergy and asthma association, mönchengladbach, germany; 8 food allergy italia, padua, italy; 9 aepnaa asociación española de personas con alergia a alimentos y látex, madrid, spain; 10 afpral association pour la prevention des allergies, paris, france; 11 asthma-allergy denmark, roskilde, denmark; 12 anaphylaxis campaign ireland, cork, ireland; 13 brainsell ltd, london, united kingdom; 14 aimmune therapeutics, london, united kingdom background: peanut allergy, one of the most common and rapidly growing food allergies, is most frequently a lifelong condition. current management is limited to avoidance and symptomatic treatment of allergic reactions when accidental exposures occur. peanut allergy can affect the quality of life (qol) of individuals and also that of parents/caregivers and family members. appeal was designed to assess the impact of peanut allergy on qol in peanut-allergic individuals and their parents/caregivers and families. method: the first, quantitative part of appeal is described here and consisted of a pan-european, cross-sectional online survey of approximately 30 minutes in length. the study was conducted in the uk, republic of ireland, france, spain, germany, italy, the netherlands and denmark. over 1800 participants were recruited via patient advocacy groups or directly through a specialist survey recruitment panel. ethics committee approval was obtained and all participants provided their informed consent. eligible participants were: (1) parents or caregivers of a child/adult with peanut allergy; (2) parents or caregivers responding as a proxy for a child aged under 18; (3) adults. all allergic subjects had self-reported diagnosed peanut allergy. after several screening questions, eligible participants answered a set of clinical questions about their (or their child's) allergies and other conditions, details on the peanut allergy diagnosis, contact with healthcare professionals, worst allergic reaction to date and use of emergency medicine. depending on whether they were an allergic adult, a parent responding on behalf of the child, or a parent/caregiver recounting their own experience, they then answered specific questions on restrictions on life choices, coping strategies and the impact of peanut allergy on feelings and emotions of families, friends and other people. sociodemographic questions completed the questionnaire. the results of the survey are being summarized using descriptive statistics and the data are being analysed on a pan-european level, by country, and according to the participant's perspective (parent, caregiver or individual). conclusion: this comprehensive, pan-european online survey has been specifically designed to uncover the psychosocial burden and effect on qol of peanut allergy in terms of individuals' lives and those of their families. results: 246 pediatric patients were included in the study. 65.9% (n = 162) were male. the median age of onset of symptoms (interquartile range) was 4 months (2-6).the median age (interquartile range) of diagnosis was 6 months (4-7). initial reactions associated with cmpa were observed in 95.8% of patients before 12 months old. patients' diagnoses were atopic dermatitis (39%), urticariaangioedema (24%), anaphylaxis (12.2%), proctocolitis (10.2%), atopic dermatitis and urticaria (8.9%), food protein induced enterocolitis (4.9%) and eosinophilic esophagitis (0.4% method: the study involved 147 patients, who are two years old (and above), diagnosed with cow milk allergy and are observed for at least six months in our hospital. socio-demographic features of the patients, their symptoms, symptom-start ages, age of diagnosis, clinical findings at diagnosis and during observation were recorded in data collection questionnaires. results: the samples were 91 (61.9%) boys. the average symptomstart age was observed to be 5 months , average diagnosis age 6 months (1-54) and average age of final check 36 months . when symptoms at entry were observed, 85.7% of the patients had dermal system, 25.2% gastrointestinal system, respiratory system disorders, and 15% were detected to have developed anaphylaxis. among the patients diagnosed with cow milk allergy, 31.3% showed food reaction to nutrients with lge agents, 51.7% to mixed types, and 17% to nutrients with non-lge agents. it was also observed that, in the end of 30.4 ± 19.8-month observations, sensitivity to cow milk was observed to continue in 34 (23.1%) of our patients. when tolerance improvement rates among the patients were compared, anaphylaxis (p < 0.001) during entry were observed to be influential in continued allergic state. 5 (3.4%) patients were able to consume yoghurt, 10 (6.8%) patients could consume dairy products and 19 (12.9%) patients could not consume dairy products. conclusion: in the end of our investigation, it was observed that 57 (50.5%) of the 113 patients developed cow milk tolerance before the age of 2. when the factors enabling the continuation of sensitivity in cow milk allergy were investigated, anaphylaxis during entry, entry specific lge and pasteurized milk antigen as well as high skinprick test results were detected to be significant. 0765 | initial lower threshold was a risk factor of severe adverse reaction during oral immunotherapy for cow's milk anaphylaxis results: before oit, median age was 5.7 years old, median threshold to induce initial reaction was 2.1 ml, to induce anaphylaxis was 14.6 ml of cm and median milk specific ige was 56.4 ku/l. twentyseven subjects (24%) dropped out from the protocol, 69 subjects 0766 | investigation of heat and matrix effect on milk proteins' allergenicity and the development of hypoallergenic food products reduce some milk proteins' allergenicity (ß-lactoglobulin) . in this project we aimed to investigate the effect of heat and matrix on different milk protein fractions through maillard reaction and eventually develop hypoallergenic food products that have milk protein with low reaction risk. method: milk cake matrix is prepared in different flour/sugar (f/s) ratio (2f/1s, 1f/1s, 0.5f/1s) and baked 30 minutes at 180°c. proteins that cake contains are separated using sds page and stained with coomassie blue to check total protein. in parallel specific proteins are detected by western blotting using pooled sera from patients with milk specific ige>60ku/l for incubation results: in normal milk cake recipe (2f/1s) ß-lactoglobulin bands are disappeared but casein bands did not differ in size. in order to investigate the matrix effect f/s ratio is changed and it is found that when this ratio decreases, with the affect of heat and maillard reaction, milk casein bands' intensities also decrease in sds gel coomassie staining. in western blot experiments it is also shown that milk specific ige bound weakly to casein bands in low f/s ratio cake (0.5f/1s) whereas in cakes that have high f/s (2f/1s) ratio it bound significantly higher. and ß-lactoglobulin proteins' structure and lower the milk specific ige bindings to milk proteins in low f/s ratio cake through maillard reaction. 0767 | extensively hydrolyzed formulas for the management of cow's milk protein allergy in infants: is extensive hydrolysis sufficient to guarantee success? method: to better understand the range of ehfs, we aimed to analyse samples of commercially available ehfs from 11 countries and various manufacturers, with a focus on suitability for cmpa management. samples were de-identified and coded for the analyses. molecular weight (mw) distribution of hydrolysates and residual proteins and peptide profiling were assessed with sds-page gel and size exclusion-high-performance liquid chromatography (se-hplc), as they reflect both the design of the formula and the quality management applied during production. osmolarity, nitrogen fractions, lactose content, total and free amino acids, β-lactoglobulin, and casein content were quantified and β-lactoglobulin residual allergenicity was assessed. results: peptide mw distribution displayed significant variation, with the percentage of peptides with mw >1.2 kda varying from 1% to 36%. mw distribution was shown to be positively correlated with β-lactoglobulin specific in vitro degranulation. twenty % of samples had non-measurable β-lactoglobulin content (smaller than or at the limit of quantification (loq): 0.010 mg/kg); however, 80% of samples had β-lactoglobulin content greater than the loq, with high variability from 0.020 to 36 mg/kg. surprisingly, even in samples featuring a high degree of hydrolysis, significant levels of residual β-lactoglobulin were quantified. conclusion: lack of consensus over the definition of 'extensively hydrolysed' is reflected in the wide range of degree of hydrolysis in commercially available ehfs, and can result in products that are mislabelled as 'extensively hydrolysed' and may be high-risk or even unsuitable for the management of cmpa. results of these analyses also highlight that degree of hydrolysis alone is not sensitive enough to characterise ehfs, and that whilst a high degree of hydrolysis is desirable, further quality control measures are essential to ensure clinically safe and suitable products. actionable guidelines to better define hypoallergenic formulas based on extensively hydrolysed milk proteins are warranted. background: assessing the effect of baked milk products on accelerating unheated milk tolerance in patients with cow's milk allergy. method: a randomized clinical trial was done on 84 patients (6 months-3 years old) divided randomly to case and control groups matched for age and sex. baked milk in form of muffin for 6 months followed by baked cheese in form of pizza for next 6 months was given to the patients in case group. skin prick test and serum ige (sige) levels (immunocap) of milk, casein and betalactoglobulin were measured before and after the study. the ones having milk sige less than 3 ku/l and being asymptomatic during the study underwent oral food challenge test for evaluating unheated milk tolerance. chualalongkorn university, bangkok, thailand; 8 kk women's and children's hospital, singapore, singapore; 9 university of the philippines, philippine general hospital, manila, philippines background: problems in recognising cow's milk allergy (cma) and lactose intolerance (li) in infancy may lead to a delayed or incorrect diagnosis, as well as inappropriate dietary interventions. method: between january and november 2017, a survey was conducted online in china, india, singapore, thailand, mexico, kuwait, united kingdom, australia, and paper-based in the philippines. the survey consisted of 12 multiple-choice questions on cma and li in infants aged under 12 months, two case scenarios (non-ige cma and anaphylaxis) and 10 questions on educational needs (likert scale [1] [2] [3] [4] [5] . data on the type of medical practitioner and clinical setting were collected. responses were summarised as percentages and categorised by country. results: 1663 responses were received from general practitioners (22.2%), paediatricians (39.7%), paediatric allergists (6.9%), paediatric gastroenterologists (11.2%) and other specialities (20.0%). there were significant misconceptions about the clinical importance of primary li in infancy. while primary li rarely manifests before 3 years of age, 73.7% of participants felt it was a significant clinical problem in the first year of life. regarding secondary li, 44% of respondents recommended lactose restriction for viral gastroenteritis, and 36% for cow's milk protein-induced enteropathy. while the management of ige cma was relatively well understood, there were greater knowledge gaps for non-ige cma. 59% of practitioners appropriately identified extensively hydrolysed formula (ehf) as first-line treatment of cma in formula-fed infants. however, the distinction between lactose-free and lactose-containing ehf appeared to be an area of uncertainty. in india, 34.4% used soy-based formulas as firstresults: patch tests were positive in 62 (79.5%) and negative in others. positivity to milk was seen in 29 patients (37.2%), to soy in 41 (52.6%), to egg white in 7/72 (9.7%), to wheat in 12/66 (18%), to potatoes 6/48 (12.5%), to corn (maize) in 3/38 (7.9%), to rice in 1/2, and to peanut in 3/37 (8.1%). patients were requested to withdraw the suspected food(s) from their diets during a 4 months period. preliminary follow-up data show the improvement of one or more symptom in 19/20 patients (gastroesophageal reflux in 10, appetite in 5, stool consistency in 1, respiratory symptoms in 10, pain in 3, eczema in 1). conclusion: patch tests are informative, easy to use tools in order to identify potential causes of common lasting symptoms in children with negative or weak rast results and introduce beneficial changes in the daily diet. longer follow-up is necessary in order to refine and assess the benefit of such strategy. background: currently in the us, 1 in 13 children suffer from food allergies. at present, there is no cure and strict avoidance of the relevant foods is the only way to prevent allergic reactions. elimination diets put infants and children at risk for nutritional deficiencies and impaired growth. we examined the role of the registered dietitian (rd) in advising patients and families of food allergic children. method: a retrospective review of clinical notes was performed for the first 13 consecutive children who required a dietetic consultation in a dedicated food allergy clinic. we examined common questions from parents that were addressed by the dietician during the consultation. results: patients were aged 10 months -9 years (median: 16 months) and were diagnosed with the following food allergies: cow's milk: 69.2%, egg: 62%, tree nut: 54%, peanut: 39%, wheat: 31%, soy: 31%, fruit/vegetable: 15%, legume: 8%, fish: 8%, sesame: 8%. the most common questions for the dietitian included: ways to meet nutritional needs following a prescribed allergen-restricted diet (31%), meeting vitamin d and calcium requirements on a milk protein-free diet (23%), suitable oral supplements and recommended serving sizes (14%), appropriate order of solid foods introduction in food protein-induced enterocolitis syndrome (fpies) (14%), cautionary food ingredient statements (7%), baked milk protein introduction (7%), cross-reactivity risk of milk protein with soy (7%) and crossreactivity of nuts in retail bakeries (7%). conclusion: parents of children with food allergies have multiple questions with regards to nutrition. dietetic input in the food allergy clinic addresses important issues for children and families including successful avoidance of allergen-containing foods while ensuring optimal nutrition, decreased exposure to high-risk situations and avoidance of allergen cross-contamination. 0773 | multicenter prospective study of a stepwise single dose oral food challenge of egg background: oral food challenges (ofcs) are necessary for allergy management. we previously reported that a low-dose ofc can avoid complete elimination, even if patients react to higher doses of causative foods. nevertheless, this approach has only been validated in a retrospective single-center trial. we have previously reported that the median time for initial symptom onset is 50 minutes for egg ofc using a single exposure. therefore, this study aimed to confirm the safety and effectiveness of a stepwise single-dose ofc in a multicenter, prospective study. who showed a positive reaction to low-dose ofc, only 1 patient (2%) showed a severe reaction: barking cough immediately improved with adrenaline inhalation. among 8 patients with a positive reaction to medium-dose ofc, none had a severe reaction. the median times to symptom onset were 60 and 50 minutes following low-dose and medium-dose ofc, respectively. patients in the three groups, divided according to threshold doses, differed significantly in sige levels against egg white and ovomucoid. conclusion: this multicenter prospective study confirmed that stepwise single-dose ofc to egg will help to clarify the severity of egg allergy, and will contribute to improved food allergy managemethod: the study design was a retrospective cohort study extracting data from the electronic chart of children older than 4 years who visited our out-patient clinic for egg or milk allergy and who underwent an oral food challenge test (ofc) twice within 24 months between november 2013 and december 2017. the patients were divided into five groups according to their treatment schedule, which consisted of those who: a) started from 1/10 of the first ofc reaction threshold and maintained 1/10 till the end of oit; b) started from 1/100 of the threshold and maintained 1/10; c) started from 1/10 000 of the threshold and maintained 1/10, d); conventional slow oit (started from just below the first ofc reaction and increased 1.2-1.5 times every few weeks); or e) continued elimination. we determined the presence or absence of an increase in threshold reacted to the allergen, any adverse events during oit, and food-specific ige reduction. results: the number of participants was 217 and their median age was 6 years. the number of patients in groups a, b, c, d, and e was 17, 51, 33, 95, and 21, respectively. the percentage of patients in groups a, b and c showing an increase in reaction threshold to the allergen was higher than that in group e (p < 0.05), and that in group b was higher than that in group d (p < 0.001). the number (percentage) for group a, b, c, d, and e was 12 (70.6%), 43 (84.3%), 23 (69.7%), 54 (56.9%), and 5 (23.8%), respectively. there was a significant difference in the frequency of adverse events during oit between group a-c and d, which was as follows: 5 (29.4%), 9 (17.6%), 8 (24.2%), and 67 (70.5%), for the respective groups (p < 0.0001). there was no significant difference in the percentage of patients showing a decrease in food-specific ige in each group. conclusion: the regimen starting from 1/100 of the ofc reaction threshold and maintaining the dose at 1/10 was safer and more effective for increasing the threshold reacted to the allergen than the 'conventional slow oit' regimen. elimination continuation was not effective for increasing the threshold reacted to the allergen. legumes allergy was presented in different clinical features; urticaria and angioedema in 32 (50%) patients, anaphylaxis in 23 (35.9%) patients, atopic dermatitis in 5 (7.8%) patients, eosinophilic esophagitis in 3 (7.8%) patients and as food-related enterocolitis in 1 (1.5%) patient. thirteen (35.1%) of the patients had asthma, 9 (24.3%) had allergic rhinitis. fourteen (58.3%) of the 24 patients with single legume allergy showed improvement. the patients who developed tolerance, of these 7 (29.1%) had peanut allergy, 4 (16.6%) had lentil allergy and 3 (12.5%) had chickpea allergy. two of 13 patients with multiple legumes allergies, it developed tolerance to all the legumes they are allergic. conclusion: peanut and lentils were the most frequent legumes that displayed allergic reactions in our study. in these patients the rate of allergy to non-legumes food is high. in patients who were allergic to single legumes, the symptoms were ameliorated in 58.3%. conclusion: cashew nut is a potent allergen and can cause quite severe reactions. avoidance of pistachio nut and other related allergens should be advised to patients after allergologic investigation. in the majority of the patients, presence of atopic dermatitis with food allergy is noteworthy. therefore, it would be useful to investigate these patients for cashew and other tree nut allergy before they present with a serious clinical reaction. and jellyfish sting. serum allergen-specific ige test was negative; skin prick test was positive for natto and pork. we performed an oral food challenge with natto, pork, crustaceans, and wheat, and she developed a general itchy rash after 7 hours of eating natto. h1blocker was administered and she recovered soon. however, the general itchy rash relapsed after 4 hours. hence, we intramuscularly injected epinephrine, h1-blocker, and steroids; then, her symptoms did not relapse. based on these findings, we inferred that anaphylaxis caused by natto could be associated with a jellyfish sting. discussion: although association between japanese fermented soybeans (natto) allergy and jellyfish sting has been previously reported, its anaphylaxis is a rare event. in this case, we suggest that anaphylaxis was caused by natto allergy, which was perhaps related to jellyfish sting. hence, further investigation is essential to elucidate the association between fermented soybeans allergy and jellyfish sting. introduction: non-celiac gluten sensitivity (ncgs) is a syndrome characterized by intestinal and extra intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease (cd) or wheat allergy (wa).once the gluten-containing foodstuff is removed from the diet, the patients will have relief of their symptoms. case: a 6-year-old girl was referred by his general practitioner with history of occasional constipation and abdominal pain (especially after main meals and defecation), short stature and low weight. the growth indices were proper for her age till she was 5. then after there was a stunting. she had short stature and low weight. despite different types of supplementation, there was no improvement in growth indices, so she was referred to a pediatric endocrinologist for gh therapy. primary investigations and anti-ttg, iga, anti-ema all were normal. after a consultation with a pediatric gastroenterologist, a genetic study of hladq2 and 8 were done because of the highly suspicion of celiac disease. the results were also negative. at last she was referred to immunology-allergy clinic for evaluation of probable food allergy. ige level was checked and a prick test was performed which they were not indicative of any suggestive food allergy. because of the history of the abdominal pain and constipation which was more prominent after meals, negative results of genetic study, spt to wheat, and serologic markers, a gluten free diet was suggested for her with the suspicious of non celiac gluten sensitivity. a significant improvement in her symptoms was noticed within 2 weeks of starting gluten free diet. she has 2kg of weight gain and height improved from 116 cm to 120 cm in 4 months. she continued to improve on a gfd and when seen in the follow-up clinic 6 months later reported complete resolution of symptoms and another 2 cm and 1 kg gain in her height and weight. conclusion: non-celiac gluten sensitivity syndrome is a diagnosis made by excluding celiac disease and wheat allergy. it should be taken into consideration especially in patients who have the suspicious symptoms of celiac without supporting lab data, and also negative spt to wheat. the young man in question along with his parents were keen to proceed, so with some hesitation we proceeded to a hazelnut oral provocation challenge, having very carefully explained the risks of undertaking such a challenge. he successfully completed the challenge and experienced no allergic symptoms and is now able to have hazelnuts in his everyday diet. discussion: this young man wanted to confirm if indeed he was allergic to hazelnuts. not being hazelnut allergic would mean that he would be no longer allergic to any nut and would not have to take precautions prior eating products. positive results to both cor a 9 and cor a 14, hazelnut storage proteins are associated with the patient possibly experiencing systemic reactions, at a higher risk of experiencing anaphylaxis it they were to ingest hazelnut. these facts in conjunction with his specific ige to hazelnut would have prevented us from proceeding to challenge was it not for this young man's persistence that he wanted to proceed to challenge despite the risks. conclusion: appearances are deceptive, as this case demonstrates; allergen-specific ige and component testing can only predict the probability of an allergic reaction, the final test in the diagnostic process is the oral provocation challenge. the patient and his family were happy for me to share the above with other health care professionals. method: we present the case of a female of 29 years old diagnosed of acu with poor control of the symptoms at maximum doses of antihistamines. we decided to associate omalizumab treatment. the patient had a good control of the symptoms with omalizumab at dose of 300 mg/4 weeks, but in the 6th month she presented an erythematous, raised and pruritic lesion in the area of injection together with localized abdominal edema at 12 hours of the administration, with two weeks of evolution without symptomatic treatment. we decided to discontinue omalizumab alter a second episode with half doses. results: we performed a skin biopsy of the lesion and epicutaneous tests with the drug. immediate hypersensitivity tests were not taking due to the impossibility of stopping antihistamines. skin biopsy showed a perivascular lymphocytic inflammation of the superficial and deep dermis with frequent presence of perivascular and interstitial eosinophils, suggestive of a hypersensitivity reaction. results: nine months before presentation at our clinic, the patient had been hospitalized and treated with imipenem and tmp/smx for pulmonary nocardiosis. once discharged, she had been prescribed oral tmp/smx alone, according to antimicrobial susceptibility. at our first evaluation, the patient presented with fever, macular erythematous non-pruritic (vasculitic-like) skin lesions on the upper limbs, polyarthralgia and bilateral ankle arthritis. tmp/smx was transiently stopped. after four days, there was a dramatic improvement, with resolution of all signs and symptoms. she was tentatively diagnosed with a viral infection and thus tmp/smx was started again. however, after three days, the symptoms (fever, arthritis and skin lesions) recurred. laboratory investigations showed increased levels of inflammatory markers. complete blood count with differential, serum creatinine, urinary sediment, liver enzymes, rheumatoid factor, antinuclear antibody, c3, c4, immune complexes, serology for rickettsia, borrelia and coxiella were all negative. hence, tmp/smx was stopped again and cutaneous lesions, fever and arthritis resolved spontaneously in five days. conclusion: given the clinical course and the resolution after the withdrawal of tmp/smx, we diagnosed a sslr due to sulfonamides. to the best of our knowledge, this is the first case of sslr occurring after a nine-month therapy with tmp/smx and allergists/immunologists should be aware of the possibility of such a reaction even after months. case report: * we received written informed consent for publication of these clinical details and/or clinical images included in my abstract was obtained from the patient. drug rash with eosinophilia and systemic symptoms (dress) syndrome is a severe adverse cutaneous reaction that usually appears 2-6 weeks after treatment with the causative drug. this syndrome is characterized by severe dermal rash, fever, eosinophilia, and internal organ involvement, and clinically, diffuse maculopapular eruption, exfoliative dermatitis, and facial edema are often observed. we performed blood tests and laryngeal fiberscopy for the diagnosis of the patient. intradermal test with delayed reading and patch test were performed 2 months after the end of treatment. a 53-year-old man had begun treatment with carbamazepine for epilepsy. after 4 weeks of treatment, he observed skin rash with pruritus on both lower extremities, and after 6 weeks, his skin lesions had begun to spread over his whole body, and he complained of several new symptoms, including hoarseness, dyspnea at rest, and dysphagia. an examination revealed maculopapular rash, facial edema, and bilateral cervical lymphadenopathy. laryngeal fiberscopy revealed both arytenoid and epiglottic swelling. laboratory studies revealed eosinophil counts of 2100 /μl and increase in alanine aminotransferase level to 65 u/l. a diagnosis of dress syndrome was definite according to the regiscar group criteria. carbamazepine, the suspected culprit drug, was withdrawn, and systemic corticosteroid was initiated. the patient experienced rapid improvements in hoarseness, dyspnea, and dysphagia. after 5 days of treatment, laryngeal fiberscopy revealed complete resolution of both arytenoid and epiglottic swelling. to the best of our knowledge, our case is the first reported case of dress syndrome to manifest with laryngeal edema. case report: bortezomib (velcade ⓡ ), a targeted therapy works by blocking the action of proteasomes in side cells, is commonly used to treat newly diagnosed as well as relapsed/refractory myeloma. bortezomib has been reported to have gastrointestinal symptoms, peripheral neuropathy, neuropathic pain and thrombocytopenia as its most common side-effects. although several cases of skin lesion caused by bortezomib have been reported, severe cutaneous adverse reaction (scar) such as stevens-johnson syndrome (sjs) is very rare. we here report a case of bortezomib induced sjs. a 71-year-old female patient, who was diagnosed with multiple myeloma, received bortezomib and melphalan /dexamethasone therapy. after the 4th dose of bortezomib, she presented with fever and maculopapular skin rashes spreading from face to the trunk. erosive lesions in the oral mucosa and corneal ulceration with conjuntival injection were observed. she was diagnosed as sjs. the symptoms of sjs improved after bortezomib was discontinued and systemic steroids and intravenous immunoglobulin were administered. drug patch test was performed, the result was positive in bortezomib. this is the first case report of bortezomib induced sjs in this country, which was diagnosed by a patch test. although the scar by bortezomib is generally considered very rare, we suggest that clinicians be aware of potential adverse reactions, including sjs. case report: we report the case of a healthy 46-year-old woman with history of red erythematous macules in both hands, one hour after taking a fluconazole (150 mg) tab for a vaginal candidiasis. it faded spontaneously. she didn't recall if she had ever taken that medicine, but denied known drug allergies. although fde is primarily a clinical diagnosis, we conducted an oral challenge test with fluconazole (150 mg). two hours after intake of the drug the patient started complaints of pain and erythema in both hands and the challenge was stopped. two days after the challenge, she developed red painful erythematous macules on the same sites of the first episode. due to the specificity of the challenge, local patch testing was not performed. introduction: the classic form of a fixed drug eruption is one or more anular or oval erythematous patches as a result of systemic exposure to a drug. these skin lesions normally resolve with hyperpigmentation and may recur in the same location with re-exposure to the drug. other types of fixed drug eruptions have been described, being fixed drug urticaria a rare form of presentation. (1, 2) case report: in the last 2 years, a 48 year old woman has developed more than 15 episodes of a wheal in the right supraciliary region 5 minutes after taking 600 mg of oral ibuprofen. the symptoms resolved in less than 6 hours without treatment and without leaving residual lesion. after the last episode, she refers good tolerance to 1 g of oral paracetamol. she denies local traumas. she also refers mild spring rhinoconjunctivitis well controlled with antihistamine, and sneezing with house dust. a 37-year-old-m patient had psoriasis vulgaris for 15 years, and had been using methotrexate at intervals of 4 years. despite the addition of phototherapy, he underwent a new treatment with biological agent (antitumor-necrosis-factor; anti-tnf), since the disease control was insufficient. before anti-tnf, preventive treatment against latent tuberculosis (tb) activation was indicated with positivity in tuberculin skin test (20 mm). he was given inh 300 mg/day, and at the 20th day of treatment, desquamation, erythema, and subsequent exfoliation developed in his hands and foots dorsum. inh was withdrawn. in order to distinguish the lesions from psoriasis attack, skin biopsy was performed and reported as erythema multiforme-like dermatitis with no relation to psoriasis. the lesions were completely improved at 3 weeks of topical steroids, and inh was re-initiated at the same dose. a week after the initiation of the drug, skin lesions similar to previous reoccurred with more severity and progression from distal to proximal extremities. cell counts, renal and hepatic function tests, and hepatitis markers in blood were in normal limits. skin lesions were retracted after 4 weeks of topical steroids, and withdrawal of inh. there was positivity in skin patch test with inh at 72 hours. finally, for tb prevention an alternative drug rifampicin (10 mg/kg/day) was given, and the patient successfully completed with no adverse event. his psoriasis lesions were improved with anti-tnf which was started after 1 month of tb prevention with rifampicin. in these days which the use of biologic agents is increasingly widespread, inh use will be more prevalent than the past. even tough, it is effective and safe in most of the patients, its adverse event dermatitis may be a reason to withdraw in patients with dermatological diseases. in this case, diagnostic drug allergy evaluation should be performed to optimize the second-line treatment of tb infection, in addition to early withdrawal of the culprit drugs. background: around 50% of cancer patients will receive radiotherapy (ionizing radiations) as a treatment, either as a single therapy or as an adjuvant to chemotherapy and surgery. several side effects have been described due to radiotherapy, of which we can mention erythema multiforme and stevens johnson syndrome, but in lower prevalence. erythema multiforme can be described as an acute skin condition and may be present within a wide spectrum of severity. erythema multiforme minor represents a localized eruption of the skin with minimal or no mucosal involvement. the papules evolve into pathognomonic target or iris lesions that appear within a 72-hour period and begin on the extremities (see the following image). lesions remain in a fixed location for at least 7 days and then begin to heal. it is considered to be a type iv hypersensitivity reaction associated with certain infections, medications, and other various triggers precipitating factors and complex interactions may trigger the appearance of signs and symptoms. these include especially recurrent herpes simplex virus (hsv), epstein-barr virus (ebv), histoplasmosis, alcohol, systemic diseases and immunological factors. method: 69-year-old male diagnosed with prostate adenocarcinoma who underwent transurethral resection and was taking trinomia (ramipril, atorvastatin, acetyl-salicylic acid) after his 8th rte external radiotherapy session, he presented erythematous maculo-papular lesions in the suprapubic area with some vesicles. therefore, withdrawal of treatment was decided and the performance of a skin biopsy. 15 days later, regarding the improvement of the lesions, rte was continued, presenting incipient exacerbations of the lesions but it allowed us to end the cycle of treatment. results: skin biopsy results (anatomical pathology): basal keratinocytes, which blur the dermoepidermal interface, with lymphocyte exocytosis at this level, associated with isolated images of spongiosis. the dermis shows a superficial perivascular lymphocytic inflammatory infiltrate of moderate intensity. compatible with erythema multiforme. conclusion: radiotherapy is a technique of increasing use, so it is important to recognize the associated cutaneous lesions that appear less frequently and are sometimes underdiagnosed. diagnosis is both clinic and pathological and is usually late in most cases so it is vital to take into account this skin disease complication in order to be properly managed. including chinese herbal medicine is usually considered to be without any allergic and adverse reaction. method: visits were made to pharmacies in hong kong and luoyang, china and a martial art monastery/temple in dengfeng, china. some cam were found to have ingredients with potential allergic and adverse reaction. results: three cam, one from hong kong (1), one from shaolin martial art monastery/temple in dengfeng (2) and one from luoyang (3), china were found to contain chinese herbal medicine with potential allergic and adverse reaction. (1) cordyceps ling-zhi complex ingredients: cordyceps sinensis "caterpillar fungus", tremella fuciformis "snow fungus", ganoderma lucidum (ling-zhi) "reishi mushroom" and others 30 years old female patient who has ulcers in oral mucosa and purple, itchy lesions on her right hand palmar area, little finger, index finger, on her left hand palmar area, pollex finger. in her history, she has relapsing vaginal yeast and she hasn't any hypersensitivity reaction with fluconazole before 1 month ago she started to take fluconazole because of vaginal candidiasis. after using fluconazole she started to itch from described areas and dark redpurple eruptions appeared. she was prescribed oral methylprednisolone and topical pomade which included corticosteroid for four days but she didn't aware of fluconazole related drug reaction. lastly four days ago she took fluconazole and metronidazole for severe vaginal yeast. 12 hours later pruritus, same eruption appear on the same area, lip and tongue angioedema than she had dyspnea, dizziness, hypotension, arrhythmia and consciousness. she had admitted to the emergency department and performed adrenalin. after a day bullae and ulcers came into existence in her oral mucosa. in her blood analysis there was mild increase in white blood cell count (13.300 /mm 3 ), eosinophil count was normal (300 /mm 3 ), biochemistry parameters were in normal limits, crp and sedimentation rate were in normal limits, total ige was 439 iu/l. introduction: tuberculosis is a disease that most commonly affects the lungs, which is transmitted by the respiratory tract and drugs are the most important factor in the treatment. non-resistant tuberculosis infection is usually treated with hrze. in rare cases, a hypersensitivity reaction may develop against one or more of the drugs during treatment. case: a 37-year-old female patient was diagnosed with culturepositive pulmonary tuberculosis and hrez treatment was started by the related department. seven days later she referred to the policlinic with edema and itchy erythematous lesions which are common in her extremities, which developed after 6 hours of taking her medication. liver and kidney function tests and eosinophil count were normal. drug eruption was considered with current physical examination findings. the treatment was interrupted, short time systemic corticosteroids and antihistamine treatment started. desensitization planned. there was no feature in the prick and patch tests with drugs. desensitization was performed with isoniazid, no reaction was observed during the procedure. six hours after the procedure, the patient applied to the emergency department with painful edema and pruritic erythematous lesions in the extremities. desensitization procedures with rifampicin, ethambutol, pyrazinamide were performed without any problems after the lesions were regressed. isoniazid was withdrawn from the treatment protocol. outcome: we would like to present on this case that drug eruption may develop in the form of maculopapular rash after desensitization. this study aims to compare ethmoid mucosa and nasal polyp regarding density of tissue eosinophil and its sensitivity, specificity, and correlation with clinical characteristics for diagnosing ecrs. method: patients with crs with polyps scheduled for endoscopic sinus surgery were enrolled. specimens were collected from polyp apex, polyp pedicle and ethmoid mucosa. tissue eosinophil from these three sites in the same patient were compared. using eosinophilic mucin as a reference, sensitivity, and specificity of each site for diagnosing ecrs was assessed. correlations between tissue eosinophilia (defined as greater than 10/ hpf) and clinical characteristics of ecrs including asthma, serum eosinophilia, and eosinophilic mucin were analyzed using each site of specimens. results: thirty patients with crs with polyps were enrolled. polyp apex, polyp pedicle and ethmoid mucosa gave similar results regarding tissue eosinophilia in 16 patients (53.3%). eleven (36.7%) patients were ecrs (having tissue eosinophilia at all sites) and five (16.6%) were non ecrs (no tissue eosinophilia at any sites). median tissue eosinophil was significantly greater in polyp apex (84, and polyp pedicle (96, iqr: 80-320) than ethmoid mucosa (21, iqr: 10-220), p = 0.04. sensitivity of polyp apex, polyp pedicle and ethmoid mucosa for diagnosing ecrs were 100%, 60% and 80% respectively. specificity were 36%, 40% and 48% respectively. correlations between tissue eosinophilia and asthma were significant when assessing ethmoid mucosa (p = 0.04), and polyp pedicle (p = 0.05) but not polyp apex (p = 0.21). correlations with serum eosinophilia, and eosinophilic mucin were not significant (p > 0.05) when assessing any specimens. gov/pubmed/) was performed using the following key words: "obstructive sleep apnea syndrome"; "allergy rhinitis"; "hypoxia"; "intermittent hypoxia"; "fluctuating hypoxia"; "cyclic hypoxia"; and "hif-1α" results: osas may affect the prognosis of ar patients based on the following evidence: 1) ar is thought to be a cause of osas. 2) exposure to hypoxia could mediate immune activation in ar and affect the response to treatment. 3) hif-1α expression may be a risk factor for ar. 4) intermittent hypoxia can induce robust expression of hif-1α. conclusion: first, improvement of ventilation during sleep represents an efficient strategy for treating ar. therefore, continuous positive airway pressure or nasal surgery to resolve a nasal obstruction could be added to ar treatment. finally, medications that target hif-1α, such as digoxin, can be tested as adjuvant therapy. method: forty patients diagnosed with allergic rhinitis and olfactory dysfunction were recruited in current study in the group 1 and 2. patients of group 1 were administered with no treatment and patients administered with the traditional chinese acupuncture therapy were incorporated into the group 2. before the treatment, all of them underwent t&t olfactory testing, nasal sinus computer tomography scanning and visual analog scale (vas; 0-100), and repeated the assessment after four-week treatment. results: improved total t&t olfactory testing scoring averages and vas scoring averages was observed in eleven patients treated with traditional chinese acupuncture compared with four patients in the observation group. no side effect was found. no significant differences in olfaction recovery were found according to age, gender, or duration of disease between the two groups. the observation group underwent nasal endoscopic sinus surgery and the control group underwent external approach surgery, and the therapeutic effect of the two groups were investigated. results: the total effective rate was 94% in observation group and 74% in control group, the total effective rate of observation group is significantly higher than control group (p < 0.05). the recurrence rate was 3% in observation group and 24% in control group, the recurrence rate of observation group is significantly lower than control group (p < 0.05). complication occurrence rate of observation group was 6% which is significantly lower than control group 24% (p < 0.05). the therapeutic effects of endoscopic sinus surgery on chronic sinusitis in geriatric patients are better than conventional external approach surgery which is worth clinical application. results: (descriptive). the equick app is user-friendly even for vkc patients with sub-optimal reading ability. home use between clinic appointments allows responsive temporal data gathering of qol, symptoms, medication scores and impact of medical interventions. equick may be used in future as a research tool in gathering outcome data following interventions for vkc. ectoine, a substance deriving from halophilic micro-organisms, is a strong water structure forming solute exerting cell protective antiinflammatory and antiallergic properties. method: purpose of our study was to assess the efficacy of the preventive administration of 2% ectoine eye-drops (3 times a day for 6 months) to shorten the duration of vkc relapses (which begin, in our country, very early in spring and usually end in october), or to mitigate the attacks, which are only controlled by topical corticosteroids or cyclosporine resulting in an important burden of side-effects. in this retrospective study, we included 192 children of both sexes (148 males and 44 females), under the age of 10 years (mean age 7.8 years), affected by vkc from more than 3 years/seasons and treated for more than 4 months during a year, with cyclosporine eye-drops. these patients underwent, from february to september 2017, the additional-to-the-usual protocol treatment with 2% ectoine eyedrops. results: 8% of the included subjects astonishingly had no relapse of vkc, 38% needed topical cs or cyc treatment but it was started 2 months later compared to previous years, 29% needed the topical drugs 3 months later and 25% had a similar to previous years course (no ectoine efficacy). the treatment was well tolerated and only 1 child had to stop it because of local allergy to the eye-drops. the preventive administration of 2% ectoine eyedrops was able to stabilize and to delay vkc attacks in more than 50% of the selected patients showing the importance of anti-inflammatory and anti-allergic properties of this product. following international criteria we considered normal levels of vitamin d the levels between 50 nmol/l (20 ng/ml) and 125 nmol/l (50 ng/ml), a potential deficiency between 30 nmol/l and 50 nmol/l and a severe deficiency less than 30 nmol/l. results: 58.8% (30 children) of akc group patients presented vitamin d low levels, among them 18 children showed a potential deficiency and 12 a severe deficiency. 24.3% (18 subjects) of vkc patients suffered a deficiency in vitamin d which was mild in 13 and severe in 5 patients. 40.3% (25 children) of sac group showed a deficiency in vitamin d which was potential in 17 and severe in 8 subjects. conclusion: our study shows that in different forms of allergic conjunctivitis many children are suffering a vit. d deficiency and it can be supposed that a correlation between the severity of the allergic form and the level of vit. d deficiency exists. we recommend allergists and ophthalmologists to check vit. d levels in children suffering from allergic conjunctivitis because its deficiency is very common and many are unaware of it; in case of a vit. d insufficiency it is fundamental to give a vit. d suitable-to-the-case supplementation. method: 83 children (57 males and 26 females, mean age 7.3 ± 5 months) affected by vkc and allergic rhinitis from more than 2 years were treated with mometasone furoate nasal spray 1 spray bid × 2 weeks in a month, for 3 consecutive months as a co-seasonal treatment at the beginning of eye allergic symptoms. other systemic or topical treatments did not vary compared to the previous 2 years. results: a quick questionnaire administered to children and their care-givers showed that nasal symptoms regressed after a mean period of 9.2 days from their beginning but, impressively, in more than 30% of them, these patients did not show a vkc typical relapse along the 3 months of mometasone treatment, moreover the following summer period was milder in subjective ocular symptoms in more than 25% of the patients. our experience pointed out that incs adjunctive treatment was positively associated with a regression of eye and nose symptoms in children suffering from vkc, confirming previous literature data which concern milder forms (seasonal allergic conjunctivitis or allergic rhino-conjunctivitis) compared to the severe forms (like vkc) we analyzed in our work. one of the involved mechanisms of action can be the alleged effect on the reduction of substance p in tears; it is supposed to reflect the neuropeptides levels in ocular tissues. 0816 | patient response to mp-azeflu in an allergen exposure chamber onset of action (ooa) timing may impact treatment adherence. mp-azeflu, intranasal azelastine hydrochloride (aze) and fluticasone propionate (fp) in a single device, has proven to have greater efficacy and faster ooa than a combination of oral loratadine and intranasal fp (lora/infp), but the clinical relevance for patients is unclear. this single-center (ontario, canada), randomized, double-blind, double-dummy, three-period crossover trial examined by which extent mp-azeflu provides clinically relevant symptom improvements according to different efficacy parameters. method: ar symptoms were induced in asymptomatic, ragweedsensitive patients via ragweed pollen challenge in an environmental exposure chamber. patients received a single dose of mp-azeflu, lora/infp, or placebo and were monitored for 4 hours. symptoms were assessed using total nasal symptom score (tnss) and total ocular symptom score. responder analyses included the number of patients to achieve relevant response (rr) to therapy (30% or 50% reduction in tnss), time to rr (ie, first time point at which rr was reached), and minimal clinically important difference (mcid) in ooa. background: nasal allergen provocation test (napt) is a standardized diagnostic tool indicated in the diagnosis of allergic rhinitis, to design and monitoring allergen immunotherapy, and to study the pathophysiology of airway allergy. unfortunately, until now very few studies have evaluated its reproducibility and safety. in this study we wanted to analyse the safety and reproducibility of napt in a large group of rhinitis patients and healthy controls. unit until december 2017. a bilateral saline challenge followed by a bilateral napt were performed in symptoms-free individuals. the response was assessed by nasal-ocular symptoms and acoustic rhinometry. all subjects signed a written informed consent. the safety of napt was checked by the occurrence of extra-nasal/ ocular reactions (enor), severe adverse events (sae), and use of rescue medication (rm). enor was assessed by clinical symptoms, physical examination, cardiopulmonary auscultation, spirometry, and oxygen saturation. the reproducibility of napt was tested by comparison of the results in 2 or more sessions with≥1-month interval. background: nasal hyperreactivity (nhr) is self-reported by a majority of patients with allergic rhinitis (ar) and is likely mediated by neural-immune interactions. the combination of fluticasone propionate (fp) and azelastine (aze) hydrochloride administered in a single spray (mp-azeflu) has been shown to be superior to fp or aze alone in patients with seasonal ar (sar). we hypothesize mp-aze-flu may reduce neuro-immune mediators in ar with nhr. in a post hoc analysis of three pivotal studies of mp-azeflu, we analyzed the efficacy of mp-azeflu, fp, and aze in patients with ar with and without nonallergic triggers. method: in three randomized, double-blind, controlled trials, patients with sar were randomized 1:1:1:1 to mp-azeflu, fp, aze, or placebo (pbo). patients self-reported sensitivity to nonallergic triggers. change from baseline in total nasal symptom score (tnss) and treatment differences between active agents and pbo were calculated. results: across 3412 patients in three studies, mean age was 36.3 years and mean age at ar symptom onset was 15.6 years. overall, 89% reported ≥1 nonallergic trigger, which included sudden temperature/humidity change (72%), tobacco smoke (61%), perfumes/fragrances (57%), incense/candles (38%), and cleaning products (38%). change from baseline in tnss for patients with ar and nonallergic triggers was greater with mp-azeflu than with fp or aze (table) , and patients with nonallergic triggers improved slightly less than patients without nonallergic triggers in both the mp-azeflu and fp groups. background: in low-income countries (lics), assessment of phenotypes, prevalence and risk factors for allergy-related diseases (ards) using allergen-specific ige may be complicated by environmental exposures such as helminths. these exposures may also induce cross-reactive carbohydrate-specific ige profiles that could inhibit allergic effector responses. we sought to elucidate the molecular basis of ige sensitisation among individuals in uganda, using a component-resolved approach to ige measurement. we employed the isac ® allergen microarray to assess plasma ige reactivity to 112 purified natural and recombinant allergen components in participants of three studies: a trial of intensive versus standard anthelminthic treatment in the rural helminth-endemic lake victoria islands (n = 126), a parallel urban survey of allergy outcomes in a lower helminth exposure community (n = 60) and a study on asthma risk factors in children from the urban setting and from nearby rural schools (n = 100). data on sensitisation to crude allergen extracts were obtained by skin prick testing (spt) with cockroach and house dust mites (hdm), and by immunocap ige testing (cockroach, hdm, and peanut). results: the rural setting was characterised by high prevalence (≥34%) of sensitisation to crude extracts (immunocap ige>0.35 ku/ l) but low sensitisation to the major, established, allergenic components on the microarray (≤2%, ige>0.30 isu). however, sensitisation to cross-reactive carbohydrate determinant (ccd)-bearing components and venoms was more common in rural (up to 14%) versus urban (up to 8%) individuals, and was associated with helminth infection. urban individuals mounted higher responses to allergenic components of dust mites but responses to other components were similar between the two settings. sensitisation to allergenic components was higher among asthmatics and spt+ children but ccd sensitisation profiles were similar between asthmatics and nonasthmatics, and between spt+ and spt-school children. conclusion: we show that, in lics, ige to crude allergen extracts (detected in standard immunocap assays) reflects sensitisation to a myriad of environmental exposures (absent in more developed countries), such as ccds expressed by helminths, and may not accurately define ard phenotypes in this setting. however, our data does not seem to indicate that ccd-specific ige detected by isac ® microarray protects against ards. considered minor allergens. due to their sequence homology and conserved structure, they show a high cross-reactivity. the objectives were to study the ige/igg binding properties of polcalcin in relation to the calcium ions, and the ige cross-reactivity between purified polcalcin from olea europea (ole e 3) and two recombinant polcalcins (rphl p 7 and rbet v 4). method: ole e 3 was purified by immune-affinity chromatography using polyclonal antibodies anti-rche a 3. serum samples were obtained from 6 patients allergic to grasses recruited at hospital de guadalajara (spain), all of them positive to phl p 7 with sige values ranging from 12.1 to 92.6 ku/l. equal volumes of all sera were used to prepare a pool. calcium binding assay was performed either by addition or not, or depletion of ca 2+ . ole e 3 was incubated with 0.1 mm cacl 2 or with 1 mm egta ph 7.5 (ca 2+ chelator agent) at the same time as the antibody in immunoblot or elisa assays with the pool of sera or with anti-che a 3 polyclonal antibody. crossreactivity assay was performed by immunocap inhibition. aliquots of the pool of sera were previously incubated with amounts of ole e 3 ranging from 0.02 to 12.5 ng. the same dilution of the pool of sera without ole e 3 was used as a control. after 2 hours of incubation, sige (ku/l) binding to rbet v 4 or rphl p 7 was determined. results: a 9 kda protein was purified from the o. europea extract and identified by lc/ms-ms as ole e 3. in the calcium binding assay there were no differences between the samples with or without ca 2+ . however, the addition of egta to the reaction completely inhibited the binding of the polyclonal antibody by immunoblot and also produced a 32.3% reduction of ige binding by elisa. in the cross-reactivity assay, a 50% inhibition of ige binding was obtained with 2.8 ng of ole e 3 for rbet v 4 and 3.9 ng for rphl p 7. the maximum rate of achieved inhibition was 68.6% for rbet v 4 and 61.6% for rphl p 7. conclusion: native purified ole e 3 contains the ca 2+ necessary to bind to the specific antibodies and the depletion of ca 2+ inhibited this binding. high cross-reactivity of ole e 3 with rphl p 7 and rbet v 4 was demonstrated. 0826 | effect of glutathione-s-transferase pi on the cysteine protease activity of the house dust mite allergen der p 1 background: environmental proteases have been proposed to be involved in the pathogenesis of allergic disorders via different mechanisms, such as the disruption of epithelial tight junctions, the cleavage of surface proteins, the activation of damage and pathogen-associated molecular patterns receptors, and the alteration of redox status. der p 1 from house dust mite is one of the most clinically relevant indoor allergens worldwide, which exhibits cysteine protease activity and has been linked to allergenic rhinitis and asthma. however, it is unknown whether the host microenvironment could regulate der p 1 activity once it reaches the mucosal surface. glutathione-s-transferase pi (gstpi) is an anti-oxidant and detoxification enzyme. gstpi is the predominant gst in human lung epithelial cells, where it is expressed in high levels. polymorphic variants of gstpi have been associated to various inflammatory lung disorders such as allergic asthma. more recently, gstpi has been identified as a redox regulator through protein s-glutathionylation, a post-translational modification where glutathione (gsh) is conjugated to cysteine residues. method: this work aimed at determining if gstpi affects the cysteine-protease activity of der p 1, compared to gstmu -a different gst isoform-by using different in vitro approaches. results: we found that gstpi increased der p 1-activity, but not gstmu. our results suggested a potential role of gstpi in upregulating the protease activity of der p 1 allergen. however, the clinical implications of these findings in allergic airway diseases needs for further investigations. 0827 | cari p 1, a novel polygalacturonase allergen from papaya acting as respiratory and food sensitizer biswas sarkar m; sircar g; ghosh n; das ak; jana k; dasgupta a; gupta bhattacharya s bose institute, kolkata, india background: papaya was globally reported to elicit ige-mediated hypersensitivity. certain papaya sensitive patients with food allergic symptoms were found to experience recurrent respiratory distresses at peak flowering period of papaya even after quitting the consumption of papaya fruits. the immunoreactive protein present both in pollen and fruit proteome was detected by ige-serology and identified by mass spectrometry. one such allergen, designated as cari p 1 was cloned, and purified as recombinant protein. the ige-reactivity of rcari p 1 was examined by immunoblot using patient sera. the allergenic activity of rcari p 1 was evaluated by histamine release assay from ige-sensitized granulocytes. the aggregation and folding pattern of rcari p 1 was assessed by size exclusion chromatography and circular dichroism spectroscopy respectively. the presence of cari p 1 in papaya fruit was searched by igg-immunoblot using allergen-specific rabbit antisera. a mouse model of papaya allergy was established to study the role of rcari p 1in eliciting respiratory and food hypersensitivity. results: a 55 kda ige reactive protein commonly present in pollen and fruit proteome of papaya was identified as endopolygalacturonase. recombinant cari p 1 remained monomer and the cd-spectra revealed predominantly β-sheet characters. the melting curve of the allergen showed partial refolding from a fully denatured state indicating the possible presence of conformational ige-epitopes in addition to the linear ige-epitopes of food allergens. 7 out of 7 papaya allergic patients displayed ige reactivity to rcari p 1. rcari p 1 at 1 μg/ml, induced histamine release from challenged granulocytes within a range of 30% to 72% (i.e. 50 ± 9.2%; n = 4 patients). expression of cari p 1 was detected in the peel and pulp tissues of papaya fruits at two edible stages of fruit maturation. in mouse model, rcari p 1 exhibited a comparable level of eosinophil infiltration and goblet cell hyperplasia in lung and duodenum histology. conclusion: cari p 1 the first major allergen reported from papaya with a dual role in respiratory sensitization via pollen inhalation and sensitization of gut mucosa via fruit consumption. the recombinant allergen can be used as marker allergen for molecular diagnosis and immunotherapeutic management of papaya allergy. background: lipids can be potent stimulators of the immune system, and their role in allergy is highly investigated and debated. since many allergens bind lipids, one question that arises is the relative importance of the lipids versus the lipid-allergen complex in eliciting the immune response. also of interest is an evaluation of the importance of the allergen-lipid complex. in our characterization of the structure of the cockroach allergen bla g 1, we discovered that it could promiscuously bind a variety of lipids in a large central cavity. this suggested that bla g 1 could be used as a prototypical allergen and lipid delivery vehicle to test in various models of sensitization. method: cd spectroscopy. nmr spectroscopy. molecular modeling. we have developed an hplc procedure to strip the phospholipids derived from the e. coli-based expression system, and reconstitute the allergen with a variety of lipids. using cd spectroscopy and nmr, we have verified that the protein conformation is highly similar in the presence and absence of lipids. temperature dependent cd spectroscopy revealed that unloaded bla g 1 is the least stable, and the melting temperature increased with increasing fatty acid chain length up to c20. similar cd melting experiments revealed that bla g 1 could bind lipoteichoic acid (lta) from gram positive bacteria, but did not interact with lipopolysaccharide (lps) from gram negative bacteria. molecular modeling studies have suggested that the stoichiometry of phospholipid binding is likely 4 phospholipids per bla g 1 and give insight as to the different binding characteristics that would allow bla g 1 to bind lta but exclude conclusion: these biophysical studies will allow the design of bla g 1-lipid systems to test a variety of sensitization models. 0829 | sal k 7, a new allergen from salsola kali sola jp; pedreño y; fernández j; cerezo a; peñalver m probelte pharma, murcia, spain background: the polcalcin from salsola kali was identified and sequenced (genbank kt254655) and the recombinant protein was characterized as a minor allergen with a prevalence of 40% of patients with a spt positive to s. kali. the objective of this study was to purify the polcalcin from s. kali pollen and to include the allergen in the website for the systematic allergen nomenclature (www.allergen.org). method: the native polcalcin from s. kali (npsk) has been purified from pollen after a first step of protein extraction and then diverse chromatographic steps: a size exclusion chromatography to remove particles minor than 5 kda, an ionic exchange chromatography, a hydrophobic interaction chromatography and a final step of size exclusion chromatography to obtain the purified sample of polcalcin. the purity of the npsk has been determined by sds-page and the binding capacity to a specific polcalcin antibody from rabbit serum was tested by immunoblot. the specific antibody had previously been obtained by immunization with the recombinant polcalcin from s. kali. the allergenicity of the npsk has been assayed by immunoblot with a pool of sera of patients sensitized to s. kali. the identity of the purified npsk has been analyzed by peptide footprint in hplc-ms/ms after digestion with trypsin. all the information about the polcalcin from s. kali was sent to who/iuis allergen nomenclature sub-committee. the npsk showed a high purity in sds-page with a molecular weight of approximately 9 kda and this purified protein reacted with the specific polcalcin antibody from rabbit serum. the ige binding capacity of the npsk was confirmed by immunoblot using a pool of sera from patients sensitized to s. kali. the analysis of peptide footprint confirmed that the purified protein is a polcalcin. the who/iuis allergen nomenclature sub-committee included the polcalcin from s. kali in the website for the systematic allergen nomenclature as a new minor allergen named sal k 7. conclusion: the polcalcin from s. kali has been purified from pollen and tested for its ige binding. it is included in the website for the systematic allergen nomenclature as the new allergen sal k 7. background: alt a 1 protein is the major allergen from the fungus alternaria alternata and responsible for chronic asthma, yet little is known about its physiological role and immunological activity. our main purpose was to investigate the mechanism through which alt a 1 induces an allergic response in bronchial epithelium. method: although alt a 1 has a unique topology, we studied the structural relationship by in silico procedures consisting of three distinct structural alignment methods in order to understand its nature. the immunological properties of the allergen were investigated by using monocyte cell line thp1 and human peripheral blood mononuclear cells. results: its crystal structure has been recently reported and claimed to be exclusively in fungi without equivalent in the protein data bank. data obtained in silico show that this allergen shows some structural relationships with a number of other β-barrel proteins such as human lipocalin 2 (lcn2). besides, our experimental data demonstrate that alt a 1 is also able to interact with lcn2, human lipocalin. in this way, the results obtained from several immunological assays showed that alt a 1 is able to produce a response of the immune system through different immune innate receptor pathway inducing the th2 cytokines. background: increasing evidence of cross reactivity syndromes between pollen grains and fruits, with immediate or delayed reactions, has been reported. while some syndromes such as the birch pollen/apple syndrome are well documented, some other such as the cypress pollen/peach syndrome remain to be understood. for the latter, significant progress has recently been made with the discovery of a new allergen family, the gibberellin regulated proteins (grps), which has been shown to be responsible for the observed cross reactivity i.e. pru p 7 and bp14 (1, 2) for the peach and the cypress pollen respectively. grps are small cationic proteins with anti-microbial properties and have been shown to be over produced in response to a stress. herein, the case of a patient, born and raised in the south of france but currently living in paris, has been studied. this patient has been suffering since childhood from allergic rhinoconjunctivitis to cypress pollen and from some oral symptoms to peach and other fruits (including pomegranate). method: in addition to the clinical exploration and cutaneous tests, a very thorough biological characterization of the patient samples has been performed through various specific ige quantitation techniques, western blotting after one and two-dimensional gel electrophoresis and flow cytometry based basophil activation testing (bat). results: specific iges to cypress pollen, birch pollen, peach, orange and apple have been found. pr10 allergenic proteins are recognized by iges but no ltps. the presence of specific iges to cypress pollen bp14, peach peamaclein (pru p 7) and a cationic 14 kda protein from pomegranate has been shown through western blotting after gel electrophoresis separation of the protein extracts. the use of bat finally enabled to demonstrate that the basophils of this patient were, ex vivo, strongly activated with protein extracted from orange and cypress pollen and also with purified proteins such as bp14 and pru p 7. conclusion: these results unambiguously show that the cypress pollen grp, bp14, is clinically relevant, similarly to its homologous protein in peach, pru p 7. it can be proposed that these two allergens are at the basis of the observed cross-reactivity syndrome. the search for new cross-reactive allergenic grps in pollen, fruits or vegetables may enable to better understand other pollen/food associated syndromes that still remain unexplained. background: nine allergens of phleum pratense have been described until now (iuis database) and classified into groups based on their function and cross-reactivity. group 1 and 5 allergens are considered the most immunodominant, due both to their greater ige-binding capacity and the number of patients ige-reactive to them. previously published studies have estimated that group 1 is recognized by almost 95% of grass pollen-allergic patients, and group 5 by 80%. however, until now a comparative of the ability of these allergens to provoke an immune response has not been performed. the objective was to study the immunogenicity of the major allergens phl p 1 and phl p 5, by analyzing the ability of the recombinant forms (rphl p 1 and rphl p 5a) to induce a humoral immune response. method: five mice were immunized with the same amount of each recombinant protein: rphl p 1 and rphl p 5a (indoor biotechnologies) (60 μg plus two boosters of 30 μg). the specific igg antibodies produced by each mouse were tested against the recombinant proteins by direct elisa and the title of each of them was determined by optical density (o.d.). additionally, the recognition of both allergens in native and depigmented-polymerized (dpg-pol) extracts of p. pratense was studied by direct elisa using these generated antibodies. results: preimmune sera were negative. all mice produced antibodies against the corresponding recombinant protein. the immune response (sigg) was statistically significant higher in mice immunized with rphl p 5 than in those immunized with rphl p 1; it was needed 8 times more rphl p 1 serum than rphl p 5a serum to obtain the same o.d. values. the difference in responses was higher in the group of mice immunized with rphl p 1 than with rphl p 5a. differences in the recognition of phl p1 and phl p 5 in native and depigmented-polymerized extracts of phleum pratense was also observed. it was necessary 8 times more rphl p 1 serum to produce the same signal than rphl p 5a serum in native extract and it was necessary 4 times more rphl p 1 serum to produce the same signal than rphl p 5a serum in dpg-pol extract. conclusion: rphl p 5a is more immunogenic than rphl p 1, which was also probed with native and dpg-pol extracts. background: glioblastoma (gbm) is an incurable primary malignant brain tumour with a median life span of less than 15 months despite multimodal treatments. therefore, there is a serious need for the development of innovative medications. several epidemiological studies underlined an inverse correlation between pre-existing igemediated allergy and gbm risk, where having such an allergy decreased the odds of developing gbm by 20 to 40%. we aim to delineate the intrinsic immuno-biological and molecular mechanisms that can be responsible for these correlations, based on the hypothesis that allergies may promote a state of increased immuno-surveillance in the brain through the presence of immunological factors such as immunoglobulins, cytokines and cells involved in th2-driven allergic reactions. we consider that as the major immune cell type of the brain, microglia should be implicated in this beneficial association and may favour the elimination of the nascent tumour in brain parenchyma in an allergic context. we implemented a long term allergic airway inflammation by repeated nasal instillation of house dust mite (hdm) extract in a syngeneic orthotropic mouse model of gbm. we followed animal survival and the tumour growth by mri. in addition, we purified microglia from allergic vs non-allergic mice in order to assess their cytotoxic function against the gbm cell line ex vivo and their secretory capacities. finally, we investigated immunoglobulin reactivity against gbm antigens in the context of allergic reactions by reverse phase protein array (rppa). we demonstrated an increase of the animal survival that was correlated with a delayed tumour engraftment and a reduced tumour growth. these phenotypes were associated with functional modification of microglia from sensitized mice. indeed, these microglia showed a rise in the production of il-6 and tnf-a as well as an increase in cytotoxic functions against a gbm cell line ex vivo. in parallel, we observed an increase in serum igg1 reactivity against gbm antigens in mice sensitized with hdm compared to control mice. results: in 23 patients (48%) with cvid we recorded at least one temporary platelet count decrease below 150 × 10 9 /l compared to only 1 patient (10%) with xla (p = 0.024). more importantly in 18 patients (38%) with cvid this decrease was observed in a period longer than 6 months compared to 1 patient (10%) with xla (p = 0.077). in 10 patients (21%) with cvid we recorded at least one temporary platelet count decrease below 100 × 10 9 /l and only in 3 patients (6.5%) with cvid this decrease was observed in a period longer than 6 months. we did not record any platelet count decrease bellow 100 × 10 9 /l in patients with xla however the difference with cvid did not reach statistical significance. no thrombocyte count decrease bellow 50 × 10 9 /l was observed in either group. none of patients required immunosuppressive treatment for immune thrombocytopenia (itp). conclusion: although the statistical significance was documented only in temporary platelet count decrease below 150 × 10 9 /l it is obvious that numbers of thrombocytes commonly fluctuate in some patients with cvid. the mechanism leading to these temporary decreases is unclear. monitoring of complete blood count is a basic follow-up investigation in patients with cvid. introduction: wegener's granulomatosis (wg) is a systemic disease that may affect all organs, most frequently the ears, noses, throats, sinuses, lungs and kidneys. it is a rare autoimmune disease, also called granulomatosis with polyangiitis, and characterized by necrotizing granulomatous inflammation in small and medium sized blood vessels. anti-neutrophil cytoplasmic antibody against to proteinase 3(c-anca) is thought to be responsible for autoimmune inflammation. the coexistence of wg and common variable immunodeficiency (cvid) is extremely rare. in this report, we describe a patient with wg and cvid who was treated with immunosuppressive drugs and intravenous immunoglobin concomitantly. case report: a twenty-four-year-old male patient was referred to our clinic for immunological evaluation due to recurrent infections, fever of unknown origin and neutropenia. the patient had been diagnosed with wg and taking immunosuppressive therapy for three years. he had chronic renal failure due to wg and had also been on peritoneal dialysis for three years. serum igg, iga levels, peripheral blood cd19 + b cell percentage and absolute count of the patients were found to be low according to reference limits. he was diagnosed with cvid after excluding secondary reasons for hypogammaglobulinemia and he started to receive 600 mg/kg intravenous immunoglobulin (ivig) therapy once in a month. also, the treatment that consists of mycophenolate mofetil (mmf) and glucocorticoids was continued to decrease c-anca levels in serum. he has been accepted as a candidate for kidney transplantation, and prepare for this purpose. discussion: the management of the patient with cvid and wg may be complicated. it is considerably difficult and needs competency and courage. moreover, the cases similar to ours, are extremely rare. therefore, the authors should share their own experiences on cvid and discuss them by comparing the data obtained from other cases. background: leukocyte adhesion deficiencies (lads) are a group of three genetic disorders leading to defective leukocyte adhesion to the endothelium and as a consequence decreased leukocyte recruitment and immune defense. lad-i is caused by mutations in the gene encoding the ß2-integrin cd18 on chromosome 21.lad-iii is a rare primary immunodeficiency syndrome, characterized by homozygous mutations in the kindlin-3 gene (official symbol fermt3). we have aimed to evaluate our patients who were followed up with lad for the last 15 years, retrospectively. method: all data of the cases were obtained from the file records of age at diagnosis. results: seven patients from separate 6 families were included in the study. four patients were lad-iii and 3 patients were lad-i. the female to male rate was 2/5. the age of diagnosis is ranged from 16 days to 4 years. the median umbilical cord detachment was 21 days (7 -53 days groups: up to 6 times (6 people) and from 6 to 12 times (6 people). 10 healthy donors were examined as a control. flow cytofluorometry method was used to study peripheral blood and assess the parameters of innate and adaptive immunity results: it was found that at a frequency of edema up to 6 times a year there are changes in the t-system of adaptive immunity, which are shown by a decrease in the expression of late activation markers (cd3 + hladr+ 3.46 ± 0.60%, in control 8.04 ± 0.14%), an increase in the number of cd3 + cd8 + cytotoxic lymphocytes (0.60 ± 0.17x10 9 /l, in control 0.39 ± 0.01x10 9 /l) and as an increase in their functional activity (cd8 + gr+ 0.53 ± 0.02x10 9 /l, in control 0.16 ± 0.01x10 9 /l). the nature of disorders of cellular factors of the innate immunity is manifested by decrease in the adaptive resources of neutrophils (kstnbt 1.62 ± 0.13u.e., in control 2.15 ± 0.02u.e.). patients with hae with a frequency of edema up to 12 times a year, we observed the disorders of the humoral link of adaptive immunity, which consist in an increase in the number of circulating b lymphocytes (0.27 ± 0.11x10 9 /l, in control 0.11 ± 0.01x10 9 /l). in addition, with the strengthening of the hae clinic, changes in the system of innate immunity progressed very fast and consisted in increasing the amount (cd16 + 0.37 ± 0.05x10 9 /l, in control 0.21 ± 0.01x10 9 /l), and functional activity (cd16 + gr+ 0.32 ± 0.16x10 9 /l, in control 0.14 ± 0.0210 9 /l) of natural killer cells results: we included 261 children, mostly males (54%), aged between 1 month and 16 years. 37.5% of patients (n = 98/261) showed abnormal absolute results of lymphocyte count for age. we found more patients evaluated in the age group of 2 to 5 years (31.8%), followed by 5-10 years (24.5%), lymphopenia was found in 15.4% of patients. b lymphocyte deficiency was the most common pattern (37%) followed, in decreasing order, by low cd4, t cd3, tcd8 and nk. many patients have more than one affected population (12.6%) . some patients were affected in all three series (4.2%). the cd4 / cd8 ratio decreased in 28.7% of the patients. the majority of the children were males between the ages of 1 month and 16 years. 37.5% of patients showed abnormal absolute lymphocyte count for age. b-cell deficiency was the most common pattern followed, in decreasing order, by low cd4, t cd3, tcd8 and nk. many patients have more than one affected population. 0847 | indicators of the humoral immunity in the mechanical jaundice of benign genesis the aim of the investigation was to study the indices of humoral immunity in patients with benign mj, depending on the level of bilirubin. method: 62 patients with mj and 125 practically healthy volunteers were examined. patients with a level of bilirubin less than 60 μmol / l -9, with a bilirubin level of 60-200 μmol / l -37 and with a bilirubin level of more than 200 μmol / l -16 patients. the concentration of immunoglobulin classes a, m, e and g in serum was determined by enzyme immunoassay. the statistical significance of the differences was determined using the ranked mann-whitney test. the critical level of significance in checking statistical hypotheses was assumed to be p < 0.05. results: of the contacted dermatologists, 136 participated (53 women, 83 men; mean age 53.2 ± 8.5) which results in a response rate of 27.3%. the guideline compliant prescription rate of biologicals in patients with csu was 6.9%. the most prevalent barriers in the prescription were the high cost of the treatment (64.7%), low reimbursement for doctors (62.5%) and the fear of a recourse claim (52.9%). however, a lack of evidence or an insufficient efficiency were not concase report: eosinophil associated gastrointestinal disorders (egids) including eosinophilic colitis are commonly associated with atopy. aeroallergen sensitization may accompany food allergy in these patients. a case with eosinophilic colitis responsive to anti-ige monoclonal antibody (omalizumab) treatment is presented. an eleven-year-old boy had bloody diarrhea lasting nearly one month in autumn for last 3 years. this year diarrhea lasted more than 3 months. colonoscopic biopsy revealed lymphoplasmacytic inflammatory cells including eosinophils leading to a diagnosis of ulcerative colitis. corticosteroid and mesalazine treatment was started with a good clinical response. recurrence of diarrhea during corticosteroid dose reduction suggested corticosteroid dependent ulcerative colitis. eosinophilic/allergic colitis was an alternative diagnosis when seasonal recurrence, lack of weight loss, eosinophils in biopsy and high serum ige level were considered. colonoscopy done after cessation of therapy for one month, revealed exudative ulcerous lesions, lacerations, loss of haustration compatible with colitis (inflammatory/allergic?). presence of significant mucosa associated lymphoid tissue in biopsy supported any inflammatory, reactive process. he had recurrent bronchiolitis until age six and allergic rhinitis in spring for three years. total ige and mix aeroallergen specific ige were high (518 iu/ml, 56.1 kua/l), absolute eosinophil count was normal (210/mm3). food skin prick and patch tests were negative. he had positive skin reactions with dermatophagoides, grass and olea pollens (induration diameter: 9, 10, 6 mm, respectively). pulmonary function test was normal. he was considered as eosinophilic/allergic colitis and omalizumab was started according to manufacturer's dosing table (300 mg/ 2 weeks). rectal bleeding decreased after first dose and ceased after the second dose. early colonoscopy examination after 3rd month of therapy showed that exudations disappeared and haustrations became evident. microscopy revealed mild nonspecific colitis. few patients with eosinophilic colitis improved with omalizumab were reported before. ige-mediated processes are responsible from eosinophilic inflammation in egids, making anti-ige therapy as a promising treatment option. 0859 | design of liposomal carriers modified by glycoconjugates for liver cell delivery of nucleic acids used. the surface of liposomal nanoparticles can be modified to increase the selectivity of intracellular delivery. it is well known that asialoglycoprotein receptors of hepatocytes have a strong affinity to galactose carbohydrate. therefore, the aim of this study was to assess the effect of the modification of the liposome surface by glycoconjugates on the selectivity of intracellular transport of nucleic acids into the liver cells. method: liposomes based on ornornglu(c 16 ) 2 were chosen previously as the effective nucleic acid delivery system. we modified liposomes with novel lactose-based derivatives. every of four glycoconjugates was added to ornornglu(c 16 ) 2 in an amount of 5, 10 and 15%. as a result, 12 variants of modified liposomes were obtained. to determine the cytotoxicity, an mtt test was used. using luciferase test, the selectivity of penetration was evaluated on nonspecific 293t (human embryonic kidney) and specific hepg2 (human liver cells) cell lines. results: modified liposomal compositions ornornglu(c 16 ) 2 -4 + lacc 16 (5%) and ornornglu(c 16 ) 2 -4 + lacggg16 (15%) had the lowest cytotoxicity similar to that for unmodified ornornglu(c 16 ) 2 . the ic 50 , calculated based on the data of mtt test, was 0.14 and 0.26, vs. 0.16 mg/ml, respectively. ornornglu(c 16 ) 2 -4 + lacggg16 (15%) showed a 1.5-fold increase in transfection activity on the nonspecific 293t cells, compared to unmodified ornornglu(c 16 ) 2 , whereas the modification of ornornglu(c 16 ) 2 -4 + lacc16 (5%) resulted in a 6-fold decrease in transfection activity. however, the ability of these variants to penetrate the specific liver hepg2 cell was significantly higher by 15 and 25 times, respectively, than for unmodified ornornglu(c 16 ) 2 . results: the greatest inhibitory effect of sbfhd was observed in mdm infected with hiv-1 bal: 90% and 50% suppression of hiv replication was achieved at concentrations of 1.5 μg/ml and 0.4 μg/ ml, respectively. the activity in pbmc and dc was less pronounced (the respective ic90 values were 5.8 μg/ml and 19.7 μg/ml). studies in endometrial hec-1a cells demonstrated that sbfhd suppressed cd4-independent entry of hiv-1 (10 3 tcid 50 /ml) by 33%, 54%, and 98%, respectively, at 1, 10, and 100 μg/ml. the effect was also observed after increasing the dose of the virus. at 10 4 tcid 50 /ml, sbfhd suppressed hiv infection by 45% (10 μg/ml) and 97% (100 μg/ml). the cytotoxicity of sbfhd in this system was low. similar results were obtained with colorectal caco-2 cells. sbfhd exhibited no spermicidal activity at concentrations of up to 3 mg/ml. combining within a single microbicide two agents that target distinct steps of hiv life cycle will maximize its efficacy (via synergistic effects and/or interference with multiple stages of the transmission). we therefore explored the synergistic potential of combinations of sbfhd and azt, the classical nucleoside rt inhibitor. in these experiments, 50% suppression of hiv infection was reached at concentrations of sbfhd and azt, which were significantly lower than the respective ic50 values of each component (determined in parallel experiments). the synergistic effect was most pronounced for the combination of 0.1 μg/ml sbfhd (which is 60 times less than the ic50) and 0.16 nm azt (which is 45 times less than its ic50). cd80 expression was increased after the co-culture with reishi, shiitake and boletus mushrooms (c -5.6(1.4-9.2)%; pma -60.5 (27.2-70.9)%; )%; shiitake -9.6(4.3-15.5)%; boletus -16.6 (14.0-24.0)%). method: the study included 38 men (mean age 34 ± 5.9 years) before and immediately after staying in countries with a hot climate. results: the development of lymphopenia observed in the first week of observation. this was accompanied by a decrease in the number cd3 + lymphocytes expressing the markers of late activation (cd3 + hladr+ 4.8 ± 1.09x10 9 /л и 3.2 ± 2.04x10 9 /л). revealed significant decrease of cd4 + cd25 + foxp3 + regulatory cells in the first week after returning from the area of adverse climatic conditions, as well as a significant sustained decrease in the number cd3 + cd8 + hladr+(p < 0.05). change of the effector link of innate immunity was determined in significant reliable decrease in relative (cd16 + 13.2 ± 2% and 4.6 ± 2.1%, respectively, p < 0.05) and absolute (cd16 + 0.3 ± 0.02 x109/l and 0.1 ± 0.03%, respectively, p < 0.05) in the number of a population of natural killer cells in the first week of observation. in the context of acute stress marked a significant increase in relative and absolute numbers of b lymphocytes (8 ± 1.16% (0.15 ± 0.04 × 109/l) before a trip to countries with a hot climate and 19 ± 3.1% (0.4 ± 0.07 × 109/l) in the first week after returning, p < 0.05). the activity is the production of antibodies was not changed. (ast) which is the intramuscular injection of patients own serum, is a promising therapy with a substantial efficiency on ciu patients. in this study we aim to assess the efficacy of ast on chronic urticaria patients by dlqi questionnaire. method: this was a single-blind randomized clinical trial which evaluated the efficacy of autologous serum therapy compared to oral antihistamines in patients with ciu. 49 ciu patients received the ast. every session 5 cc of each patient's blood was centrifuged at the speed of 2000 rpm for 10 minutes and 2.5 cc of the serum was injected intramuscular into the patient's deltoid muscle weekly for 9 weeks. the control group consisted of 51 ciu patients took 10 mg of cetirizine daily for 9 weeks. patients answered the dlqi questionnaire at the first session of treatment as baseline and 7 weeks after the last session(week 16) as response to treatment. the mean baseline score of dlqi for ast group was conclusion: pharmacotherapeutic and inpatient costs for patients with prevalent ar and asthma were lower in those prescribed ait than in those not prescribed ait in all years, both with and without including the cost of ait itself. this indicates that treatment with ait is associated with lower cost burden for health services. background: immunotherapy with peptides rather than conventional whole allergens is being developed to improve the benefit/risk balance of subcutaneous immunotherapy (scit). lolium perenne peptides (lpp) demonstrated reduced allergenicity following ex-vivo analyses, allowing higher doses to be given over a shorter period to improve treatment adherence and compliance. such treatment resulted in significant reduction in symptoms and rescue medication intake during the grass pollen season. here we report the safety of lpp immunotherapy in adults. background: a new allergoid from alternaria alternata was characterized to determine its reduced allergenicity in vitro. the objective of this study was to determine the skin response to the allergoid and to evaluate the clinical tolerance of the immunotherapy with the allergoid product using a rush schedule. method: to assess the skin response (sr) two groups of patients were included: group 1 with patients sensitized to a. alternata and with respiratory disease caused by this mold; group 2 (control) with patients sensitized to others allergens and non-atopic patients. the sr was determined by spt using three concentrations of the allergoid: p1 (lowest concentration), p2 (four times higher than p1) and p3 (estimated to obtain a wheal area similar to histamine 10 mg/ml). in spt was also used a native extract of a. alternata (n) and histamine 10 mg/ml (h). all products were tested in duplicate in all patients and the sr was evaluated by comparing the median of the wheal area produced by different products. to evaluate the clinical tolerance to immunotherapy the patients of group 1 were treated with the allergoid product using a rush schedule consisting in a dose of 0.2 + 0.3 ml the first day and 0.5 ml after one month (maintenance dose). the clinical tolerance was determined as the percentage of adverse reactions (ar) to the treatment and the classification of ar was established according to eaaci. the number of patients included to evaluate the sr was 46 (group 1: 25; group 2: 21, 16 atopic and 5 non-atopic) with an average age of 34.8 (range . the spt data from group 1 were expressed as median and interquartile range of wheal area (mm 2 ): h: 19.58 (15.3-25.2); n: 22.71 (11.1-33.1); p1: 0.99 (0-5.7); p2: 6.44 (0-12.5); p3: 19.78 (12.0-30.4 ). it was determined that sr of allergoid was reduced in 87% respect to the native. the products n, p1, p2 and p3 did not produce any response in patients of group 2. to evaluate clinical tolerance, 21 patients of group 1 were treated with the allergoid product with a rush schedule and only two ar were registered (3.2% of doses). these were retarded local reactions with a wheal diameter higher than 5 cm. no systemic reactions were registered and all patients continued the treatment. the allergoid from a. alternata produces a significant reduced response to spt due to its reduced allergenicity. the treatment with an allergoid product in a rush schedule is safety and clinically well tolerated. background: in our study we aim to determine the more effective, the total cost of 3 years of patients using scit was 15665 tl per person whereas the total cost of 3 years of patients using slit was 15271 tl per person. when we compare the total cost data of both groups, we found that they are close to each other. while the greatest portion of the cost data of patients with scit treatment was direct costs associated with the treatment itself (72%); the remaining part of the total cost was indirect (16%) with non-medical expenses such as transportation (12%). in the slit group, direct costs including drug expenditures have a larger percentage (92%) and it was significantly more costly compared to the direct costs of the scit group (72%). transportation costs were found to be more costly in the scit group (12%) when compared to the slit group (4%). similarly loss of parent work days in the scit group(%16) was found to be significantly more expensive compared with slit group (4%). our study results show that slit is a similar treatment for clinically and laboratorially and has a similar efficacy to scit to reduce the patients' complaints and to the need for medication. for cost-effectiveness however medicines for treatment of scit are less costly; when long term total treatment costs are calculated slit and scit treatment are economically close treatments. the protein content of the new acd was 182.28 μg/mg and the protein profile in sds-page and sec-hplc confirmed the presence of proteins with high molecular weight and the absence of smaller proteins. the content of free lysine in acd, involved in glutaraldehyde modification, was reduced in 91.96% respect to ncd and it can be considered as the polymerization degree. regarding to the allergenic profile, through elisa inhibition was determined a reduction of 18 times in the capacity to bind ige of the proteins in acd respect to ncd, whilst the igg binding capacity was maintained. in immunoblot there was no reaction of acd proteins to specific ige from sera. the analysis by peptide footprint determined the presence of fel d 1 and others allergens in acd. the content of major allergen fel d 1 in acd was determined as 11.9 μg/mg. the new developed and characterized allergoid from cat dander has an excellent safety profile and will allow a safer immunotherapy to treat the allergy to felis domesticus. results: the protein content of the new aaa was 65.6 μg/mg and the protein profile in sds-page and sec-hplc confirmed the presence of proteins with high molecular weight and the absence of smaller proteins. the content of free lysine in aaa, involved in glutaraldehyde modification, was reduced more than 85% respect to naa and it can be considered as the polymerization degree. regarding to the allergenic profile, in immunoblot there was no reaction of aaa proteins to specific ige from sera and by elisa inhibition was determined a reduction of 91% in the capacity to bind ige of the proteins in aaa respect to naa. the igg binding capacity in aaa was maintained. the analysis by peptide footprint determined the presence of alt a 1 and others allergens in aaa. the content of major allergen alt a 1 in aaa was determined as 2.4 μg/mg. a. alternata shows an excellent safety profile and allows a safer immunotherapy to treat the allergy to this mold. she was an otherwise healthy woman: she took no drugs and she did not have any remarkable concomitant diseases. the distribution and appearance of the remaining body hair was normal and the hormonal level profiles (lh, fsh, estrogens, progesterone and testosterone) did not show any significant alteration according to her age. a 30 year old woman with allergic rhinitis underwent sq glutaraldehyde-modified ait to house dust mites (d pteronyssinus and g domesticus) without any incidences and complete tolerance to maintenance dose without local reactions during a 5 year period. two years after ait discontinuation, patient first experienced a local urticarial reaction with multiple hives at previous sq ait injection sites 40 minutes after 600 mg of ibuprofen intake. these symptoms recurred at least in seven occasions when patient was exposed to ibuprofen (in five) and metamizol (in two). results: case 1: dermatologist diagnoses localized hypertrichosis. case 2: a single blind, placebo controlled oral challenge (sbpcoc) with ibuprofen 600 mg was performed and elicited multiples hives in the circumscribed area in the arm where ait was conducted. subsequently, sbpcoc with aspirin was carried out showing the same reaction although a controlled challenge with celecoxib was negative. conclusion: local hypertrichosis is a very rare injection-disease associated with injected allergen vaccine treatment. we also firstly described a recall urticaria phenomenon after allergen immunotherapy which has been only elicited after different nsaids intake. results: there were included 47 patients, in five spanish hospitals. following aria 2010 guidelines, 95.7% of patients were diagnosed of persistent moderate/severe rhinitis. the mean age was 37.7 ± 11.8 years, being 59.6% female. moreover, 57.4% of the patients had concomitant mild/moderated asthma. the period between the diagnosis of rhino-conjunctivitis and the informed consent signing was 9.8 ± 7.5 years. according to international 2006 guidelines, eight systemic reactions were registered, representing 1.9% of the administered doses: five reactions grade 0, (described as nonspecific ocular pruritus, nasal herpes, general discomfort, localized non-specific pruritus plus nausea and non-specific pruritus in throat), a grade i reaction described as rhinoconjunctivitis and two reactions grade ii, registered as generalized urticaria and asthma. all reactions were classified of mild or moderate intensity and only two required symptomatic treatment. there were five clinically significant delayed local reactions, which were higher than 10 cm or involved modifications in next dose. regarding efficacy parameters, immunoglobulin titers between baseline and final visit according to specific igg and igg4 significantly increased. cutaneous reactivity also decreased significantly in the dose response skin prick test. results: 47 patients were included, 24 to accelerated and 23 to polymerized cluster group schedules. according to aria criteria, 89.4% of patients presented persistent moderate/severe rhinitis. the mean age was 31.1 ± 9.9 years, being 40.4% male. moreover, 61.7% had concomitant mild/moderated asthma. immunoglobulin titers method: the quantification of total proteins in the products was carried out by means of a colorimetric technique using the bradford reagent (sigma-aldrich™, us) in accordance with the manufacturer's instructions. the absorbances of each standard and samples were obtained in a scinco™ s-3100 spectrophotometer (seoul, korea) at 595 nm. all samples were analyzed in duplicate. the electrophoretic profile of the proteins in the tested allergens was obtained according to the procedure described by laemmli, under denaturing conditions in a polyacrylamide gel at 12.5% concentration and stained in silver. in each lane approximately 30 μg of total proteins were applied. commercial extracts of the main allergens marketed in mexico were obtained, rossel ® , alk ® , alerquin ® , alergomex ® , allerstan ® , ipi asac ® ; and they were assigned randomly with the numbers 1, 2, 3, 4, 5 and 6. results: the following protein concentrations were found in the various extracts analyzed: see table 1 conclusion: differences were found in the protein profiles anabackground: a new allergoid from cat dander was developed and characterized to determine its reduced allergenicity in a 95% and the maintenance of igg binding capacity. the objective of this study was to develop an immunogenicity assay in mice with the new allergoid and a native extract from cat dander. the study included 24 female balb/c mice separated in three groups of 8 mice each: group 1, immunized with a mold allergen extract (control); group 2, immunized with a native extract from cat dander with a fel d 1 content of 0.525 μg per dose; group 3, immunized with the new allergoid from cat dander with a fel d 1 content of 2.36 μg per dose. all mice were immunized four times by subcutaneous injections with a volume corresponding to 1/10 of the recommended human maintenance dose with an interval between injections of 2 weeks. one week after the last injection the mice were sacrificed and the serum was obtained. to determine the specific antibody title indirect elisa were performed using a cat dander extract as antigen, sera from mice as primary antibody and antimouse igg or igg1 as secondary antibody. elisa assays were performed using serial dilutions of sera or a simple dilution by duplicate to determine the specific antibody title as arbitrary units/ml (au/ml). the data were analyzed by one-way anova and tukey hsd test to compare the averages of specific antibodies in each group. results: the immunization with both the native extract and the allergoid from cat dander produces specific igg and igg1. regarding to igg, a higher title was observed in group 3 respect to group 2 in a curve obtained after elisa with serial dilutions of sera. the specific igg title obtained in terms of au/ml was 18.6 ± 2.6 in group 1, 105.0 ± 15.0 in group 2 and 139.9 ± 16.6 in group 3. concerning to igg1 the au/ml obtained was 5.7 ± 0.4 in group 1, 73.5 ± 16.8 in group 2 and 97.5 ± 18.8 in group 3. the increase of specific igg or igg1 in mice from group 3 respect to mice from group 2 and control group was statistically significant (p ˂ 0.01). the safety profile of the allergoid from cat dander allows a treatment with higher dose of allergens to produce a greater response to immunotherapy to induce formation of specific this was an open, multicenter clinical trial, in patients aged between 18 to 60 years with rhinoconjunctivitis with or without concomitant mild asthma sensitized to house dust mites (hdm). the aim was to evaluate the safety and tolerability of the vaccine. secondary endpoints included were: changes in immunoglobulin levels (specific ige, igg and igg4) versus d. pteronyssinus and d. farinae and changes in cutaneous reactivity. patients were under study treatment for 17 weeks: five for the induction phase (weekly injections) and 12 for the maintenance phase (monthly injections). results: 42 patients were included. there were 6 withdrawals from the trial; no one was related to treatment. the patients mean age was 33.6 years, being 50% female. 71.4% were diagnosed of persistent moderate/severe rhinitis according to aria guidelines and 31.0% presented concomitant mild asthma. regarding to safety results, 22 systemic adverse reactions were registered which corresponded to 7.9% from a total of 277 administered doses. the most of systemic reactions were grade i, (5.4%) described as rhinitis or urticaria, grade 0 or nonspecific (2.2%) and 1 reaction (0.3%), was grade ii. all of them were mild or moderate and only 4 needed treatment. among local reactions, 21 (7.6%) were clinically relevant late local reactions, meaning a wheal at injection site >10 cm and /or requiring a dose readjustment in the next administration; 6 (2.2%) were clinically relevant immediate local reactions meaning a wheal >5 cm. concerning the efficacy parameters, cutaneous reactivity at the final visit versus baseline was, in average, significantly decreased, and specific titers of igg and igg4 against tested hdm increased significantly at final visit. 162 patients completed the study. mean values in rqlq questionnaire (total score) decreased from 2.56 to 1.24 points (51.6% score reduction) in final visit, reflecting a statistically significant improvement (p < 0.01). annual episodes of rhinoconjunctivitis decreased from 13.7 to 9.7 (p < 0.01). 43.8% of patients improved from persistent to intermittent rhinoconjunctivitis (p < 0.01) and 46.9% from moderate/severe to mild intensity (aria) (p < 0.01). moreover, 16 .1% of asthmatic patients at baseline, did not have any bronchial symptoms after 1-year treatment (p < 0.01). mean value of treatment satisfaction was 7.2 (sd=1.8) and 7.2 (sd=1.7) for patients and physicians respectively. 0884 | evaluation of safety and tolerability of "allergovac poliplus" in polysensitized patients with allergic rhinitis-rhinoconjunctivitis with or without asthma: an observational prospective study (apolo) background: the objetive of this study was the safety and tolerance assessment of "allergovac poliplus" scit treatment, with 2 allergen combination-mixtures in polysensitized patients, as well as the evaluation of the clinical improvement and patients' satisfaction after treatment. method: this is a prospective observational clinical study. allergovac poliplus treatment is being administered in a "1-day" or in an abbreviated schedule. polysensitized patients (to pollens or mites), with rhinitis or rhinoconjunctivitis, with or without asthma, and between 5-60 years have been included. all adverse events are being recorded. visual analog scales (vass) are being used to evaluate clinical improvement, tolerance and satisfaction after treatment (10 months). results: a total of 147 patients have been included, with an averresults: in all groups prevailed severe forms of the disease and the phenotype of frequent exacerbations. groups were comparable in age composition and structure of severity. observations in the group of vaccinated pcv13 continue the dynamics of decreased dyspnea up to 1.66 (1.11;2.21) results: of a total of 631 pts under scait, 110 were excluded due to data unavailability, and 521 included (♀283 (54%), mean age 32 ± 13 years (minutes: 7 max 73 md30), age range [18-30] being most prevalent (40%). the most frequent diagnosis was rhinitis/rhinosinusitis (97%), followed by asthma (43%), diagnosis coexisting in abstracts | 479 214 pts (41%). other diagnosis such as conjunctivitis (24%), atopic eczema (15%) and food allergy (9%) were also found. mite sensitization occurred in 422 patients (81%) of which 199 (47%) were monosensitized. the pollen sensitization was verified in 288 (55%) with 88 monosensitized pts (31%). the double sensitization mitespollens was displayed in 189 (36%). sensitization to epithelia and fungi occurred respectively in 100 (19%) and 42 pts (8%). it was found that 20 pts (4%) presented sensitization to the 4 groups of allergens (mites, pollens, fungi, dander). an average of 58 ± 23 pts started this treatment per year. prescription included 10 laboratories with the following %: a-39.6; b-29.3; c-13.2; d-5.4; e-4.7; f-4.2; g-2.5; h-0.9; i-0.1; j-0.1. option for extract of physical modification (5%), physical-chemical (16%) and chemical (79%). table 1 shows the frequency of distribution of scait composition. conclusion: in this population sensitization to mites was predominant being the most prescribed scait followed thru sensitization to grasses with the respective scait. the majority of the population was polysensitized. however, in composition preference the choice of 1 group of allergens prevailed and only 5% had more than one sort of pollen and 4% pollen+mites. polysensitization is a reality, nonetheless the choice of ait composition should be guided thru scientific criteria and not through the availability of mixtures encouraged by laboratories. background: allergen immunotherapy (ait) has been proven to be an effective treatment of allergic diseases in numerous studies. however, its use in seniors remains limited and questionable, due to common comorbidities and limited evidence of efficacy and safety of ait in aging population. the aim of presented study was to assess the safety of ait in patients over 55 years of age undergoing subcutaneous immunotherapy (scit) and analyze the potential risk factors of adverse reactions in this population, compared to younger adults. we followed subcutaneous immunotherapy in a group of 1302 patients treated in the outpatient clinic of medical university of lodz, of whom 163 were aged 55 and older (118 between the age of 55-60, 31 aged 61-65 and 14 patients above the age of 65). we recorded detailed information of each administration and corresponding adverse reactions over the period of 2 years. we compiled results of our observations with patients' medical records to compile a database, which we then analyzed using statistical software. method: a total of 46 cases with seasonal allergic rhinitis undergoing pre-seasonal immunotherapy and 28 cases followed with conventional drug treatment were included in the study. immunotherapy and control groups were divided into monosensitized (only pollen) and polysensitized (at least 1 additional allergen except pollens) patient groups according to skin prick test reactivity. all patients were followed between march-september 2013 with symptom and medication scores, and visual analogue scale (vas). the quality of life was assessed using the mini-rqlq questionnaire. phleum pratense (phl p) specific ige and specific igg4 (uni-cap 100, phadia) measurements were performed before and after 7 weeks of immunotherapy in all patients. gramineae pollens were counted during the grass pollen seasons. results: mean age was 34.9 ± 10.6 and 34.2 ± 12 years, female/ male ratio was 29/17 and 17/11, the number of monosensitized/polysensitized patients were 37/9 and 20/8 in immunotherapy and control groups, respectively. in the immunotherapy group, june-july symptom scores, may-june-july-august vas scores and june combined symptom-medication scores were lower than the control group (p = 0.005). furthermore, improvements in activities-practical problems and other quality of life scores were significantly different between two groups (p < 0.05). in immunotherapy group, phl p specific ige and phl p specific igg4 levels measured after immunotherapy were significantly higher compared to those before immunotherapy (p < 0.001, p < 0.001, respectively). phl p specific igg4 levels measured after immunotherapy were also significantly higher in the immunotherapy group than in the control group (p < 0.001). there was no difference in terms of clinical and immunologic parameters in monosensitized and polysensitized patients (p > 0.05). conclusion: clinical improvement with pre-seasonal allergoid immunotherapy is accompanied by an important increase in specific igg4 blocking antibodies despite short-term injections. our findings show that pre-seasonal allergoid immunotherapy has similar clinical efficacy and b cell response in polysensitized subjects compared to monosensitized patients. 0891 | the safety trial of sequential sublingual immunotherapy with japanese cedar droplet and house dust mite tablet matsuoka t 1 ; kuroda y 1 ; igarashi s 1 ; fukano c 2 ; natsui k 2 ; ohashi-doi k 2 ; masuyama k 1 1 university of yamanashi, yamanashi, yamanashi, japan; 2 torii pharmaceutical co. ltd., tokyo, japan background: sublingual immunotherapy (slit) is recognized as the only treatment option with the potential to provide long-term posttreatment benefits. in japan, the prevalence of japanese cedar (jc) pollinosis is very high, about 30% of the population, of which the majority are co-sensitized to hdm. slit is now well established, safe and convenient treatment form for allergic disease, and recently, jc slit-droplet and hdm slit-tablet products were approved in japan for treatment of jc and hdm induced allergic rhinitis, respectively. however, the safety of sequential jc slit-droplet and hdm slittablet has not yet been investigated. therefore, we investigated the safety trial on slit combined with jc droplet and hdm tablet in allergic patients. method: eleven subjects with jc pollinosis and hdm rhinitis were enrolled. patients were treated once-daily with jc slit-drops for 4 weeks, followed by 24 weeks of sequential slit treatment where the jc slit-drops and the hdm slit-tablets were administered daily with a 5 minute interval (1st: jc-slit drops, 2nd: hdm slit-tablet). the primary endpoint was the frequency and severity of adverse events (aes) during sequential slit by common terminology criteria for adverse events (ctcae) v4.0 and slit grading system. serum antibodies were measured as the secondary endpoint. results: eleven patients were recruited. aes after jc slit-drops administration were found in 9 patients out of 11 cases (82%). aes after sequential slit were found in 8 patients out of 10 cases (80%). all aes were graded 1 or 2. no severe aes were observed during the study period. the levels of jc-and hdm-specific ige and igg4 in serum were increased during treatment. conclusion: sequential-administration of jc slit-drops and hdm slit-tablets was well tolerated by patients suffering from both jc pollinosis and hdm rhinitis. background: according to the ema guideline on the clinical development of products for specific immunotherapy products should be tested in phase ii at different doses in several study-arms to establish a dose-response relationship for clinical efficacy before confirmatory trials can be initiated. allergen exposure in an aec may be used as primary endpoint. the study was a single-center, randomized, double blind, placebo-controlled, phase ii trial, treatment duration 10 months. 168 grass pollen allergic patients (18-65 years of age) with seasonal rhinitis/rhinoconjunctivitis (arc) with (mild, gina i) or without concomitant asthma were randomized to three different dosages of a liquid phase iii study is in preparation. as part of an effort to prepare the analysis plan using the csms as primary endpoint, the grass pollen data of the european aeroallergen network (ean) was used to identify the window within the grass pollen season (gps) with optimal correlation between the grass pollen counts and the csms. method: ean currently includes information from more than 400 active and 300 historical pollen-monitoring stations in europe including 39 countries. the ean database used for analysis included grass pollen data collected during 2009-2016. the daily allergy symptoms and medication were recorded spontaneously using an app questionnaire on the subject's smart phone. the csms was re-calculated using the ean database, using the recorded symptom scores with estimation of the medication score using similar methods as recently published. the correlation between the daily grass pollen count and the daily csms was analyzed with a mixed effects model accounting for patient-specific correlations and symptom levels. conclusion: these results confirm a statistically significant correlation between grass pollen counts and the csms. importantly, these findings suggest that the optimal window to observe treatment effects after immunotherapy may be a short interval after start of the gps and during the peak gps, due to generally higher csms values. this provides sufficient basis to consider additional sensitivity analyses to evaluate the treatment effect of grass mata mpl scit on the primary csms endpoint during a shortened window after the start of the gps and to consider excluding the overlapping period between the bps and gps from the primary analysis. 0894 | combo-vas as a tool to assess efficacy of allergen immunotherapy ciprandi g 1 ; silvestri m 2 ; olcese r 2 ; tosca ma 2 1 ospedale policlinico san martino, genoa, italy; 2 istituto g. gaslini, genoa, italy background: allergen immunotherapy (ait) is at present the unique cure for respiratory and venom allergy. usually, ait lasts for some years, but its efficacy is longstanding. criteria for assessing ait efficacy are mainly based on symptom severity improvement and saving of symptomatic medications. in this regard, there are different score grading for both measuring symptom severity and drug use. visual analogue scale (vas) is a well-defined and validated method widely used in many diseases, including allergic disorders. vas is a psychometric tool measuring the patient's perception of symptoms, emotions, pain, drug use, etc. recently, it has been published an eaaci position paper concerning the recommendations for the standardization of clinical outcomes used in ait trials for allergic rhinoconjunctivitis, but it is complex. so we would propose a simpler way to measure ait efficacy by vas, in particular a combo-vas based on one vas for symptom and one for medications. results: globally 150 patients were retrospectively evaluated. all of them were treated with a 3-year ait course: 120 were defined as responders and 30 as non-responders. in responders group the combo-vas mean value was 14 (iqr 12-15) at baseline and 4 (iqr 3-6) after ait treatment. in non-responders group combo-vas mean value was 13 at baseline and 11 (iqr 9-12.5) at the end of ait. the difference was significant (p = 0.012). the d combo-vas was −66.67% in responder group and −10% in non-responders group (p < 0.0001). conclusion: combo-vas, i.e. the sum of vas for symptoms and medications, could be an easy and quick tool for assessing ait efficacy and reflects the patient's perception. therefore, it could be very fruitful in clinical practice. 0895 | rapid up-dosing in sublingual specific immunotherapy is safe, well-tolerated and effective in patients suffering from tree pollen allergic rhinitis background: an optimised up-dosing period of specific immunotherapy (sit) is desirable for better patient compliance because a long or complicated up-dosing scheme is sensitive to disruption. the aim of this study was to compare the safety, tolerability and effectiveness of an optimised up-dosing scheme with two preexisting schemes of sublingual sit (slit) in patients under standard medical care. method: this was a prospective, open, active controlled, multi-center non-interventional study in germany and austria to document the treatment of children and adults with allergic rhinoconjunctivitis and/or allergic asthma treated with a slit containing purified, aqueous extracts of birch, alder and hazel pollen. the investigators were free to select an up-dosing scheme for included patients: scheme a consisted of an up-dosing period of up to 12 days at the patient's home using three different solution strengths to reach the maximum dose; ultra-rush scheme b performed only with the highest solution strength at the physician's office within 2 hours, and the optimised scheme c which was initiated at the physician′s office and continued at home using exclusively the highest solution strength within 2 (long-term) or 4 (pre-seasonal) days. data on up-dosing and maintenance treatments were documented by physicians during 5 patient visits and by patient diaries. the study was approved by ethic committees, and all patients or parents gave their informed consent. results: in total, 164 patients aged 3-76 years were included into this study. scheme a was applied by 90 patients, 29 patients decided on regimen b, and 45 patients on the optimised scheme c. conclusion: one-day ur-scit conducted in an outpatient clinic was safe and well-tolerated in patients with ad sensitized to hdm. ur-scit can be a safe and useful option to start a subcutaneous allergen immunotherapy for ad. 0899 | factors affecting on adherence to allergen specific immunotherapy results: among 1162 enrolled patients, 228 (19.6%) patients failed to complete at least 3 years of ait, which were regarded to be nonadherent in this study. univariate analysis revealed that male, younger age group less than 40 years, cluster and ultra-rush schedules, atopic dermatitis, the absence of associated diseases, and follow up of other department were found to be associated with nonadherence to ait. in multivariate analysis, younger age group less than 40 years (or 2.31, 95% ci 1.55-3.45), cluster (2.37, 1.56-3.60) and ultra-rush schedules (6.03, 3.18-11.42) , and absence of follow up of other department (2.11, 1.31-3.40) were independently associated with non-adherence to ait. no association was found in gender, diagnosis of allergic diseases, kind of allergen extracts, and patients' distance from hospital. conclusion: various factors are related with ait non-adherence to interfere the effectiveness of immunotherapy. clinicians need to be aware of the factors associated with non-adherence to ait and consider them when choose to maximize ait adherence. 0900 | cost-effectiveness of allergen immunotherapy to grass in patients with allergic rhino-conjunctivitis and asthma background: allergen immunotherapy (ait) has been shown to reduce symptoms and medication use in subjects with rhino-conjunctivitis and asthma. however, long-term cost effectiveness of this therapy needs to be evaluated. our aim was to assess cost effective of ait, both subcutaneous immunotherapy (scit) and sublingual immunotherapy (slit), vs. pharmacotherapy alone in subjects with rhino-conjunctivitis, with or without allergic asthma, to grass pollens. method: a markov cohort state-transition model with a time horizon of 9 years was used to assess the costs and effects of 3-year ait in adults. relative efficacy of the treatments expressed as standardized mean difference was estimated using an indirect comparison on symptom and medication score extracted from available meta-analyses. the rhinitis symptom utility index was used as a proxy to estimate utility values for symptom score. the societal perspective, through the human capital technique, was used to estimate indirect costs, to represent the scenario of a country with nationalized medicine. data on drug and other medical costs were derived from published sources as well as ait duration and asthma occurrence. additional sensitivity analyses were performed to test the robustness of our results. results: in the base case analysis, using italy clinical practice patients with moderate-to severe allergic rhino-conjunctivitis (ss ranging from 6 to 15 points) and a mean age at entry of 21 years, both scit and slit were associated with increased cost but superior efficacy compared to pharmacotherapy alone. the results were most sensitive to variation in efficacy estimates and ait persistence rates. conclusion: this analysis suggests that ait is cost effective relative to pharmacotherapy alone. scit, despite significantly higher indirect cost burden, seems to be the most cost effective option. the results should be interpreted in the context of the data input and modelling assumption used. 0901 | ielisa as a tool to measure ige binding towards single modified peanut allergens background: immunotherapy has shown to be a potential treatment for food allergies but needs further research to improve safety. modification of peanut allergens to reduce their allergenicity is a promising approach to develop a safe and effective immunotherapy as shown by the successful completion of a first-in-human safety and tolerability study using hal-mpe1 in adult patients with peanut allergy (eudract 2013-004238-13) . in order to assess the impact of modification on individual peanut allergens and to assess its impact on ige binding by individual patient sera, we have developed peanut allergen-specific inhibition elisas. with this methodology we are able to identify patients with residual ige binding to modified peanut allergens. method: ige inhibition elisas (ielisas) were developed and performed to test ige binding towards purified ara h2 and ara h6 and their reduced and alkylated (modified) versions, using the individual responses of single patient sera. results: ara h6-specific ielisas showed that modification of ara h6 results in >95% reduction in ige-binding for all individual sera tested. ara h2-specific ielisas showed that modification of ara h2 also results in >95% reduced ige-binding for most of the sera, but some sera were identified which showed residual, 10%-20% ige binding to mara h 2. in some of the latter sera, the presence of ige binding to a linear hydroxyproline-containing peptide could be confirmed as a possible source for the residual ige binding to mara h2. we have developed a methodology to assess residual ige binding to modified peanut allergens. the sensitivity of the allergen-specific ielisas allowed us to discriminate between patient sera in which ige binding to mara h2 and to mara h6 was virtually completely absent and sera in which 10-20% residual ige binding to ara h2 was observed. the clinical importance of these observations is yet unknown. future clinical studies will need to reveal whether the patient-specific ige binding profiles to individual modified peanut allergens do correlate with the adverse events profile of immunotherapy with modified peanut extract. 0902 | design of a phase ii allergen immunotherapy study to determine the optimally effective and safe dose of subcutaneously administered tyrosine adsorbed modified grass allergen+mpl (mpl) adjuvants for the treatment of allergic rhinoconjunctivitis (arc) due to grass pollen. there is increasing evidence that the effectiveness of allergy immunotherapy to control arc symptoms is related to the cumulative allergen (or allergoid) dose administered. previously, two clinical studies have been conducted using a conjunctival provocation test (cpt) as primary efficacy measure for a similar scit mata mpl product for birch allergy [eudract 2012-004336-28 and 2015-000984-15] . these studies showed a 5.5 fold increase in cumulative dose to achieve~50% increase in efficacy, with a relative reduction in total symptom score (tss) of 32.3% compared to placebo and no safety signals of concern. the shape of the dose response curve was curvilinear, where this high dose almost reached plateau. method: this is a multi-center (~47 clinical study centers across europe), randomized, double-blind, placebo-controlled, parallel-group study in~440 adult patients with moderate to severe seasonal arc with or without mild asthma. a positive cpt is to be achieved at screening and verified prior to randomization. the primary outcome is the post-treatment tss following cpt. a wide range of cumulative dose regimens is used (5100, 14400, 27600 and 35600 su) applied over 6 weekly injections to establish the shape of the dose response to support dose selection for phase iii. the design of the current phase ii grass allergoid scit study will be discussed, including the rational of using 4 cumulative dose regimens and placebo and the pre-selected shapes of the dose response curves. in addition, the number of patients screened and randomized will be presented by country, gender and/or age category and screen failures will be categorized. conclusion: this phase ii study was initiated to establish the dose response of a grass mata mpl scit product, using cpt to measure the effect of a wide range of cumulative dose regimens. the achievement of its aim will be an important milestone in the development of an efficacious and safe state-of-the-art grass scit. conclusion: we observed that the specific nasal challenge with house dust mite generates an inflammatory response within the first hours, but we did not demonstrate any correlation with the response to immunotherapy after six months. 0905 | tolerability of a two week rush updosing with modified allergens in pollen allergic subjects in the day-to-day practice background: in two phase iv studies the tolerability of a subcutaneous rush up-dosing, using three injections in two weeks, has been tested and proven to be save in adults. in the course of a non-interventional study (nis) now the tolerability of this treatment scheme was tested in the day-to-day practice. conclusion: over 97% of the patients could reach the highest dose of 0.5 ml. the overall tolerability is very good. the data from daily practice confirm the data that were previously obtained in two phase iv studies. siges from 40 patients, evaluated during the 1st semester of 2017 at an outpatient clinic. all patients presented persistent moderatesevere allergic rhinitis, in pollen season and had not been submitted to it. all patients had positive spt for grasses (grass) and olive (olea). sige-tot for phleum pratense and olea europaea and some sige-crd (rphl p 1, rphl p 5, rphl p 7, rphl p 12, role1 and nole7) were determined. physicians were divided into 2 groups (group 1 if <10 years of practice and group 2 if≥10 years of practice) and were asked to choose which it to prescribe for each patient (none, only grass, only olive or both grass and olive), according to spt and sige results. results: fifteen physicians (60% with ≥10 years of practice) participated in the survey. considering only the sige-tot results, the it choice (group 1/2) was: no vaccine in 10%/3%; grass vaccine 50%/ 58%; olive vaccine 5%/10% and both grass and olive vaccines in 35%/30% of the patients (p = 0.42), the intergroup agreement was 70% (kappa 0.612). according to the sige-crd results the physicians chose (group1/2): no vaccine at 10%/13%; grass vaccine in 63%/60%; olive vaccine in 10%/5% and both vaccines in 18%/23% of patients however, data on control of allergic rhinitis (ar) after discontinuation of therapy are insufficient. the aim of our study was to assess sustained control of ar in three consecutive years after grass-pollen slit discontinuation. method: a total number of 35 patients [24 (68.57%) males; mean age 32 years, age range 15-56] well-controlled after a three-year course of slit with grass pollen extract were prospectively evaluated in three consecutive years after discontinuation of therapy. conclusion: a three-year course of grass-pollen slit seemed to have a long-term effect on control of symptoms in patients with ar. the authors declare no conflict of interest. results: all patients showed a positive sensitization profile by skin prick test to either betula and/or alnus. in 40% of patients this profile was furtherly confirmed with serum specific ige levels to betv1, (mean 13.56 ku/l). allergic symptoms in patients with birch/alnus pollen allergy after ingestion of certain food can result from crossreactivity of bet-v1-specific ige to homologous pathogenesis-related proteins, particularly the pr-10 protein. conclusion: within the allergy history we emphasize on focusing on sao symptoms as many patients under-recognize them. among the sensitization profile of these patients it is quite important to highlight cross reactivity between bet v1 and alnus. the other patient suffered from anaphylaxis(grade ii) induced by minimum amount of lettuce consumption without co-factors. both patients suffered from oral allergy syndrome to peach and allergic rhinitis. spts to foods and pollens were performed with commercial extracts, prick-through-prick with fresh plant foods, while specific ige was determined accordingly. ltp syndrome was defined as a sensitization to pru p 3 and symptoms elicited by at least 2 unrelated plant foods. co-factors were also investigated. results: the first patient was sensitized to lettuce, peanut, hazelnut, sunflower's seed, peach and banana, and plane tree, olive tree, grasses, parietaria and mugwort. sige to lettuce was 2.04kua/l, to pru p 3 was 20.8kua/l and total ige was 703.4u/ml. co-factors, such as exercise, were involved. the second patient was sensitized to peanut, walnut, hazelnut, almond, sunflower's seed, cashew, lettuce and peach, and, plane tree, olive tree, grasses, parietaria, mugwort and willow. sige to lettuce was 27.6kua/l, to pru p 3 was 37 and total ige was 1705.9ku/l. no co-factors were identified. background: garlic (allium sativum) is a vegetable that belongs to amaryllidaceae's family. hypersensitivity to garlic is not very common. it has been mainly reported in occupational allergy but it also may cause contact dermatitis, rhinoconjunctivitis, asthma, urticaria, gastrointestinal symptoms and anaphylaxis after its ingestion. some studies have identified alliin lyase, a 56 kda protein, as a major garlic allergen and it seems to be a heat-sensitive allergen. we report on a 9-month-old infant who presented, 15 minutes after an accidental ingestion of garlic sauce, generalized erythema and cough. she was still breastfeeding and she had never abstracts | 491 eaten garlic before (although the mother usually consumed garlic). the patient had never tasted other vegetables belonging to amarylidaceae's family either but zucchini, with good tolerance. we performed skin tests and specific ige (sige) to different vegetables. a raw garlic extract was also carried out and analysed in the patient by sodium dodecyl sulfate polyacrylamide gel electrophoresis (sds-page). results: prick by prick with garlic was positive (10 mm) and negative to onion, leek, asparagus, zucchini and saffron. skin prick tests to commercial extracts of mugwort, grass pollen, peach ltp and profilin were negative as well. specific ige to garlic was 3.15 ku/l (out from a total ige 32 ku/l) and 0 ku/l to onion and asparagus. sds-page immunoblotting assay with patient′s serum revealed ige reactivity with proteins of 6 kda and 8 kda. conclusion: we report a garlic ige-mediated anaphylaxis case in an infant with proteins of 6 and 8 kda as the relevant allergens. the mechanism of sensitization in the present case remains unclear. the authors hypothesized that breastfeeding, cutaneous contact or inhalation might be possible mechanisms involved. chong kw 1 ; saffari se 2 ; chan n 3 ; seah r 3 ; tan ch 3 ; goh sh 1 ; goh a 1 ; loh w 1 1 allergy service, department of paediatric medicine, kk women's and children's hospital, singapore, singapore; 2 centre for quantitative medicine, office of clinical sciences, duke-nus medical school, singapore, singapore; 3 yong loo lin school of medicine, national university of singapore, singapore, singapore background: the predictive decision points for both peanut skin prick test (spt) wheal size and serum ige concentrations, in peanutsensitized children, have not been evaluated in singapore. we aim to assess these for purposes of risk stratification and prediction of oral food challenge (ofc)s' outcomes by means of a retrospective chart review. results: the number of patients evaluated was 328, of which 269 had clinical diagnosis of peanut allergy based on recent immediate reaction to peanut (pa group) and 59 were tolerating peanuts regularly (pt group). the mean age of both groups were similar, 3.9 ± 3.2 and 3.7 ± 3.3 years in pa and pt groups respectively. there was a high prevalence of atopic diseases in both groups, with atopic dermatitis (75.8% in pa, 79.7% in pt), and other food allergies (55.4% in pa, 44.1% in pt). presence of rhinitis was statistically higher in the pa group compared to the pt group, with odds ratio of 2.52 (95% ci: 1.42-4.47) . a wheal size of ≥8 mm and a peanutspecific ige of ≥6 ku/l provided for a 95% positive predictive value. the larger the wheal size on spt, the higher the probability of a clinical reaction to peanuts. the results will help us in deriving preliminary cut-off values when conducting future prospective studies with ofcs in our peanut-sensitized cohort (whom had no prior peanut exposure), and to eventually reduce the need for expensive and potentially risky food challenges. 0913 | ginger: flavory, spicy …allergenic? a report of four patients with allergy to ginger background: ginger (zingiber officinale) belongs to the family zingiberoidae, along with cardamom and turmeric. the edible portion is the horizontal rhizome, and it is very appreciated for its aroma and spicy flavor. it also presents great interest for its therapeutic and culinary use. hypersensitivity to ginger is rare and has been scarcely reported. we report 4 cases (p1, p2, p3, p4) of adverse reactions to ginger after its ingestion and with good tolerance to cardamom and turmeric. method: skin prick tests (spt) to environmental allergens and prick-by-prick with ginger were carried out. total ige, and specific ige to ginger were also determined. a raw ginger extract was prepared. this extract was analyzed in all the patients by sodium dodecyl sulfate polyacrylamide gel electrophoresis (sds-page). background: food allergy is divided into 3 groups according to pathophysiology: ige-mediated, ige-and non-ige (mixed type), and non-ige (cellular type). however, in clinical practice, patients who fall under more than one group may be observed. method: patients who were diagnosed with food allergy at our clinic from january 2012 to december 2016 were included in the study. the medical files of patients were retrospectively evaluated, their symptoms and findings after consumption of foods were recorded, and they were categorized into 3 groups (ige-mediated type, non-ige type, and mixed type) according to their symptoms and findings. results: a total of 587 patients (63.5% male) with food allergies were included in the study. according to categorization via symptoms and findings, the distribution of patients was as follows: 140 (23.8%) ige-mediated type, 44 (7.5%) non-ige type, 195 (33.2%) mixed type. the remaining 208 (35%) patients were found to show various combinations of symptoms and findings that fit more than one group. in this study, we observed that food allergy symptoms and findings were distributed in a broad range which caused difficulties in the categorization of more than one-third of our patients. background: fish allergic patients suffer a lifetime of strict dietary restrictions. crocodile meat is a nutritious alternative choice in many countries around the world; however, it has recently been reported to also trigger severe allergic reactions. in these two case reports from 2017 pediatric patients were sensitised to the major fish allergen parvalbumin (pv), a potential cross-allergen. bony fish contain predominantly pvs of the β-lineage, which are the most common trigger of allergic reactions in fish allergic patients. in most other vertebrates, pvs of the α-lineage are most abundant, which have been reported as a causal allergen in frog, cartilaginous fish, and chicken allergies. we aimed to evaluate the allergenicity of crocodile meat in fish allergic children, with focus on pv. method: over 70 children with clinical history of ige-mediated fish allergy were identified, skin tested to commonly consumed fish species using commercial and in-house preparations, and serum samples were collected. a sub-cohort was skin tested to crocodile using heat-treated tail muscle tissue from saltwater crocodile (crocodylus porosus). extracted proteins and purified pvs were analysed by sds-page, immunoblotting, and mass spectrometry. serum from all fish allergic children was analysed for ige reactivity to the crocodile pv. this reactivity was compared to those of raw and heated crocodile protein extracts as well as protein extracts and purified pvs from frequently consumed fish species. results: more than 5 fish allergic children were positive on skin testing to crocodile (wheal size>3 mm), demonstrating its clinical reactivity. in vitro analyses revealed ige reactivity to crocodile pv in serum from more than half of all patients. two βand one α-crocodile-pv isoforms were identified. pvs constituted approximately 90% of total proteins in heated crocodile extracts, with β-pv (11 kda) being 10 times less abundant, but up to 500 times more ige-reactive than α-pv (13 kda). αand β-pvs from crocodilians, including alligators and crocodiles, share more than 96% and 74% of their amino acid sequence, respectively. conclusion: crocodile pv is a new allergen as per the iuis guidelines. fish allergic patients may be at risk of severe allergic reactions upon ingestion of crocodile meat due to strong ige cross-reactivity of β-pvs. this study suggests that fish allergic individuals and health professionals need to be aware of potential allergic reactions to meat from crocodilians, termed 'fish-crocodile syndrome'. background: we present a 39-year-old nonatopic woman that in december 2016 after eating a seafood paella with green pepper presented asthenia, nasal obstruction, incoercible vomiting and diarrhea. later she ate a grilled loin sandwich in a bar and she had the same symptoms (she asked the waiter at the bar and the chef had cooked her sandwich in the same pan where he had cooked green pepper just before). after that, she suffered from abdominal pain, nausea, abdominal distension without diarrhea two hours after she ate an omelet sandwich with certain flavor of green pepper. at present even the casual smell of pepper causes her nausea. the woman eats everything including spices and just avoids pepper. method: skin prick tests were performed using extracts from food (nuts, fish, mollusk, fruits, vegetables, legumes), aeroallergens (mites, abstracts | 493 pollens and epithelia) and purified proteins (pru p 3, profilin, polcalcin, alfalactoalbumin, betalactoglobuline, casein). we also performed prick by prick to raw and cooked green pepper. sds-page immunoblotting according to laemli under reducing conditions (with 2-mercaptoethanol) was performed to study the molecular mass of the ige-reactive proteins. extracts from green pepper and green pepper seed were used. the prick tests were all negative and the prick by prick test to raw and cooked green pepper was positive in both cases. blond was taken from all patients to specify the levels of allergenspecific ige against 112 allergen components of immunocap isac test, the result≥0.30 isu-e was assumed as positive. results: in the study group, in 12 patients (24%) specific antibodies against ltp were detected, the isu-e level range 0.3-34 average 5.26 isu-e on average, in patients with detected ltp ige was detected for 3.5 components belonging to the ltp, however the highest number 41% patients were detected ige only for 1 ltp. in 9 subjects (75% of respondents with detected ltp), ige was detected against art v 3 and this is the only ltp component whose occurrence was statistically significant (p = 0.044). in 6 patients ige was detected against pru p 3, jug r 3, pla a 3,; 5 patients ige to ara h 9; 4 patients cor a 8; 3 patients ole e 7, 2 patients tri a 14, and in 1 person para j 2. background: the birch pollen-associated oral allergy syndrome (oas), an ige-mediated local allergic reaction, is the most common manifestation of pollen-associated food allergies. its origin is explained by cross-reactions between birch pollen-and food-allergens belonging to the pathogenesis-related protein subfamily 10 (pr-10). [1] so far, there is no marker available for its detection and no standardized test established to evaluate objectively the subjective feelings experienced by oas. the diagnosis is based on a characteristic history and on detecting the sensitization to triggering allergens in skin prick test (spt) and laboratory examination. method: the aim of this study was to evaluate whether the food skin prick test could be a helpful marker in the diagnosis of a birch pollen-associated oas. for this exploratory study, data from 2016-2017 was collected retrospectively at the dermatological outpatient department of the ordensklinikum linz elisabethinen. patients with positive spt results for birch pollen were included. the variables age, gender, tree pollen-(birch, alder, hazel) and food-spt, laboratory tests (ige, bet v 1, bet v 2, gly m 4) and symptoms (oas, rhinoconjunctivitis allergica, atopic dermatitis, anaphylaxis) for statistical analysis. results: there was an association between food-spt and oas but also between the negative oas patients and food-spt (p = 0.9-0.1). all of the bet v 1 sensitized patients with positive gly m 4 results had also a positive food-spt result. conclusion: there was no evidence for a possible role of food-spt as helpful markers in the diagnosis of birch pollen associated oas. maybe gly m 4 could be a helpful marker, but more data are needed. bet v 1 seems to be the cause of birch-pollen associated oas, due to the dominant sensitization pattern to major allergens in austria. background: eggs are among the foods most frequently causing allergy. the most common one is hen egg, although we may consume other bird's eggs such as duck's, those of goose, quails and seagulls. clinical and serological crossreactivity between hen egg proteins and those of other birds eggs have been described. allergy to other species eggs are less frequent and are usually described in patients allergic to hen eggs. we report a case of food allergy after ingestion of duck egg in an adult patient without hen egg allergy. the patient was a 50 year-old man who had symptoms of generalized itching, swelling uvula, erythema neck and deglutition difficulty immediately after he ate eggs from duck and hen. he claimed to have eaten hen eggs almost daily without clinical symptoms and he had not previously ingested duck egg. he denied allergic reactions to any other food but did complain of seasonal allergic rhinoconjunctivitis in the spring. we performed skin prick test with extracts of egg and feathers, prick by prick test with cooked and fresh yolk and white from duck and hen egg and oral challenge with hen eggs. specific serum ige was measured to hen proteins and we carried out a western blot with the proteins of allergenic extracts from different eggs (white and yolk of quail, chicken, goose and duck) and an inhibition of western blot with ovalbumin as inhibitor allergen. results: skin test with extracts of eggs and feathers, cooked and fresh hen and duck eggs were positive. total serum ige was 29.2 ku/l. specific ige to hen's egg was class two for hen egg white, ovoalbumin and class one for yolk and ovomucoid. oral challenge with heated egg yolk negative and with egg white was positive. the patient's serum recognized mainly and intensely several proteins of white and egg yolk of quail and duck with a molecular mass around 45 to 50 kda respectively. on the other hand a protein around 45 and 50-52 kda was unique recognized in white eggs of hen and goose. the western blot inhibition revealed ovalbumin inhibited the protein recognized in the egg white but not egg yolk involved in. background: management of tree nut allergy is usually based on the avoidance of the suspected tree nut (tn), as well as peanuts and seeds, either because of the risk of cross-reactivity and/or contamination, or due to the clinical severity. objective: to assess the sensitization pattern and clinical reactivity patterns to different tn, peanut and sesame seeds (ss) in patients with a history of reaction to at least one of these foods. results: a total of 47 patients with confirmed nut allergy were included; 70% female, median age [interquartile range] of 28 years; 72% were atopic. the most frequently involved foods were walnuts (53%), hazelnuts (40%), almonds (32%) and peanuts (38%). anaphylaxis was the clinical presentation in 51% of the patients. in those with a history of reaction to only one nut (24), the most prevalent was peanut (42%). in the 23 patients that reacted to more than one nut, the most frequent combinations were walnut/hazelnut (15), walnut/almond (12) and almond/ hazelnut (10). of these patients, 5 tolerated other nuts. two had sesame seed allergy, one reacted only to ss. nine patients (19%) were sensitized to foods that they tolerated. fourteen (30%) patients were sensitized to ltp and 8 of them reacted to more than one nut. conclusion: these data concur with the existence of different sensitization profiles (primary, concomitant or cross-reactive), which may predict different clinical reactivity patterns and therefore, influence dietary recommendations. background: buckwheat (fagopyrum esculentum) is a polygonaceae weed, not a cereal, which is increasingly been consumed and used as an alternative food in the diet of celiac patients. despite its wide use, allergy to buckwheat has unfrequently been reported in our setting. method: two female patients, aged 37 and 58, suffered an immediate severe allergic reaction after eating a bread and a pancake containing buckwheat among its ingredients. the first patient presented generalized urticaria, palpebral angioedema and pharyngeal occupation. the second one showed those same symptoms, as well as abdominal pain, nausea, dyspnea, dizziness, hypotension and loss of consciousness. skin tests and specific ige determination to aeroallergens and food allergens were carried out, including prick-prick test with buckwheat and all other components contained in the food involved. buckwheat allergens were studied by sds-page and ige-immunoblotting of one of the patients. results: prick-prick tests yielded strongly positive results to the food itself and buckwheat, and negative to the remaining food components in both cases. cap was positive to buckwheat (11.30 ku/l and >100 ku/l, respectively). basal serum tryptase levels were normal. both patients were not sensitized to cereals, ltps, profilins or pr-10 proteins. for the first patient, the skin tests were negative for other foods, seeds and nuts. the cap was negative for ltps, profilins and storage proteins of peanut and other nuts. the second patient who had the most severe reaction, was also sensitized to hazelnut(cap 13.7 ku/l), pistachio (1.44ku/l), almond(0.66ku/l), walnut(29.7ku/l) and sesame(4.47ku/l), which were not included in the pancake. the buckwheat immunoblot of the first case, under non-denaturing conditions, revealed a ige-binding protein of 60-kda. ige-immunoblotting under reducing condition showed protein bands of 30, 20, 17 and 14 kda in the buckwheat extract. conclusion: two cases of anaphylaxis by buckwheat flour contained in two frequently consumed foods are presented. the absence of sensitization to ltps, together with the pattern of specific ige binding in the immunoblot in one of the cases suggests that the responsible allergen could correspond to a storage protein of buckwheat, without cross-reactivity with other seed and nut allergens. buckwheat must be taken into account as an unsuspected food allergen capable of causing severe allergic reactions. background: allergy to linseed (linum usitatissimum) has infrequently been reported despite of its wide use in bread and in a range of "health food" products. linseed contains potent allergens which have not yet been characterized. we studied three patients who presented allergic reaction after eating different foods which contain linseed. two of them (patient p1 and patient p2) had anaphylaxis and the third one (patient p3) had oral syndrome, abdominal pain and diarrhoea. p2 was also allergic to mustard and p3 to sesame seed. all of them tolerated the remaining seeds, nuts and food. baseline tryptase levels were in normal range in all patients. skin tests and specific ige determination to inhalants and food allergens were carried out. linseed allergens were studied by sds-page and ige-immunoblotting. skin tests: patient 1: prick tests were positive to pollens and linseed, and negative to ltp, profilin, nuts, seed and the remaining food; patient 2: prick tests were positive to linseed and mustard and negative to other food and inhalants; patient 3: prick tests were positive to linseed, pollens, sesame and nuts (peanut, hazelnut, almond, pistachio). we present three cases of severe allergic reactions to linseed. the pattern of specific ige binding in the immunoblot seems to lead to storage proteins as the responsible allergens. 0925 | pr-10 sensitization-looking it up in food allergy background: pr-10 protein group sensitization is found in patients with respiratory allergy, mainly in areas inhabited by trees of the betulacea or fagacea families. its role in food allergy is, however, more frequently described in the context of cross reactivity. our aim was to characterize the pattern of molecular sensitization of food allergic patients sensitized to pr-10 protein group with immu-nocap isac ® (isac). the remaining patients, with more severe reactions, were all co-sensitized to either ltp and/or storage proteins (sp). only 2 of the 7 patients without pfa were co-sensitized to ltp or sp versus 7 of 9 with pfa (p < 0.05). conclusion: pr-10 sensitization is rare in our population. approximately half of the patients had allergy to plant foods, but the majority were co-sensitized to ltp and/or sp. the few patients only sensitized to pr-10 had minor reactions. among the patients without plant food allergy, co-sensitization to ltp and sp was significantly less common. according to these results, in our population, pr-10 seems to be less relevant to food allergy, when compared to reported results from other european countries. gür çetinkaya p; uysal soyer ö; esenboga s; sahiner üm; sekerel be hacettepe medical school, ankara, turkey background: pistachio is a tree nut belonging to "anacardiacea" family, and constitutes 7% of tree nut allergies. this nut most often abstracts | 497 cross-reacts up to 95% with cashew which is located in the same family. pistachio allergy is mostly seen in iran, turkey, the united states, and china where this tree nut is frequently consumed. in this study, we analyzed age and cut-off values for development of tolerance to pistachio. method: children who had reported allergic reactions with pistachio, and who have not consumed pistachio, but had positive spt and/or specific ige levels were enrolled into the study. spt and specific ige levels were measured in all patients. oral provocation(op) tests with pistachio were performed by 82 patients, and 21 of them had positive test result. the median age of tolerance development was 60 months (iqr: 48.0-89.0 months). the most commonly involved systems during op tests were skin (90%, n = 19), gastrointestinal system (33%, n = 7), and lower respiratory tract (24%, n = 5). concomitant allergic diseases were atopic dermatitis (70%), asthma (40%) and allergic rhinitis (17%). there was a positive correlation between skin prick test diameter (spt) and specific ige levels (spige) (r = 0.331, p = 0.001). spt of≥8.25 mm to pistachio nut was found as highly predictive of clinical allergy (auc: 0.83, 95%ci: 0.73-0.94, p < 0.001). any relation was not determined between eosinophil, basophil counts, triptase levels, and op test positivity. conclusion: pistachio allergy is one of the frequently seen nut allergies in turkey which may cause serious allergic reactions including anaphylaxis. op test showed that tolerance was achieved by the median age of 60 months, and a cut-off level of 8.25 mm was best predictor for positive reaction. in an oral challenge test, the patient responded with generalized urticaria, swelling of the lips and difficulty breathing at a cumulative dose of 0.1 g peanut protein, however, without blood pressure drop. (grade 2, moderate symptoms). the patient was treated with anti-ige for 3 months (with 450 mg every 4 weeks sc). oral desensitization began with ingestion of 500 μg peanut, escalating to 500 mg, on the first day and escalating weekly doses of peanut from 500 mg to 4000 mg (8 peanuts). then anti-ige was discontinued while the patient ingested 8 peanuts every day. we have followed the patient's sensitivity to peanuts from before anti-ige treatment to after anti-ige washout with basophil testing. results: the patient completed desensitization without side effects, and continues to ingest 8 peanuts a day. basophil sensitivity was reduced 13-fold by anti-ige treatment, but returned to baseline levels after anti-ige washout. conclusion: anti-ige allows rapid desensitisation of peanut allergic subjects with peanut oral immunotherapy. in the majority of subjects, this desensitization is sustained after anti-ige is discontinued. additional studies will help clarify which patients would benefit most from this approach. the return of basophil response to pre-treatment levels suggests that the patient is desensitised, and depends on the daily ingestion of allergen. what do we (not) know? background: the use of biologic prosthesis is a well-established surgical procedure. acute and delayed complications may occur, but accurate epidemiologic data about allergic reaction to graft tissue is lacking. methods: a 9 years old boy referred to our unit for urticaria and gastrointestinal symptoms which developed a few years before. he received a biologic porcine vascular duct during a cardiovascular surgery at 20 days of life. at the age of 5 urticarial episodes occurred, and a diagnosis of beef allergy was made. after the exclusion of beef meat from the diet, most symptoms resolved, but the child began to complain about occasional episodes of vomit and diarrhoea. results: skin prick tests confirmed the beef meat sensitization and prick-prick test resulted positive against raw pork meat but not against cooked pork meat. in vitro tests demonstrated the presence of pork meat specific iges (14.1 kua/l). component-resolved diagnostic tests revealed allergy sensitization toward bos d 6 (bovine serum albumin, bsa; porcine serum albumin was not tested due to lack of a specific test). after accurate exclusion of pork meat from diet, a complete remission was achieved, and the diagnosis of pork meat allergy was confirmed. conclusion: bsa is a major beef allergen, responsible for the raw beef-cow milk cross-reactivity but with a scarce importance in milk allergy. it is highly homologous with human serum albumin and other mammalian serum albumins, including porcine albumin. porcine albumin is also highly homologous with cat serum albumin and therefore responsible for cross-reactivity in patients affected by cat-pork syndrome. we hypothesize that the implanted porcine tissue was the trigger for pork meat allergy in our patient, as this condition is exceptional in childhood and that our patient never owned a cat. few cases of pork allergy due to porcine tissue implantation have been reported so far. of interest, pig sensitization was recognized as a rare but possible cause of blood-culture negative endocarditis in patients with porcine bioprosthesis according with anamnesis, increased ige level against pork, tissue eosinophilia during autopsy. background: desensitization to foods is assuming a new paradigm in food allergy. this technique is becoming widespread especially for patients with egg and milk allergy, but the effect of desensitization on the consumption of similar but not identical foods is still uncertain. material and methods: we describe the case of a 16-year-old patient, with a history of chicken egg allergy, who had been successfully desensitized tolerating cooked and raw chicken eggs for a year. the patient came to the office after presenting an episode of anaphylaxis immediately after eating fried quail eggs. an immunological study was carried out. we performed skin prick test with chicken egg′s proteins (white, yolk, ovoalbumin and ovomucoid). an immunoblotting to detect specific ige to egg proteins was also performed. for this purpose, the following extracts were used: chicken egg white and yolk (commercial extract form alk) and quail egg white and yolk prepared following a similar procedure (extracted in 10% phosphate buffer (w/v)). conclusion: we present the case of a patient with specific allergy to quail egg white and yolk, probably through ovotransferin, but not to chicken egg. the desensitization against chicken eggs does not allow the consumption of eggs of other species of birds, such as quail eggs, and this indication must be made specifically to patients after a protocol of desensitization against chicken′s eggs. case report: seven years ago we presented the case of a 32year-old male, who suffered two acute episodes of oral pruritus, lip angioedema, epigastric pain, generalized urticaria and dizziness after ingesting lettuce. he previously tolerated salads (including lettuce). he was later diagnosed with non-ltp-dependent lettuce anaphylaxis and an aspartyl protease was identified as a new lettuce allergen with cross-reactivity with other members of the compositae family. since the diagnosis he has avoided lettuce and all the other compositae. we present the patient's curious outcome after 7 years of follow up. methods: total ige, basal tryptase, specific ige to lettuce by immu-nocap, prick-prick and oral challenge tests with lettuce and other compositae. sds-page, immunoblotting and molecular characterization of ige binding bands by mass spectrometry. skin prick tests and specific ige to lettuce were repeated on several occasions in the following years. after 7 years an oral challenge test with lettuce was carried out. results: prick-prick test was positive to fresh lettuce (11 × 15 mm) and to other compositae (raw endive, chicory, thistle, artichoke and chamomile). prick-prick test was negative with these boiled compositae. basal tryptase was 7.07 μg/l. total ige in serum was 189 ul/ml. specific ige by immunocap was positive to lettuce (7.35 ku/l) and negative to profilin, ltps and thaumatin. oral challenge test with endive was positive and negative with cooked compositae (artichokes and thistle). sds-page and immunoblotting detected an intensely binding ige band about 46 kda, common for endive and chicory, which was identified by mass spectrometry as an aspartyl protease. no bands were detected at ltp (9 kda) and profilin (16 kda) . in the first two years after the diagnosis, prick-prick test and specific ige to lettuce remained positive (cap 1.91 ku/l and 0.44 ku/l, respectively). after 7 years, prick-prick test and specific ige to lettuce became negative (cap 0.08 ku/l). with this findings a new oral challenge test with lettuce was carried out which result turned out negative. we report the first case of spontaneous tolerance to lettuce in a patient who previously presented lettuce anaphylaxis and identify an aspartyl protease as the causative allergen. introduction: eosinophilic esophagitis (eoe) is an emergent allergic inflammatory disease that is triggered by food allergens and characterized by progressive esophageal dysfunction. recently, it has been seen that eoe develops in up to 2.7% of patients with ige-mediated food allergy undergoing oral immunotherapy (oit). ingestion of baked milk and egg was associated with increased development of tolerance to regular milk and immunologic changes have been reported in subjects ingesting baked milk and egg, similar to those seen in food oral immunotherapy studies. case description: we present the case of a 13-year-old girl, with history of ige mediated cow′s milk allergy and rhino conjunctival and bronchial asthma symptoms. prick test against milk proteins showed: milk 6 mm, alpha-lactalbumin 6 mm, casein 3 mm and to beta-lactoglobulin: negative. total ige: 469 ku/l. specific ige to milk: 3, 15 alpha-lactalbumin: 3, 16 ku/l; casein: 2 ku/l and beta-lactoglobulin: 0.10 ku/l. we performed an oral food challenge with baked milk which was well tolerated. then, we performed an oral food challenge with fresh milk and she presented facial urticaria and pharyngeal pruritus. after 3 months eating baked milk every day, she had symptoms of dysphagia and esophageal food impaction. for this reason, we performed an esophagogastroduodenoscopy (egd) and biopsies which showed white exudates and vertical furrows. the histological study showed eosinophil count>20 per high-power field. eosinophilic esophagitis was diagnosed and she started treatment with esomeprazole 20 mg. the egd was repeated 8 weeks later with similar results in the biopsy. she was treated with a comprehensive diet free of cow′s milk proteins. after 8 weeks she was asymptomatic and endoscopy and biopsy findings were normal. we report the case of a cow′s milk allergic patient who developed eoe after introduction baked cow′s milk which apparently was tolerated in her diet. the avoidance proved efficacy in inducing the remission of eoe. method: we examined 87 bottle-feeding infants with food allergy aged from 1 to 12 months. serum vitamin levels were measured by immunoassay methods (retinol binding protein (rbp), vitamin b6, 25hydroxy vitamin d), biochemistry methods (vitamin c, vitamin e) and microbiology methods (vitamin b1, vitamin b2). as criteria for complete sufficiency standards adopted in the russian federation were used (the lower limit of normal levels: rbp -0.52 μmol/l; b6-8 ng/ml; 25-hydroxy vitamin d-15 ng/ml; vitamin c -0.4 mg/dl, vitamin e -0.8 mg/dl; vitamin b1 -28 μg/ml; vitamin b2 -6 ng/ ml). results: complete sufficiency were observed in 21 infants (25.9% cases), one vitamin deficiency in 33 infants (40.7%), two vitamins deficiency in 23 infants (28.4%), three and more vitamins deficiency in 6 infants (7.4%). should be used after vitamin status asses, mainly using monovitamin medication. results: patients were followed with the diagnoses of cma and asthma. age at the beginning of symptoms and start of oit were in the range of 3-6 months and 4-19 years, respectively. they had high total ige (139-843 iu/ml), milk spige (2.9-418 kua/l), casein spige background: food allergies may affect up to 6% of school-aged children. it has been shown that approximately 20% of all anaphylactic reactions caused by food allergy are firstly presented at (pre) school. therefore, it is of high importance that (pre)schools have a policy on food allergy management and the use of an epinephrine auto-injector (eai). to our knowledge, limited is known on the policies of food allergy management at (pre)schools. the aim of this study was to investigate the policy on food allergy management in preschools and primary schools in the northern part of the netherlands. results: we included 87 preschools and 110 primary schools in this study. we showed that 80.5% of the preschools and 73.6% of the primary schools had a child(ren) with food allergy. only 13.8% of the participating preschools and 27.2% of the primary schools had a policy on allergen avoidance and only 35.6% of the preschools and 35.8% of the primary schools had a policy for the use of an eai. the majority of the pre-and primary schools in the northern part of the netherlands have children with food allergy. however, only a limited number of (pre)schools do have written guidelines for food allergy management in (pre)schools. additionally, there is limited experience how to use an eai at (pre)schools. therefore, an evidence-based policy on food allergy management in (pre) schools is needed. background: food allergies are the most common cause of anaphylaxis in childhood. here we present 3 cases had anaphylaxis due to cow 's milk allergy, and treated with specific oral tolerance induction (soti̇) to cow' s milk. method: soti protocol was administered according to previously published by longo et al. skin prick test were performed according to standard methods with allergens. cow's milk specific ige was investigated with immunocap system. in all cases, the wheal size of the cow's milk in skin prick tests or the specific ige levels was higher than level of positive predictive value of 95%. results: case 1: a 7 years old male patient who had 3 anaphylaxis after milk consumption. soti treatment was started one year ago. there was no complications during the dose increasing phase. however, he had two episodes of anaphylaxis during the maintenance phase. in the final visit, we observed that he could drink 200 ml milk and could consume dairy products. case 2: eight-year-old male patient has an intensive care-of-hospitalization story due to anaphylaxis three times after milk consumption. his accordance to strict diet was bad, and had frequent asthma attack. anaphylaxis developed 2 times during the dose increasing phase in soti protocol. after soti treatment, he could consume 200 ml cow's milk and dairy products without problems. case 3: a 7-year-old male patient followed-up for asthma and cow's milk allergy. it was learned that anaphylaxis developed 2 times after milk consumption. he was fed in accordance with the milk-free diet. he has used fluticasone nebules, montelukast, mometasone nasal spray, and cetirizine. anaphylaxis developed 4 times during the dose increase phase of soti administration. there were many mild to moderate anaphylactic episodes during the maintaining phase. after the soti treatment, he could consume 150 ml milk and dairy products. background: cow's milk protein allergy (cmpa) is one of the most common food allergies in early childhood. small dietetic group sessions for parents of infant with non-ige mediated cmpa were held to meet increasing demands and reduce waiting times. parents were given information on cmpa, advice on weaning and milk reintroduction using a locally designed milk ladder. parents were also advised to contact the dietitians via telephone if they had further questions. we aim to evaluate the sustained effectiveness and patient satisfaction of the group sessions. method: parents and carers who attended the group dietetic sessions held between november 2015 and july 2016 were included in the survey. feedback were obtained via a self-designed questionnaire using a likert-type scale, rating several questions from 1 (least satisfied) to 5 (most satisfied). initial feedback was obtained directly after the session. we followed these patients up a year after the initial session via telephone and postal questionnaire. results: overall attendance rate of the 9 group sessions held was 58% (n = 40). during the initial survey, participants found the group session useful (mean score 4.7 out of 5) and felt more confident in managing cmpa (mean score 4.8). we successfully obtained follow up feedback from 13 participants. majority agreed that the group sessions have been informative (mean score 4.8). they also said they felt confident weaning their child on milk-free diet (mean score 4.8), and in reintroduction of cow's milk in diet (mean score 4.3). 30% (n = 4) said that they would have preferred an individual session. 38% (n = 5) have contacted the dieticians via telephone after the initial session, and 15% (n = 2) had requested individual consultations. 69% (n = 9) have attempted reintroduction of cow's milk in their child's diet using our local milk reintroduction guide. the mean age at first challenge was 14 months (age range 6 to 26 months), with average of two attempts. 31% (n = 4) have been successfully challenged and are managing well on a normal diet. we recognised the limitation in obtaining feedback via telephone and postal questionnaire, which resulted in the poor follow-up response rate. overall, parents felt more confident in managing cmpa and the positive responses were sustained a year on, highlighting the success of these group sessions. follow up opt-in sessions could be offered to provide additional support and allay parental anxiety in challenging their child with cow's milk at an appropriate age. results: goats and rabbits were immunized with specific allergoids, the allergoid-specific igg titer determined and sera pools produced. the allergoid reference material was comprehensively characterized. while ige reactivity of the allergoids was not detectable anymore, igg reactivity was maintained. allergoid-specific assay parameters as serum dilution, reference dilution and sample dilution factor to obtain at least six data points within the pseudo-linear range of the inhibition curve were determined. with these set parameters the evaluation of the analytical method was performed. the assay showed very good results in terms of linearity, accuracy, precision, reproducibility and robustness for all investigated allergoids as well as aluminum-adsorbed allergoid-preparations. conclusion: with the developed immunological inhibition assay, it is possible to determine the specific igg reactivity of allergoids in different preparations. the performance of the analytical method met all pre-defined acceptance criteria, which will be confirmed in the next step by a validation procedure according to ich-guidelines. case report: we present the case of a 32-year-old patient, diagnosed with rhinitis and asthma due to sensitization to pollens, as well as dyshidrosis and allergic contact dermatitis to cobalt. the patient presented a cutaneous pattern consisting of erythematous papules, some scaly, very pruritic, of initial appearance in the upper limbs 2-3 days after initiation of administration of specific immunotherapy extract (depigoid forte grasses, leti ® ). subsequently generalize lower limbs and neck. she presented them repeatedly and late after 2-3 days of the first 3 doses administered. she referred partial control of pruritus with oral antihistamines, without total resolution of lesions for weeks. immunotherapy was suspended persisting the skin lesions for 3 more weeks. according to the personal history of sensitization to metals, and the clinic presented in a temporal relationship with the use of an extract of immunotherapy with aluminum hydroxide, a study was requested with epicutaneous tests with aluminum hydroxide as well as with epicutaneous tests with immunotherapy extract. aluminium hydroxide and depìgoid forte grasses extract epicutaneous test were negative. in subsequent visits the patient reported that coinciding with the start of immunotherapy, presented at home and mainly in her bedroom a plague of cimex lectularius, popularly known as bedbugs, proving that they had been the cause of bites on their skin, and later skin reaction. patient reported that with the elimination of said pest the skin lesions disappeared. the administration of its immunotherapy extract was tolerated. cimex lectularius, commonly known as bed bugs, is a hemiptera insect of the family cimicidae. the clinical picture usually corresponds to multiple pruriginous lesions from the prurigo type, to multiple erythematous plaques, some infiltrated and others with a urticarial appearance, or even bullous. the lesions last for 3 to 6 weeks without treatment, and while the older ones heal, new ones may appear. in our patient it was not considered as an initial diagnosis, having considered immunotherapy as an etiological factor, but we must not forget that although in our country it is not a reason for frequent consultation, either due to underdiagnosis, because of the transitory nature of the pathology or because of scarce number of causative agents, it is important to consider insect bites in the differential diagnosis of dermatosis. di cara g; salvatori c; testa i; pacitto a; bizzarri i; isidori c; tarsia m; esposito s università degli studi di perugia-dipartimento di scienze chirurgiche e biomediche, perugia, italy background: house dust mites (hdm) are one of the most important allergens involved in childhood respiratory diseases, and the most frequently prescribed extract for sublingual immunotherapy in children (slit). despite the improvement of standardization methods for the production of slit, the differences in cultivation and purification processes used to produce raw materials for specific immunotherapy extracts may still impact on the final composition of mite allergen extracts. our study investigated the total protein and main allergen content of five commercial hdm sublingual immunotherapy extracts using sds-page and immunoblotting. recombinant allergens of group 1 and group 2 major allergens were used to test the immunogenicity of such extracts. method: hdm slit extracts were purchased from five italian suppliers (alk-abellò, allergy therapeutics, anallergo, lofarma, stallergenes). the protein composition of extracts was evaluated analysing equal volumes (15 ml/lane) by sds-page (12% separating gel) and subsequent immunoblotting. for identification of allergens in the extracts, western blot analyses were performed with rabbit monoclonal antibodies (raybiotech) against der p 1 and der p2. the total protein content in the five tested commercial extracts showed a relevant variability. the protein contents ranged from 32.9 to 44.2 μg/mg for what concerns der p1, while der p2 showed a greater variability, ranging from 4.2 to 14.6 μg/mg. sds-page showed a similar pattern of distribution in 3 of the tested extracts, which showed protein bands of comparable intensity, while 2 extracts showed a lower total protein count. extract 2 showed a higher intensity band corresponding to the molecular weight of tropomyosin. western-blotting showed a similar concentration of der p 1 in most extracts, while der p2 was more variable. conclusion: our analysis of five commercial extracts commonly used for sublingual specific immunotherapy against hdm showed important variations in term of total protein content. a less evident but still relevant difference was also evidenced when testing the major allergen content, with up to 25% variation in der p1 and up to a 3-fold variation in der p2 concentration. this differences, likely related to the different production and extraction methods, could still be responsible of a different immunological response in children who underwent slit. method: we evaluated 29 children who had completed their immunotherapy treatment. along with demographic data we were able to record skin prick test (spt) results and mrqlq at start and end of treatment. we only included patients who had completed pre and post treatment questionnaires in the study to allow a comparison. the scores were evaluated using a student t test. results: patients' starting age ranged from 6 to 17 years (mean 11 years). 29 of the 48 children had completed pre and post treatment questionnaires. all 29 had grass pollen allergy confirmed on spt at the start of treatment. 10 patients (34%) had isolated grass pollen allergy on spt and 19 (66%) had multiple allergies. mean start treatment score for all patients was 37 on mrqlq. mean score at end of treatment was 24, indicating a 35% reduction in total mrqlq score (p value <0.05). for those with multiple allergies the mean total mrqlq scores were 33 at start of treatment and 25 at end of treatment, indicating a 27% reduction (p value 0.16). for those with isolated grass pollen allergy scores were 44 at start of treatment and 23 at end of treatment indicating a 50% reduction (p value <0.05). conclusion: for children with uncontrolled symptoms of allergic rhinoconjunctivitis, grass pollen immunotherapy is associated with statistically significant improvement in quality of life. this improvement is most beneficial for patients with isolated grass-pollen sensitivity on spt. those with multiple aeroallergen sensitivities on spt did show an improvement (not statistically significant) post-treatment. grass-pollen immunotherapy is an effective treatment for rhinoconjunctivitis to offer patients in a rural dgh setting. background: allergic asthma is a common clinical refractory disease, most patients with asthma are accompanied by varying degrees of allergy. in clinical practice, treatment of this disease using specific immunotherapy has proven effective. in the current study, we examined the effectiveness of specific immunotherapy in a total of 99 patients admitted to our hospital from 2015 to 2016. method: to investigate the clinical efficacy of allergic asthma-specific immunotherapy. 99 patients were selected, of which 49 were males, aged 22 to 61 years, 50 females, aged between 23 to 64 years old, all patients were clinically diagnosed only as allergic asthma. the 99 patients were randomly divided into two groups, including the observation group containing 50 cases, the control group of 49 cases. all patients were first treated with conventional basic treatment. the observation group was subsequently treated with specific immunotherapy. both groups were followed-up and the treatment efficiency were analyzed. results: after treatment, both two groups of patients showed improvement, in the observation group, the effective rate was 93%, while for the control group, the effective rate was 75%. observation group showed significantly better outcomes than the control group. conclusion: in allergic asthma treatment, adding specific immunotherapy on the basis of routine treatment is beneficial and could be widely used in clinic. case report: atopic dermatitis(ad)is the most common itchy dermatosis that affects millions of children and adults. during recent years, diagnosis and treatment based on component resolved diagnostics (crd)is recommended. we report a 9-year-old boy with severe atopic dermatitis. he had positive family history of atopy. the atopic dermatitis was developed since infancy. he was referred to our clinic when he was 5 years old. he had generalized xerosis with ulcerative eczematous lesions on his neck, popliteal and antecubital areas. he had mild eosinophilia and his serum total ige level was 590 iu/ml. daily bleach bath, moisturizing agents, topical steroids and systemic antibiotics in addition to antihistamine were prescribed. he had multiple food and aeroallergen sensitization in skin prick test (spt). he started to eliminate some foods according to the spt results. he was suffering from recurrent relapse even after strict food avoidance; so treatment with cyclosporine was initiated for him, with partial response. crd showed sensitization to alternaria alternata (alt a1 specific ige:10.97 ku/l). allergen immunotherapy by alternaria alternata was started. after accomplishment of buildup phase, he had significant improvement and we were successful to taper and finally discontinue cyclosporine. now he is on maintenance phase of immunotherapy, his skin is in optimal condition only by hydration and moisturization. result: a 15-year-old thai girl is a known case of severe asthma since one year old. her asthma was uncontrolled asthma even treatment with high dose combination of inhaled corticosteroid and long acting beta agonist (ics/laba), montelukast and omalizumab. spirometry revealed the force expiratory volume in one second (fev1): 34% predicted, fev1/forced vital capacity (fvc): 48% predicted and 14% improvement of fev1 after salbutamol 400 ug inhalation. allergic sensitization showed specific ige to cat: 2.04 kua/l. slit with cat allergen started at the dose of 450 au per month and increased to 1500 au per month (scit dose is 1000 au per month) for three-year-and-six-month course. after slit, her asthma symptom improved significantly. she can exercise without exacerbation and plays sport at school. her last episode of asthma exacerbation was 1.5 year ago. her fev1 (% predicted) was improved from 34% predicted to 48% and the fev1 bronchodilator response decreased from 14% to 6%. conclusion: an improvement of pulmonary function and asthmatic symptoms of the presenting case would support the efficacy of slit of cat allergen in a patient with severe asthma. ra developed during pollen scit in this case might be related with immunomodulation effect of immunotherapy. background: we report a case of 20-year-old woman with allergic rhinoconjunctivitis and mild persistent asthma due to sensitisation to seasonal pollens and molds with bad clinical evolution and not response to conventional drug therapy. we decided to start subcutaneous allergen specific immunotherapy with alternaria extract in our immunotherapy unit in accordance with the guidelines of the european academy of allergology and clinical immunology (eaaci) and we used a cluster regimen. the immunotherapy was not well tolerated: the patient had two grade 2 systemic reactions with the first dose in two attempts. method: sensitisation was diagnosed through skin prick test with aeroallergens standard panel and serum specific ige by elisa. due to the bad tolerance to immunotherapy, molds molecular diagnosis by immunocap, study of the molecular weight to specific ige binding proteins by sds-page ige immunoblotting, and cross-reactivity study by means of immunoblotting-inhibition assay were performed. a. fumigatus extract was able to produce a total ige binding inhibition on the 38 kda band of a. alternata extract when ige immunoblotting assay was performed. conclusion: respiratory allergic disease due to alternaria is difficult to control, the use of subcutaneous specific immunotherapy could be of significant benefit. most of the allergic patients to a. alternata are sensitized to alt a1, major allergen from a. alternata. however, our patient is sensitized to a 38 kda alternaria protein due to cross-reactivity with a. fumigatus allergens, this sensitization could explain the bad tolerance to the alternaria immunotherapy. background: the association between natural pollen exposure, clinical symptoms as well as allergen-specific immune responses has not been investigated at a molecular level. our aim was to monitor the effect of seasonal birch and grass pollen exposure on clinical symptoms as well as specific b cell and t cell responses to defined allergen molecules in sensitized subjects during two consecutive years. method: grass pollen sensitized (n = 10) and birch pollen sensitized (n = 13) subjects were included in this study and were followed for two consecutive years (2013) (2014) . subjects were taking part in a clinical trial for the recombinant grass pollen vaccine (bm32) but did not receive immunotherapy for the allergen they were sensitized to. before, during and after the respective seasons ige and igg levels as well as t cell responses to the major birch pollen allergen bet v 1 and the major grass pollen allergens phl p 1, 2, 5 and 6 were measured. pollen counts were recorded throughout the year and patients kept a daily diary including symptom medication score (sms) and visual analogue scale (vas). results: we noted that ige levels specific for bet v 1 and the grass pollen allergens increased most in the seasons in which patients experienced the highest peak symptoms according to vas and sms but not depending on cumulative pollen counts. increases in allergen-specific t cell responses were observed in the pollen seasons as compared to shortly before the pollen seasons in the grass pollenallergic patients also in association with vas and sms but not in the birch pollen allergic subjects. no relevant changes of allergen-specific igg levels were observed during the two years observation in grass and birch pollen allergic patients. we found an association of increases of allergen-specific ige increases shortly after the pollen season with clinical symptoms in the pollen season as reflected by vas and sms which was not necessarily reflected by cumulative pollen counts in the season. these results may be important for the analysis of allergen-specific immunotherapy trials. background: the morbidity and mortality of severe asthma is much higher than that of mild to moderate asthma. this study was performed to understand the clinical characteristics of severe asthma in korea. results: data from the questionnaire showed that bronchial asthma was diagnosed before pregnancy only in 193 women (4.83%). 43 patients (1.1%) were diagnosed with chronic bronchitis at the pregestation stage. asthma attacks were experienced repeatedly during a lifetime in 4.2% of patients, 12.7% of patients noted long periods of dry cough at night, among them 8.1% had wheezing. the cold did not precede the wheezing breathing in 5.1% of patients. difficulty in breathing on waking was noted in 2.6% of patients, at night-4.3%. after examination, the diagnosis of asthma was confirmed in 14.65% of the respondents (586 people). symptoms of rhinitis are noted in 58% of women surveyed, 18% of rhinitis was allergic. before examination, the diagnosis of ar was only in 3.5% of patients. the incidence of symptoms of asthma and ar in pregnant women is significantly higher than the reported cases of these diseases, which leads to untimely initiation of treatment. method: a total of 117 nonsmoker asthmatic patients without concomitant pulmonary pathology are recruited to our study. all patients underwent spirometry tests, measurement of fraction of exhaled nitric oxide and sputum induction to asses sputum cell counts, demographic features and current medications were recorded. using the variables of age at onset, bmi, allergy status, fev1%, fev1/fvc, asthma severity and induced sputum cytology cluster analysis is performed. results: 4 clusters are identified. cluster1: (n = 43) early onset atopic asthma, consists of mild asthmatics with a good asthma control and lower bmi. cluster 2: (n = 14) severe atopic asthma, consists of lowest spirometry measurements with a least act scores. induced sputum cytology shows a neutrophilic character, while having also the highest percentage of eosinophils. cluster 3 (n = 27) late onset obese asthma, nonatopic asthmatics having high spirometry measurements, with a lower act scores. cluster4 (n = 33) nonatopic mild asthma, consists of patients with the best respiratory functions and least inflammation in means of lowest total ige, feno, sputum cell counts. conclusion: identification of asthma phenotypes in different countries will improve our understanding on the heterogeneity of the disease among the different geographies. results: results and discussion. in the course of analysis, obesity was more common in children with bronchial asthma −25% than in the comparison group-in 9.3%. obesity of the 1st degree was diagnosed in 10 patients of the main group, ii degree-in 8, and iii degree-5 and iv degree-in 2 patients e diagnosis of obesity, the sds indices of body mass index (bmi) were determined. obesitymore than +2.0 (i degree: sds bmi 2.0-2.5, ii degree: sds bmi 2.6-3.0, iii degree: sds bmi 3.1-3.9, iv degree: sds bmi ≥4.0). conclusion: thus, the results obtained indicate a high prevalence of constitutional-exogenous obesity in children with bronchial asthma and precedes the formation of the underlying disease e diagnosis of obesity, the sds indices of body mass index (bmi) were determined. obesity-more than +2.0 (i degree: sds bmi 2.0-2.5, ii degree: sds bmi 2.6-3.0, iii degree: sds bmi 3.1-3.9, iv degree: method: postal questionnaires were distributed to an unselected group of asthma patients (n = 190). healthy non-asthmatic volunteers were recruited amongst university and hospital co-workers (n = 53). the presence of self-reported nhr, the type of triggers evoking nasal symptoms, asthma phenotype, medication use and environmental factors were evaluated. results: 114 patients and 53 controls completed the questionnaire (responder rate of 60% and 100% respectively). nhr was reported in 71% of asthma patients and 22% in non-asthmatic controls (p < 0.0001), with changes in temperature being the most important inducer of nasal symptoms (74% of asthmatics), followed by strong odours (62%) and cigarette smoke (61%). interestingly, nhr was more prevalent in patients with severe (79%) compared to mild (50%) asthma symptoms (p = 0.015), and more prevalent in atopic (77%) compared to non-atopic (55%) asthmatics (p = 0.028). most asthma patients reported more than one trigger evoking nasal symptoms, with 44% of patients reporting 3 or more triggers evoking nasal symptoms. results: the mean score of cbcl questionnaire in case group with 28.12 ± 2.06 was significantly higher than in comparison with a control group with 17.33 ± 9.7 (p = 0.01). the mean scores of the subscales of social isolation (the case group: 5.83 vs control: 1.18, p = 0.006), anxiety-depression (4.99 vs 2, p = 0.22), intellectual problems (4.8 vs 2.3, p = 0.000), and aggressive behaviors (5.1 vs 2.3, p = 0.003) were significantly higher in children with asthma than in healthy children. the study showed a significant correlation between the mean duration of asthma and a general score of cbcl (p = 0.012, cc=0.8). moreover, there was also a significant correlation between asthma severity and cbcl scoring (p = 0/001, cc=0.03). conclusion: behavioral disorders in children with asthma are significantly more than healthy children. the duration of asthma and the severity of asthma, are related to and can predict behavioral disorders in children with asthma. background: assessment of asthma control is an integral part of the management of asthma. whilst asthma control test (act) is a commonly used questionnaire to assess symptom control, its utility in predicting long term risk of exacerbation has not been well studied. aim: to analyze the factors associated with uncontrolled asthma symptoms using act and its impact on predicting future exacerbation. method: severe asthma patients on at least step 4 background: most of the asthma-scoring tools detect the asthma severity from patients' symptoms but there is no scoring tool using parameters to define risk of asthma exacerbation. thus, this study use factor analysis to evaluate the relationship of parameters in childhood asthma. method: the descriptive study using factor analysis in asthmatic children aged less than 15 years old, who attended thammasat university, the center of excellence for allergy, asthma and pulmonary diseases, thailand. the participants or caregivers were inter the factors which have the major impact on asthma control are changing bed sheets less than once per month and using dust mite-proof bed sheets. this study is supporting non-pharmacological strategies but further studies are needed to create a more efficient asthmatic symptom checker. were not different between the controlled and uncontrolled group. the act score in the controlled group was significantly higher than the uncontrolled group (p < 0.001). the study showed that cigarette smoke is one of the significant factors that can trigger asthma exacerbation (p < 0.001) and mosquito repellent coil smoke is also significantly associated with asthma exacerbation (p < 0.03 background: experimental studies have demonstrated that tumor necrosis factor family member 14 (tnfsf14/light) plays an important role in airway remodeling. there is little data available concerning in vivo regulation of tnfsf14/light expression in humans. the aim of this study was to evaluate serum concentration of tnfsf14/ light in different subsets of asthmatic patients. the study was performed on 36 nonsmoking asthmatic patients (a), including 24 mild-moderate-severe asthmatics controlled on inhaled corticosteroids (aics) and 12 asthmatics evaluated twice during asthma exacerbation (aex) and during subsequent remission (arem). in addition age and sex matched 24 nonsmoking healthy controls were included (hc). serum tnfsf14/light concentration was evaluated using elisa method. in asthmatic patients lung function tests, exhaled nitric oxide concentration (feno), serum total ige concentration (t-ige), allergen-specific ige concentration (s-ige) and peripheral blood eosinophilia were evaluated. (250 + /-134 pg/ml) was significantly greater than that in hc (72 + / -32 pg/ml; p < 0.001). among all asthmatic patients studied the greatest tnfsf14/light serum concentration was demonstrated in aex (357 + /-79 pg/ml), which was significantly greater than that in aics (194 + /-123 pg/ml p < 0.001). during resolution of asthma exacerbation a significant decrease in serum tnfsf14/light concentration (118 + /-70 pg/ml; p < 0.001) was demonstrated. in arem the mean serum tnfsf14/light concentration was comparable to that seen in aics (p = 0.06) but was still significantly greater than in hc (p < 0.01). no significant correlation could be demonstrated between serum tnfsf14/light concentration and baseline lung function parameters, exhaled nitric oxide concentration, serum t-ige or s-ige concentration or peripheral blood eosinophilia. conclusion: enhanced production of tnfsf14/light seen in asthmatic patients, which is further upregulated during asthma exacerbations may play an important role in asthma pathogenesis. method: two models of aspergillus fumigatus-induced allergic airway inflammation were used in the study: long terms (4 weeks) and short terms (2 weeks background: chalcone 4 is identified as an inhibitor of the interaction between cxcr4 or cxcr7 and their ligand cxcl12. therefore it is called a neutraligand. the chemokine cxcl12, interacting with the cxc-receptor4 (cxcr4) can play a role in the progression and development of bronchial asthma. asthma is defined as a chronic disease characterized by episodes of obstructive events which affects about 300 million people over the world. the aim of this study is to approach the mechanism of the anti-inflammatory effect of the cxcl12 neutraligand chalcone 4 and also to assess its impact on the migration of dendritic cells in a murine model of allergic airway inflammation. method: chalcone 4 is administered intranasally to balb/c ovalbumin (ova) asthma mice and control groups as well. our results indicate that the cxcl12 neutraligand chalcone 4 can modify the inflammatory reaction in an airway allergic hypereosinophilia model. furthermore, found out that cxcl12 neutraligand chalcone 4 prevents dc migration to the airways and airway jnc ganglia during allergic airway inflammation. the detection of the cxcr4-cxcl12 pathway and its role in the pathophysiological actions of asthma offers a promising target for allergic diseases treatments. method: four groups of balb/c mice were defined: control and asthmatic, with and without treatment. asthmatic groups were sensioverexpression of ptgdr in pulmonary cells associated to a generalized increase of cytokine expression. conclusion: in a mouse model we confirmed the involvement of ptgdr in allergic asthma by the increase of its expression levels after ovalbumin sensitization. we also identified a reduction of ptgdr levels in response to dexamethasone treatment. the in vitro model suggests that ptgdr induces an inflammatory response, increasing the cytokines levels. 0979 | immune imbalance between transcription factor t-bet/gata3 and allergic asthma results: t-bet mrna expression of peripheral blood lymphocytes in patients with allergic asthma was lower than that of the normal control group, and the expression level of gata-3 mrna was higher than that of the normal control group (p < 0.05). the th1 percentage of peripheral blood lymphocyte subsets was lower than that of the normal control group (p < 0.05), the percentage of th2 cells was significantly higher than that of the normal control group (p < 0.05), and the changes in t-bet/gata3 expression and th1/th2 ratio was highly correlated. our objectives were to assess the changes of bmp4 and bmp7 serum levels in the response to allergen and methacholine challenge tests and the correlation between bmp4 and bmp7 serum levels and fev1 before and after allergen and methacholine challenge tests. method: study group consisted of 59 patients with asthma and 48 healthy volunteers. spirometry, skin prick tests, allergen and methacholine challenge tests were performed in compliance with eaaci, ers and ats guidelines. personalized clinic surveys including act ™ were performed. venous blood was collected before and after 1 hour, and 24 hours afterwards the provocation to edta-ke-filled test tubes. evaluation of bmp4 and bmp7 serum protein levels was performed using specific elisa immunoassay kits according to the manufacturer's protocol. results: the increase in bmp4 and bmp7 serum level 24 hours after provocation test correlates significantly with the concentration methacholine during provocation time (p < 0.05). bmp7 serum level before the provocation, 1 hour and 24 hours after provocation, correlates negatively with fev1 change (p < 0.05). the median bmp7 level 24 hours after provocation was significantly lower in patients with negative methacholine challenge test compared to the control group (p = 0.03). the median bmp4 level 24 hours after provocation was higher in patients with positive allergen provocation test than in patients with negative test results (p = 0.03). the bmp7 serum level 24 hours after positive methacholine test is lower and correlates inversely with fev1 change in every time point, which could indicate that serum level of bmp7 is a predictive factor of fev1 change. the higher bmp7 serum level, the lower fev1 change was observed. this could suggest the protective influence of bmp7 in patients with obstructive pulmonary disease, i.e. asthma. the higher bmp4 serum level 24 hours after positive allergen provocation test result shows that the bmp4 could be an indicator of the response to a specific trigger. background: inflammation and coagulation are closely linked events. thrombin is the key enzyme in coagulation system. besides its well-known functions in hemostasis, thrombin plays a role in inflammation. the aim of our study was to evaluate thrombin generation in children with mild asthma and demonstrate associations between thrombin levels and control of asthma. method: forty-two children with mild asthma and forty-nine healthy children included in the study. asthmatic children had no asthma exacerbation during the last 6 months. patients (n = 27) who had mild persistent asthma, were using either inhaled steroid or montelukast. all patients performed spirometry. thrombin levels were measured by thrombin generation test. thrombin peak levels, endogenous thrombin potential, thrombin lag time, time to thrombin peak and thrombin tail time were recorded. results: thrombin lag time was significantly longer in children with asthma (3.98 ± 1.2) compared to those in control group (3.29 ± 0.6) (p < 0.01). children with asthma also had longer thrombin tail time compared to control group (19.5 ± 8.9 vs 16.7 ± 2.9, p = 0.02). thrombin peak was inversely correlated with fef 25-75 (-0.41, p < 0.01). thrombin lag time was inversely correlated with fef 25-75 (-0.39, p < 0.01). thrombin generation parameters did not show difference according to asthma control treatment, asthma control scores and having atopy. conclusion: coagulation/anticoagulation balance is disturbed in mild asthma but this disturbance may not be as strong as to increase thrombin levels. factors increasing inflammation may cause an increase in lag time, and increase in inflammation and excessive fibrin deposition may contribute to airway narrowing. background: cytokines represent key mediators in the onset and persistence of inflammatory process, in both asthma and copd. il-31, which belongs to il-6 family, it might act in a similar way with il-6 at the beginning of the inflammatory process. its role in atopic skin diseases has already been demonstrated, but there are conflicting results related to its role in respiratory allergic diseases. the aim of the study was the evaluation of il-31 plasmatic level in patients with asthma and copd and the its correlation with clinical and lung function parameters. method: fifty consecutive patients with bronchoobstructive diseases were included in the study. thirty-two patients presented asthma and 18 patients had copd. the evaluation included: number of exacerbation in the last year, disease's severity, spirometry. plasmatic levels of il-31 and il-10 were determined in all patients. results: the mean age was higher in patients with copd dermatophagoides pteronyssinus [house duste mite (hdm), 100ug/ mouse] were administered oro-tracheally on days 0, 7, 14, 21, 28, 35, 42 and 49 . at was performed in a treadmill during 4 weeks in moderate intensity, from day 24 until day 52. results: at inhibited hdm-induced total cells (p < 0.001), eosinophils (p < 0.01), neutrophils (p < 0.01) and lymphocytes (p < 0.01) in bronchoalveolar lavage (bal), and eosinophils (p < 0.01), neutrophils (p < 0.01) and lymphocytes (p < 0.01) in peribronchial space. at also reduced bal levels of il-4 (p < 0.001), il-5 (p < 0.001), il-13 (p < 0.001), cxcl1 (p < 0.01), il-17 (p < 0.01), il-23 (p < 0.05), il-33 (p < 0.05), while increased il-10 (p < 0.05). airway collagen fibers (p < 0.01), elastic fibers p < 0.01) and mucin (p < 0.01) were also reduced by at. at also inhibited hdm-induced airway hyperresponsiveness (ahr) to methacholine 6.25 mg/ml (p < 0.01), 12.5 mg/ml (p < 0.01), 25 mg/ml (p < 0.01) and 50 mg/ml (p < 0.01). mechanistically, at reduced the expression of stat6 (p < 0.05), stat3 (p < 0.001), stat5 (p < 0.01) and jak2 (p < 0.001), similarly by peribronchial leukocytes and by airway epithelial cells. socs1 expression (p < 0.001) was upregulated in leukocytes and in airway epithelial cells, socs2 (p < 0.01) was upregulated in leukocytes and socs3 down-regulated in leukocytes (p < 0.05) and in airway epithelial cells (p < 0.001). conclusion: at reduces asthma phenotype which is followed by positive modulation of socs-jak-stat signaling in peribronchial leukocytes and in airway epithelial cells. rodolfo a 1 ; paciência i 2 ; rama t 1 ; leão l 1 ; silva d 3 ; rufo j 2 ; mendes f 4 ; padrão p 5 ; oliveira fernandes e 6 ; moreira p 7 ; delgado l 8 ; moreira a 9 porto, portugal; potentially irritating chemicals that may have a cutaneous drying side effect. this study aimed to evaluate if skin barrier function, as measured by transepidermal water loss (tewl), is affected by a training session in swimmers compared with football players. environment impact on the human respiratory health (clinicaltrials.gov identifier: nct03017976) and football players were invited to participate. due to the lack of prior information no sample size calculation was possible and all athletes that provided informed consent were included in the analysis (n = 58, 29 females, aged 12 to 21 years). tewl was measured using the tewameter ® tm 300 before, immediately after, and 30 minutes after a 2 hours training session. the probe was held on the dorsum of hand, the volar forearm and the antecubital flexure for 60 s. the average of two consecutive measurements was recorded. non-parametric statistic was used were appropriate. ethical approval was obtained from the university clinical research ethics committee and informed consent provided. results: mann-whitney u test showed significantly higher baseline median tewl level on football players hand's dorsum compared with swimmers, median (p25-p75) respectively 17.1 (14.7 to 21.7) and 13.7 (11.9 to 16.2); p = .001. friedman test revealed a significant effect of swimming on tewl on the hand's dorsum, volar forearm and antecubital flexure (p < .001) while football training affected only the hand's dorsum (p = .008). differences in changes after swimming and football training were significant only for tewl in volar forearm (p = .028). in conclusion, our exploratory findings do not provide support for a specific deleterious effect of swimming, compared with football training, on the training induced changes in tewl. background: exercise-induced bronchoconstriction (eib) is defined as transient, reversible airway narrowing occurring during or after exercise, is common among elite athletes and associated with epithelial damage. however, little is known about the existence of eib in young athletes. the goal of this study is to investigate the presence and to evaluate potential (bio)markers of eib in young high-school elite athletes in different sport disciplines versus age-matched control subjects. method: high-school selected elite athletes (12-13 years) from different sport disciplines: basketball (n = 26), football (n = 44) and swimming (n = 47) performing at least 12 hours of sport per week (median=13 h) and 17 control subjects (performing less than 6 hours of sport per week) were recruited. the eucapnic voluntary hyperventilation (evh) test was performed according to ats guidelines and adapted for this age group. lung function was measured before, immediately after and 5, 10, 15 minutes after the evh test. the test was considered positive if a maximal fall in fev1 of 10% was measured on at least one time point and exhaustion was excluded. a blood sample was obtained at baseline. sputum induction and skin prick test for the most common allergens were performed after the evh test. results: fifteen swimmers had a positive evh test (33.3%), which is higher than in basketball players (18.2%), football players (17.95%) and controls (17.65%). 40.4% of the swimmers were atopic which is also higher than in basketball players (23.1%), football players (31.8%) and controls (23.5%). serum clara cell secretory protein (cc16) levels are significantly higher in swimmers (7.6 ± 2.5 ng/ml) compared to indoor athletes (5.1 ± 2.2 ng/ml) and controls (5.2 ± 1.2 ng/ml). a significant positive correlation was found between the magnitude of maximal fall in conclusion: young elite swimmers have a higher prevalence of eib compared to basketball and football players. atopy and/or chlorine is a risk factor for the development of eib in young elite athletes. cc16 levels and sputum uric acid levels are increased in athletes compared to control subjects suggesting the presence of epithelial damage already at young age. this is especially observed in young elite swimmers, pointing to a probable role of exposure to chlorineby-products in combination with intensive exercise. results: data from 237 subjects (134 females, 56.5%) were analyzed. frast was positive in 97 (40.9%) patients (55 females, median age of 14 years (iqr 11-18)). in this group, 55 (56.7%) had a previous diagnosis of asthma, 27 (27.8%) practiced federated sports, 18 (18.6%) had smoke cigarette exposition and 3 (3.1%) had a bmi >30 kg/m 2 . 82.5% of patients showed a δfev1% >10% in the first 5 minutes after finishing the challenge. median fev1 reduction was 13.4% ) and 390 ml . frast was more frequently positive in patients with previous diagnosis of asthma (p < 0.01). there were no differences related to conclusion: frast is an important tool to diagnose exerciseinduced bronchospasm without asthma (eib wa ), as well as to diagnose asthma. in our study, frast was fundamental to access eib wa in 28% of patients with rsee, and confirmed asthma diagnosis in 53% of cases with previous asthma diagnosis and negative sbt. there was no difference in the prevalence of atopy between patients with positive and negative frast. patients older than 9 years-old presented higher δfev1% compared to younger patients (p = 0.04). higher levels of feno were observed in patients with positive frast (p = 0.032, p = 0.045), both in patients with and without previous diagnosis of asthma. a positive correlation was observed between feno levels and δfev1% in the whole sample (r = 027, p = 0.009); when these data were analyzed considering a previous diagnosis of asthma, only patients with this condition showed a positive correlation of feno and δfev1% (r = 0.29, p = 0.031). conclusion: our results evidenced that higher feno was associated with atopy and a positive frast, both in patients with and without previous diagnosis of asthma. higher feno seems to correlate with δfev1% in patients with previous diagnosis of asthma. background: specific immunotherapy is the casual treatment for allergic rhinitis. a 28 year old professional footballer suffer from severe allergic rhinitis since two years. during may, june and july his level of playing, concentration and durability decreased about 20%. patient was complaining of runny nose, nasal blockage, each eyes, sneezing, tearing. method: we did skin prick tests -which showed greatest allergy to grass pollen. we confirmed the allergy by specific ige and nasal provocation tests. spirometry was done-fev1 116%. the patient was qualified to undergo specific immunotherapy. however, because of his profession, it was hard to find a day without trainings to get the vaccine. after long discussion, patient decided to start specific immunotherapy-scit. results: the patient start the immunotherapy. he was attuning very irregularly, because of matches, injuries, trips, trainings, and lack of time. several times we had to call the patient to remind him about the immunotherapy. after one year of scit the patient felt big improvement. during grass pollen season he suffered from mild allergic symptoms, and just for few days. after next year of immunotherapy, the patient had no symptoms of allergic rhinitis during the grass pollen season. however, it was the reason for him, to stop sit, before 3rd year of immunotherapy. conclusion: such a treatment-specific immunotherapy-is a burdensome method for both, for professional athletes and doctors. such a patients need to be on special observation, and cooperation with trainers must be obtained, if we want to see results. to improve compliance we have to keep in touch with patients, to remind them about next visit. gherasim a 1 ; choual i 1 ; radu c 2 ; khayath n 2 ; beck n 1 ; jacob a 1 ; schoettel f 1 ; domis n 1 ; de blay f 2 1 alyatec, strasbourg, france; 2 hôpitaux universitaires de strasbourg, strasbourg, france background: late allergic response (lar) is a good asthma model. it has been shown, in individual challenge tests that mite allergen induces more frequently late allergic responses (lar) than cat allergen. the aim of this study is to compare the frequency of lar in asthmatic subjects allergic to mite with asthmatic subjects allergic to cat. method: 24 asthmatic subjects allergic to mite were compared to 21 subjects allergic to cat (gina 1 or 2). the subjects had prick tests≥5 mm compared to the negative controls and specific ige ≥ 0.70 ku/l. the dose selected for the mite and cat allergen was the airborne allergen concentration inducing the most frequently early asthmatic response (ear) (a 20% drop in fev1) and lar (a 15% drop in fev1). results: the frequency of lar with mite allergens was 66.6% and 20% with cat allergens (p = 0.007). the frequency of ear for mites was 78.2%; of 91.3% for ear or lar, and 50% for ear and lar. in contrast, with cat allergens, 55% of patients had an ear, 60% had ear or lar and 25% had an ear and lar. no significant differences was observed between cat and mite allergen regarding the severity and the time necessary to obtain an ear and lar. no significant differences was observed between cat and mite allergen regarding the severity and the time necessary to obtain an ear and lar. the frequency of lar in asthmatic subjects allergic to dust mite exposed in alyatec ® eec was higher than in asthmatics sensitized to cats. our results confirmed previous results with individual bronchial challenge. therefore, it appears that the mite model is more interesting in the study of asthma. exposure chamber in strasbourg (alyatec ® ) in asthmatic patients allergic to cat allergens gherasim a 1 ; choual i 1 ; radu c 2 ; khayath n 2 ; beck n 1 ; jacob a 1 ; schoettel f 1 ; domis n 1 ; de blay f 1 1 alyatec, strasbourg, france; 2 hôpitaux universitaires de strasbourg, strasbourg, france background: as recommended by the task force on environmental exposure chamber (eec), allergenic and non-allergenic exposure must be better controlled in eec. it is the aim of alyatec's eec. the aim of the study is to validate alyatec's eec by determining the concentration of fel d1 inducing 50% of early asthmatic response (ear) and/or late phase asthmatic response (lar) in subjects sensitized to cat. method: it was a randomized, double blind, cross-over study including group a:20 asthmatic subjects allergic to cat and group b:10 asthmatic subjects allergic to another allergen. all subjects were first exposed to placebo. group a was exposed to 2 fel d1 concentrations. the number and size of particles were recorded online during the exposure. group b was exposed to the concentration of fel d1 which fulfills the objective of the study. the mean age of subjects was 29 years (±8). for the 2 concentrations of fel d1, we obtained more than 50% ear and/or lar. the mean time necessary to obtain an ear was: 59.7 ± 8 minutes and 138.6 ± 90 minutes for the lar. the mean fall in fev1 during ear and lar was −29.22% and −17.64% respectively. we didn't observe any severe reaction. no subjects in group b experienced any symptoms during exposure. we have validated alyatec's eec in asthmatic subjects allergic to cat allergens. we also demonstrated its specificity. background: the best test and strategy for diagnosing asthma especially in those patients with negative bronchodilator reversibility tests still remains unclear. in this study we aimed to investigate the diagnostic yield of peak expiratory flow (pef) variability for the patients with symptoms suggesting asthma but negative bronchodilator reversibility tests. method: subjects referred to our outpatient clinic with suspicion of asthma were enrolled in this study. demographics and referral symptoms were recorded, asthma control test (act) scores and health related quality-of-life scores (aqlq, sf36) were calculated. monitoring of pef variability during 2-weeks and bronchial challenge test with methacholine (bpt) were analyzed. asthma was diagnosed by having pef variability ≥20% and/or positive bpt. results: thirty out of 50 enrolled patients were diagnosed as having asthma. when we compare asthmatic patients with nonspecific respiratory symptomatic subjects there were statistically-significant differences regarding to wheezing (p = 0.020), activity limitation (p = 0.058), total symptom score (p = 0.028) and basal fef (p = 0.050) in the favor of asthma cases. multiple logistic regression analysis revealed that lower basal fef 25-75 was an independent predictive factor of asthma diagnosis (p = 0.05). when the bpt positivity was assessed as gold standard for the diagnosis of asthma, the sensitivity and specificity of pef variability for different cut-offvalues (≥20%, >15% and >%10) were 61.5-83.3%, 88.5-62.5% ve 100-16.7%, respectively. conclusion: fef 25-75 is an important diagnostic parameter for asthma. although current guidelines recommend pef variability of 10% for the diagnosis of asthma in general, this cut off level may not be appropriate for this defined group of subjects. our results suggest to use a cutoff level of >15% while excluding asthma and ≥20% while confirming the diagnosis of asthma for patients with asthma suspicion but without shown reversibility. de barayazarra s background: in recent years obesity has been considered as a factor that contributes to the development of asthma, increases exacerbations and leads to poor control of it due to resistance to drugs to control this pathology. it is known that obesity produces chronic systemic inflammation; one of the markers that are affected is the levels of c-reactive protein (crp), which are increased. objective: evaluate, lung function, the use of medications to control asthma and systemic inflammation, after bariatric surgery. results: 15 obese asthmatic patients with surgery, 15 non-asthmatic obese patients with surgery, 16 obese asthmatic patients without surgery. a significant difference was found between the severity of obesity and forced expiratory volume in patients with asthma and without asthma of 1 second (fev1) before surgery with an average of 87.9% at the beginning of the study and 105.5% at 12 months (p:0.0004). in the non-operated group, fev 1 at the beginning was 69% and 83.04% at 12 months (p: 0.0018). the crp, before surgery in all operated patients had crp: 9, at 12 months after surgery they became negative, crp: 0 (p: 0.004). in obese asthmatics with surgery at the beginning, 100% used medication, and at 12 months only 20% in obese asthmatic patients without surgery, 93.75% used the medication at the beginning, at 12 months 62.5% (p:0.0006). method: 20 patients with asthma aged 18 to 80 and a predetermined positive methacholine pc20 were recruited and underwent a single challenge to cause bronchoconstriction of~20% comparing the outcome of the device with spirometry. the subjects were monitored at baseline, after a~20% fall in fev 1 and after bronchodilation back to baseline. the study protocol allowed for an interim analysis of the initial 8 subjects at which point the sensor was calibrated to optimise sensitivity. a further 12 subjects were studied using the optimised sensor. results: all 20 subjects successfully completed the study. the device was found to be straightforward to use by both operator and subject with no concerns regarding safety. the initial sensitivity of the device was found to be suboptimal in the first eight patients to reliably detect changes in lung function. after adjustment to the device the tests results of the remaining 12 subjects were analysed. 66.6% of subjects were female. the mean age of all subjects was 45.8 years. an average baseline fev 1 value of 2.575 (s.d. 0.881) was observed. changes in lung function were detected in 100% of subjects. a baseline value, drop in lung function and reversal were measured in 66% of subjects. the mean percentage drop observed in 66% of subjects using the investigational device was 13.04 %. the mean percentage increase observed using the investigational from drop to reversal was 25.36 %. the device (using ebc 1 ) was able to detect changes in lung function tracked using fev 1 . this provided proof of concept that the device could potentially be used to monitor lung function more effectively in the home than peak flow and supports further development to optimise the device and demonstrate functionality in clinical asthma. method: ninety four patients under 18 years of age seen in the allergy department due to common asthma symptoms (wheezing, dyspnea, cough, chest tightness) with normal spirometry and negative bronchodilator response, underwent mct during 2016 and 2017. the variables studied were: sex, age, body mass index (bmi), asthma symptoms, exercise symptoms, rhinoconjunctivitis, family history of atopy, sensitization to respiratory allergens, spirometric data and fractional exhaled nitric oxide (feno). results: of the total sample, half were women (51.06%) and the other half were males (48.94%). mean age was 11.8 years. bmi was normal in most of them (with an average of 19.55 kg/m 2 ). the most common symptom among the patients with positive mct was cough (79.8%), followed by dyspnea (62.76%), wheezing (34%) and chest tightness (11.7%). 43.6% had symptoms of asthma with exercise and 70.2% had rhinoconjunctivitis. 37.23% had a family history of atopy. 74.4% were sensitized to aeroallergens, mainly to pollens (grass and olive tree). 75.5% of the mct′s were positives, with a mean pc 20 of 1.89 mg/ml. 62.7% had a moderate-severe result (pc 20 ≤4 mg/ml), 7.4% mild (pc 20 4-6 mg/ml) and 5.3% bordering (pc 20 6-8 mg/ml). the mean feno was 19.62 ppb. conclusion: in our series, the completion of a test of hrb was decisive to confirm the diagnosis of asthma in most patients of a pediatric population with symptoms of suspicion (cough, mainly), normal spirometry and negative bronchodilator response (with normal feno in most of them). therefore, we consider it important to include in the routine clinical practice hrb tests in the pediatric population with suggestive symptoms of asthma, despite normal functional and/or inflammation tests. 1000 | cut-points of the ′control of allergic rhinitis and asthma test′ (carat) asthma subscale based on an international survey patients with asthma) in kashan, iran. the data collection tool was a questionnaire with 38 questions, designed to gather information on demographic asthma patients, the current use of mobile functionalities, and the willingness to use these functionalities to receive selfmanagement services, which was distributed among patients with informed consent. the collected data were analyzed by descriptive statistics method using spss software. results: the most use of patients from mobile phone functionalities was to receive information about asthma symptoms and allergens and irritants via mobile internet (42.1%). patients were most likely to use social networking (31.7%) in comparison with other mobile phone functionalities, to receive reminders about appointments and medication. the respondents were most likely to use social networks through mobile phone functionalities, to receive asthma self-management information (53.1%), to communicate with other patients (55.9%), to receive reminders about medication use, and to perform a peak flow meter test (52.4%) and to get an alert when the asthma is not controlled (53.1%). the findings show that asthma patients are currently using the internet search for educational information and they have a tendency to use social networks to receive asthma-related services. patients believe that mobile health is an appropriate intervention for providing educational information, reminders, and alerts and communication with other patients. 1002 | concordance between the determination of asthma control through the gina 2015 guidelines and the act questionnaire-results of the efimera study background: the exacerbation of asthma, progressive worsening of acute episodes, is one of the most frequent attending reasons at hospital emergency unit 1 . several factors causing poor control of asthma, such as inadequate therapy, have been described. in the present study, estimations of asthma severity by researchers were assessed by comparing the concordance between the assessment of asthma control through the gina 2015 guidelines and the act questionnaire method: cross-sectional observational study on the evaluation of factors related to treatment that influence the poor control of asthma was assessed through the gina guidelines and the act questionnaire. patients referred to a pneumologist or allergist by a primary care for the first time were evaluated. two variables were collected for the assessment of asthma control: one derived from the gina 2015 guidelines and another derived from the act questionnaire. regarding the gina assessment, researchers' evaluations guidelines were compared with the scoring calculated from the variables registered in the crd. both measures were compared in terms of sensitivity-specificity to determine their ability to classify patients. the patients included in this study (n = 1682) had a mean age of 45 ± 17 years, with a 64% of women and an average disease evolution of 14.9 ± 14.1. the control of asthma according to "gina results: pts were reasonably representative of those in sls asthma (at sls baseline: 43.8% male; mean age 48.4 yrs; mean asthma control test [act] score 16.5) . the most frequently reported symptoms during sls asthma for these pts were cough/ breathlessness, followed by wheeze, phlegm and chest tightness; breathlessness and wheeze were perceived as the biggest impactors on pts' lives. the aspects of daily life most impacted by asthma were reported as walking at a hurried pace, strenuous physical activity, and asthma-related frustration. since sls began, 50% of pts in this subset reported improvements in overall asthma (44% no change; 6% worsening). perceived changes in symptoms are shown (table) . most pts (66.0%) reported avoiding places with dust, smoke or fumes. most pts (57.5%) perceived no change in overall qol; 36.3% reported improvement. being an act responder during sls (total act score ≥20 or ≥3 change at end of sls) was associated with reported improvements in overall asthma symptoms, lower impact of asthma on qol, and higher perceived confidence/control in managing asthma. more pts (65.8%) in the ff/vi arm reported an overall improvement in asthma vs uc (34.3%); the most evident differences between treatment groups were for breathlessness, wheezing and chest tightness. improvements in confidence/control in managing asthma were reported by 53.8%/49.3% of pts (ff/vi) vs 31.3%/25.3% (uc). conclusion: breathlessness and wheezing were key symptoms in sls asthma and had the biggest impact on pts' daily lives. this patient-centred study enriches the findings of sls asthma. funding: gsk (study 204500) 1004 | asthma and copd treatment adherence and breach using tai questionnaire suarez-vergara m; fuentes-soltero f; garcia-nunez i; ignacio-garcia j background: adherence is defined as medication (inhalator) intake following the dosage and schedule prescribed. adherence mistakes are a public healthy problem according to the big morbi-mortality presented in patients with an incorrect intake. our aim is to evaluate the adherence level and fulfillment in patients with asthma or copd using tai (inhalators adherence test) questionnaire. method: patients with a diagnosis of persistent asthma or copd were selected. we used to size adherence and breach type the tai questionnaire. adherence is defined as good when patient′s test reaches 50 points, medium (46-49 points) and bad (less than 45 points). breach type is defined as erratic when points between questions 1 to 5 are less than 25, deliberate when questions 6 to 10 are less than 25, and unconscious when questions 11 and 12 are less than 4 points. a correct fulfillment is defined when questionnaire reaches 50 points plus 4 points of conscious fulfillment. results: fifty-five patients more than 14 years old (mean age 50.61 years and 50.9% males) were selected. a 67.27% of them were asthmatics, 30.9% copd and 1.81% a mix phenotype. a 21.81% presented a correct fulfillment with conscious fulfillment, and the other 78.18% presented good, medium or bad adherence with a breach type. according to adherence level, a medium adherence was defined in 16 patients (29.09%), with an erratic mistake in 8 patients (50%). bad adherence was seen in 21 patients (38.14%) , with the three breach types in 9 patients (40%). good adherence with unconscious breach type was defined in 6 patients (10.9%). conclusion: tai questionnaire confirms a good adherence and fulfillment in less than 30% patients. an erratic mistake is the most frequent breach type defined in our patients. educational protocols should be applied to improve adherence and fulfillment. 1005 | what is adhesion to treatment of asthmatic patients like in argentina according to the tai questionnaire? background: asthma is a chronic inflammatory disease of the airways, which requires an adequate treatment and control. the adhesion of a patient to an asthma treatment is a critical factor in order to achieve and maintain control. this adherence arises from a consensual agreement of the doctor-patient relationship; it is a complex multifactorial variable in which the variability in human behaviour in relation to its environment influences. background: the association between ambient pollen and asthma has been studied intensively with inconsistent results, attributed to differences in study population, geographic factors (geoclimatic features), data sources, measurement of pollen (different types of traps), and different outcome occurrence (hospitalizations or emergency department visits). we investigated the associations between daily sales of short-acting β2-agonists (saba) and outdoor pollen concentrations in the central france area. the relationship between daily changes in pollen concentrations and daily saba sales obtained from the social security database was analysed with generalized additive models, taking into account confounding factors such as air pollution, weather conditions, and day of the week. results: the daily saba sales (mean, sd) rose from 46. 5 (23.6) conclusion: this study indicates that outdoor pollens contribute to asthma morbidity in the general population. it confirms the highly allergenic role of fraxinus, betula and quercus pollens, but also shows a relatively unknown association between treated asthma and carpinus and platanus pollens, despite their counts being less than 1% of overall pollen concentration. results: of 15 437 asthma patients (mean age 47.8 years, female 62.6%), regular ocs use was identified for 223 patients (1.4%), periodic ocs use for 3054 patients (19.7%), and no ocs use for 12 160 patients (78.7%) 1-year post-index. regular ocs users had a greater mean age, were more often male, and had greater eosinophil counts, lower lung function, and greater prevalence of comorbidities than did the periodic and no ocs users (p < 0.001). total yearly cost was greatest for the regular ocs users (€ 5509), followed by periodic ocs users (€ 2892) and no ocs users (€ 2042) (p < 0.001). among regular ocs users, hospital admissions were the main cost driver (41.5% of total cost), while gp consultations were driving the total cost in periodic and no ocs users (48.0% and 52.9% of total cost, respectively). conclusion: in this sample of patients with asthma in sweden, the total yearly cost of health care resource utilization for a regular ocs user is twice as high as for a patient with no ocs use, demonstrating substantial economic and clinical burden in asthma patients on regular oral steroid treatment. method: children with physician-diagnosed asthma who attended to an outpatient pediatric allergy and asthma center were enrolled in the study along with control subjects. asthma severity and control status of the patients were evaluated according to recent gina guidelines. laboratory investigations including skin prick tests, complete blood counts with differential, total ige levels, serum periostin levels and pulmonary function tests were performed. results: a total of 158 children (125 with asthma and 33 age and sex-matched control subjects) with a median age of 10.2 years (range 5.9-17.0) were enrolled. asthma severity was mild in 41 (32.8%), moderate in 63 (50.4%) and severe in 21 (16.8%) children. children with asthma had significantly higher periostin levels than controls (53.1 ± 13.1 vs 43.0 ± 11.2 ng/ml; p < 0.001). the mean serum periostin levels of children with severe asthma (63.8 ± 10.8) were significantly higher than in children with moderate asthma (53.3 ± 12.7) and mild asthma (47.4 ± 11.1) (p < 0.001). serum periostin levels were found to be significantly correlated with asthma severity (spearman's rho [r]=.41, p < 0.001). analysis using roc curves identified the role of periostin levels in determining children with severe asthma (auc: 0.77, 95% ci: 0.67-0.87, p < 0.001]. conclusion: serum levels of periostin, a novel asthma biomarker, were higher in asthmatic children, and were associated with asthma severity. adam i 1 ; selevestru r 1 ; rogut v 2 ; sciuca s 1 background: nowadays, data from several epidemiological studies confirm the important role of fungi in respiratory disease in the indoor as well as in the outdoor environment. in general, exposure to fungi occurs via inhalation, skin contact, or ingestion. alternaria alternata is one of the most common fungi associated with presence asthma and persistence and severity of asthma. although exposure to a. alternata is also may represent a risk factor for development of asthma. in ukraine has been an increase in the number of the mold sensitized children for the last few years. at the same time we can see increasing frequency ba at the children of pre-school age. method: thirty five children aged 3-7 years with allergic rhinitis and high level of asthma predictive index (api) sensitized to a. alternata were included in a 2-year cohort study of the efficacy and safety of slit (diater laboratories, spain) using standardized sublingual extracts containing molds (alternaria alternata). treatment efficacy was analyzed using the score of symptoms such as difficulty in nasal breathing, rhinorrhea, sneezing, itching of the nasal mucosa (upper palate) and discharge from the nose and recurring wheezing. we also have analyzed the level api during the period investigation. symptoms were measured before starting treatment, and at 4, 12 and 24 months after starting immunotherapy. results: slit significantly reduced both symptoms and medication score: nasal symptoms (38% vs. control group) and the use of rescue medications (38% vs. control group), and improved fev1 (in children aged≥5 years). in the slit group, api decreased by 15% for the first year, by 31% for the second year. no patient had a systemic reaction during therapy. our results have shown that slit is an effective treatment in pediatric patients suffering from allergic rhinitis and high api with significantly improved clinical outcomes (less symptoms and less medication intake) in comparison with children treated with symptomatic drugs only. in this study, large and statistically significant differences in symptom and medication scores were demonstrated in patients receiving slit compared to control group. sublingual immunotherapy is effective for allergic rhinitis in children especially early age and is generally advantageous because of the convenient administration and safety profile and ensure prevention of developed ba. bednarek a background: the classification of asthma based on the severity of its clinical course has been recommended by gina since 2008. this division is useful for the patient's initial assessment when asthma is being diagnosed and essential decisions concerning an appropriate therapy are made. the objective of the work is to evaluate the influence of a clinical form of asthma on vaccine immunity in preschoolers following three years after the programme of mandatory vaccination has been realised. the study encompassed 172 preschool children (mean age of 5.22 ± 0.34 years old) with asthma being newly diagnosed, including 140 patients with mild asthma and 32 ones with moderate asthma, whose vaccine immunity (igg specific antibody titer) was assessed after the mandatory early childhood vaccines had been administered. monovalent vaccines (hbv+ipv+hib) along with a three-component combined vaccine (dtwp) were given to 86 children while a six-component vaccine (dtap+ipv+hib+hbv) was given to the remaining 86 children. the vaccine doses were consistent with the polish immunisation programme and manufacturers' recommendations. the elisa immunoenzymatic method was applied to assess titer of specific antibodies to diphtheria, tetanus, pertussis, poliomyelitis and h. influenza type b. the level of hbv antibodies was measured chemiluminescently. the immunity class for particular vaccinations was assessed according to the test manufacturers' instructions. results: children suffering from mild asthma had considerably more frequently vaccinations on time (p < 0.001) and the type of vaccines (monovalent, highly-combined) administered to them did not have a significant influence on a clinical form of asthma in the children examined (p > 0.6951). apart from the vaccines against hepatitis b and rubella where considerably more frequently a high antibody titer occurred in children with mild asthma, the titers of antibodies to other vaccines, namely diphtheria, tetanus, pertussis, hib and mumps, were not associated with a clinical form of asthma. the protective antibody titers in the children with asthma were found in 100% after vaccinating them against poliomyelitis (≥12u/ ml) and measles (≥300 ml u/ml). significantly higher current weight was solely found in the children with mild asthma (m = 20.80, sd=3.77; p < 0.05). conclusion: there are some clinical and cultural differences among the four southern chinese cities within the canton province. this study identifies potentially modifiable environmental and treatment factors associated with poor asthma control and qol for healthcare interventions. having a smoker in the family is independently associated with poor asthma control and qol. were classified into two groups (levocetirizine group (l) and montelukast group (m)) and we treated each group for another 10 week. to evaluate the therapeutic effectiveness, we used symptom score (ss) and ebc leukotriene e4 (lte4). ebc samples were collected with rtube. each parameter was checked at 0, 2, 12 week therapeutic period. results: most ar patient showed clinically improvement with 2 and 12 week fluticasone therapy (0 wk ss=6.6, 2 wk ss=3.2, 12 wk ss=1.9 p < 0.01 in l group; 0 wk ss=6.8, 2 wk ss=3.6, 12 wk ss=2.0 p < 0.01 in m group). lte4 levels of ar were higher than control (0 wk 77 vs. 12 pg/ml), and were reduced after 2 week flutimic were: md allergic rhinitis, wheezing apart from colds, eosinophilia ≥4%. outcome was defined as md asthma and at least 1 episode of asthma during the previous year or more than 3 episodes of wheezing during the 12 months regardless of asthma diagnosis. results: from a total of 144 of parents approached, 86 (58%) agreed to participate in a phone interview. 18 (21%) children were diagnosed with asthma. the age at the time of admission (mean, abstracts | 533 (sd)) was 27.0 (9.9), at the time of phone survey 77.6 (10.9) months, respectively. positive loose api at 2-3 years of age had sensitivity of 77.8%, specificity 75%, positive predictive value (ppv) 45.2%, negative predictive value (npv) 92.7%. positive stringent api at 2-3 years of age had sensitivity of 50%, specificity 91%, ppv 64.3%, npv 85%. background: asthma is the most common chronic airway disease in childhood, with a high unmet need for new treatments due to insufficient symptom control in a relevant percentage of patients. ethics and resource factors limit the feasibility of large, long pediatric trials required to assess outcomes such as exacerbations and symptoms. for diseases like asthma, where the disease process is largely similar in children and adults, with the same expected therapy outcome, the international council for harmonisation advise extrapolating adult data to those of a younger age, reducing unnecessary pediatric trials. here we assess the partial extrapolation used in the clinical development of tiotropium. phase 3 trials in adults (aged 18-75), adolescents (aged 12-17) and children (aged 6-11) with symptomatic severe (primotina-/pensie-tina-/vivatina-asthma) or moderate asthma (mezzotina-/rubatina-/ canotina-asthma), respectively. trials lasted 12-48 weeks, all with tiotropium respimat 5 μg add-on vs placebo as two puffs once daily. results: in adult trials, lung function, symptoms and exacerbation endpoints were evaluated in a confirmatory manner: tiotropium significantly improves lung function and asthma control, and reduces risk of exacerbation, vs placebo ( conclusion: based on similarities in disease profile and magnitude of treatment responses between age groups, it is reasonable to expect tiotropium add-on to produce clinically meaningful improvements in exacerbation and symptom endpoints in children and adolescents, as in adults. the robust tiotropium clinical program supports using a partial extrapolation to avoid overly long and large trials in pediatrics. 1019 | clinical state of treatment and examination during last 3 years before remission about asthmatic children in long-term remission cases method: remission cases (no symptom and no therapy) for 3 years of asthmatic children were studied. clinical background and treatment (drugs) was studied during last 3 years before remission annually. acetylcholine inhalation test by standard method was performed, and respiratory threshold of acetylcholine (rt-ach) was obtained. fev1%, and serum ige also examined. these data were compared before remission with 3 years after remission. results: mean age of 25 cases at 3 year before remission was 9.2 years old. male to female ratio was 1.3. severity of asthma was all mild type, and number of attack was 2 to 8 times in a year. there was no admitted case during this study. the long-term therapeutic drugs were leukotriene receptor antagonist (anti lt) in 20 cases, and/or inhaled corticosteroids (ics) in 12 cases, but 5 cases had no treatment for the control. geometric mean of rt-ach (after then: 3 years before and after remission) was 2900 μg/ml and 5800 μg/ml. the mean fev1% was 83% and 90%. geometric mean of serum ige level was 360 iu/l and 410 iu/l. complicated cases of atopic dermatitis decreased after remission, but the incidence of allergic rhinitis increased slightly. conclusion: characteristics of asthmatic children during last 3 years before remission were mild type, had several times of attack in a year, and the treatment was mainly anti lt and/or ics. fev1% was within normal range, and serum ige level was not changed after remission. rt-ach had the tendency to improve during 3 years before and after remission. these data is supposed that airway hyperresponsiveness is one of the indicators for quitting treatment. 1020 | clinical aspects of polyvalent mechanic bacterial lysate (pmbl) treatment in children with uncontrolled asthma our results indicate that long-term treatment with omalizumab in children can help to achieve better asthma control and reduce the amount doses of basic therapy. method: allergic rhinitis (ar) and allergic rhinoconjunctivitis (arc) diagnosed-patients' demographic information, accompanying-asthma, the allergic history of the family, the onset of symptoms, types of aeroallergens sensitivity were noted from patients' files in our hospital's pediatric allergy clinic. results: in this study, 675 patients were evaluated. the mean age of the patients were 11.65 ± 3.85 years and 61% (n = 412) were male. 452 (67%) patients had ar and 223 (33%) patients had arc. background: allergic rhinitis (ar) is a disease characterized by symptoms of nasal discharge/congestion, sneezing, and pruritus, and is caused by an ige-mediated immunological response to inhaled allergens. we aimed to evaluate pollen season and out of pollen season pulmonary function tests (sft) of patients with ar in our study. method: in our study, the demographic characteristics and aeroallergens were recorded from patients' files with ar diagnosed. in addition, pollen season and out of pollen season sfts were evaluated and compared. conclusion: in patients with ar, fev1 and fvc values are seen to be lower during the season even though there is no lower respiratory symptom. therefore, sfts of patients with ar should be evaluated during pollen season. results: among the clinical manifestations, the most common combination of allergic rhinitis (ar) and conjunctivitis (ac) is noted in 83.80% of adults and 55.11% of children, but in children aged 3-7, the combination of ar and ac is observed only in 48.40%, among 8-12 years old-51.25%, while in the remaining age groups it is encountered in more than 80%. higher percentage of isolated ar is also observed among young children-17.55%, and those of the results: allergic rhinitis was a main symptom in 69.8% of children with pollen-food sensitization. in all of them concomitant allergic disorders were noticed: bronchial asthma (77.7%), atopic dermatitis (77.8%). only in 26.7% temporal association between ingestion of pollen-related foods and nasal symptoms was observed (mainly apple and peanuts); occurring also outside the pollen period. the simultaneously sensitization to animal origin food allergens was stated in 63.3% of children with sar, but only in two of them milk and white egg proteins were an additional exacerbation factor of nasal symptoms. in 18.5% anaphylactic reactions to food allergens were registered. 36.7% of children were asymptomatic despite pollen-food sensitization. the statistically significant differences were noticed in comparison to the control group. conclusion: 1. allergic rhinitis in children, similar to adults, is a common manifestation of pollen-food syndrome and this type of sensitization should be taken into account regardless to age. 2. children with pollen-related food allergy have the predisposition to multiorgan clinical manifestation. 3. the lack of association of symptoms with plant-origin foods in the majority of cases and the asymptomatic course of food sensitization in more than one third of patients indicate the need for follow-up. 1026 | clinical benefit of the screening of suspected food allergen using multiple allergen simultaneous test in the patient with pollen-food allergy syndrome (pfas) background: the quantitative fluoresce enzyme immunoassay immunocap (ic) system has been widely used for detection of allergen-specific ige for the diagnosis of allergy. however, the system can only detect ige against a single allergen, the multiple antigen simultaneous tests has been developed such as the fluorescence enzyme immunoassay view allergy 39 (va) or chemiluminescent enzyme assay mast iv (ma) and both assay detect more than 39 allergen-specific ige. in this study we examined the diagnostic capability of these two systems for screening test in the patient with pfas. method: total number of participants are 37 (male/female: 20/17), aged 12.0 ± 3.9 (range 3~20) years old. all the patients showed oral allergy syndrome (oas) to rosaceae family plants (apple, peach) and/ or kiwi and/or banana, also showed tree pollen allergy. specific ige assay were performed using ic, ma or va. results of greater than class 1 were to be regarded as positive, and the concordance rates between the assays were assessed. results: the correlation of sensitivity between pr-10 (rbet v1, rmal d1, rpru p1, measured by ic) and specific ige to apple (measured by va), specific ige to peach (measured by ma) in 27 oas patients to rosaceae family plants were assessed. rbet v1, rmal d1, rpru p1 were found to be 96.0%, 96.3%, 92.6% positive measured by ic while the specific ige to apple (supposed to be including pr-10) were found to be 100% positive measured by va. on the other hand, the specific ige to peach (supposed to be including pr-10) were found to be only 33.3% positive measured by ma, this detection rate was lower than that of va (p < 0.0001). also, the correlation of sensitivity between pr-10 (ract d8, measured by ic) and specific ige to kiwi in 17 patients with oas to kiwi were assessed. ract d8 were found to be 76.5% positive measured by ic while the specific ige to kiwi (supposed to be including pr-10) were found to be 64.7% and 17.6% measured by va and ma, respectively (p < 0.005). additionally, all the 3 oas patients to banana found to be positive for the specific ige to banana measured by va, but only 1 patient was detected as positive measured by ma. conclusion: in this study, we found that va showed better agreement of sensitivity and specificity with ic compared to ma in the oas patients to rosaceae family plants, kiwi, or banana. therefore, it may be clinically useful for screening of allergen specific background: the hygiene hypothesis for autoimmune and allergic diseases, which exists nowadays, shows that human immune system is dependent on various environment factors. we consider the effects of humic substances (hs) to be important in understanding the hygiene hypothesis. due to urbanization, the amount of human interaction with hs found in soil has significantly dropped. the goal of our work was to study allergenic potential and antimicrobial activconclusion: hs appear to be exogenous immunocorrectors, and also to have an ability of suppressing propagation of allergic reactions and sensibilization, which leads to conclusion that they seem to play a major role in hygiene hypothesis. moreover, hs selectively interact with bacterial cell wall, and this effect could be used in order to create antimicrobial drugs based on hs. background: peach tree pollen has been identified as having relevant allergens (the third most prevalent after olive tree and grass pollen) in areas of high cultivars (murcia, east-spain). when analyzing molecular components in sensitized patients, along with pru p 3, we have identified other relevant inhalant allergens one of which was named pru p x. because pollen of different species share allergens and with plantderived food, we have also studied peach tree pollen sensitization in a non-exposed population (madrid, central-spain). the aim was to study the association between peach tree pollen and several panallergens, as well as the relevance of pru p x in our area (madrid). method: a total of 328 patients who came to our allergy unit in those patients with positive spt to at least one pollen we also performed peach tree pollen spt. if positive, we tested pru p 3, pho d 2, pho d 3 and pru p x. to study the clinical relevance of these findings, we also performed nasal provocation test (npt) with peach tree pollen and pru p x. results: a total of 57 patients were sensitized to peach tree pollen. from these, 33% had also positive spt to pru p 3 and none of them to pru p x. positive spt to polcalcin were found in the 33% of the cases and to profilin in the 13%. in 7 patients sensitized to peach tree pollen npt was performed being 4 cases positive to peach tree pollen and none to pru p x. conclusion: peach tree pollen sensitization in non-exposed patients with allergy to other pollens is high although primary sensitization is unlikely. these patients present clinical response when exposed to that pollen that needs further evaluation. in our study, one third of the patients were also sensitized to polcalcin and pru p 3 and none to pru p x. we have not found clinical response to this new inhalant allergen identified in highly exposed peach tree pollen population. results: the bet v 1 elisa 2.0-ep complete kit format (including pre-coated plates and all buffers and reagents) allowed for the consistent measurement of bet v 1 in birch pollen extracts within the same lab (intralab cv=5.5%) and between different labs (interlab cv=13.5%). the average recovery from matrix spiked samples (crs in birch pollen extracts) ranged from 75-112%, with an average recovery of 91% (n = 10). assay time was reduced from several days to two hours compared to the original method. the performance of the bet v 1 elisa 2.0-ep kit was comparable to that of the stallergenes greer candidate standard method and has been successfully cross-validated. this will enable allergen manufacturers and regulatory authorities to adopt a standard method for bet v 1 determination, which, ultimately, may be included in the european pharmacopoeia. the development of a certified elisa represents a major step forward in the standardization and quality control of allergen products. 1031 | an isoform of the ole e 7 allergen assembled by proteomics could explain the cross-reactivity with pollen and food nsltps results: a total of 457 peptides were obtained by de novo sequencing. ten of them allowed the completion of the full-length amino acid sequence of the allergen. after purification, role e 7 was obtained with a yield of 1.5 mg/l of cell culture. immunological assays confirmed that the recombinant isoform of ole e 7 shared most of the allergenic and antigenic properties of the natural allergen. moreover, we observed its implication in cross-reactivity with pollen extracts, and plant-derived food extracts. conclusion: these results suggest that the presence of this isoform in the olive pollen could explain the co-sensitization observed in some allergic patients between ole e 7 and nsltps from foodderived extracts and might be used for a more effective clinical diagnosis of olive pollen sensitized patients. background: penicillium oxalicum, one of the prevalent airborne fungi in india, was selected to detect its spores as potential source of allergens and also to identify and characterise its major ige-reactive component. the airborne spores of penicillium oxalicum was detected by andersen 2-stage air sampler at different parts of west bengal. the allergenic potency of p.oxalicum was tested by spt, elisa and immunoblotting. total protein was resolved in 1-d and 2-d gel electrophoresis and allergens were identified by 1-d and 2-d immunoblots. identification of major ige-reactive protein spots was made by mass spectrometry based maldi-tof-tof. major allergen was partially purified by ion exchange chromatography. results: aerobiological investigation clearly indicated the predominance of p. oxalicum spores (56 cfu m −3 ) in the air of west bengal, india. sensitivity of patients to spore antigens was highly correlated with rhinitis. in sds-page, 80 bands were detected with molecular weight range of 16-180 kda. the allergenic potency of spores was confirmed by skin-prick test, elisa and dot-blotting. eleven ige-reactive proteins were detected as allergens by 1-d and 2-d immunoblots, of which 43% patients were sensitized to 22 kda allergen. this 22 kda protein was found to be the major allergen which was further characterized by mass spectrometry based maldi-tof-tof. this major allergen (pi 6.08) was partially purified by ion exchange chromatography. the eleven allergens were identified from spore of penicillium oxalicum fungi for the first time from india. immuno-proteomic identification of major ige-reactive protein (22 kda background: airway epithelium (ae) is one of the largest cellular surfaces exposed to the environment. ae constitutes a physical barrier due to the presence of intercellular apical junctional complexes between neighboring cells. in the past years evidence indicates an association between epithelial airway dysfunctionality and allergic asthma. it is still unclear if an impaired epithelial barrier could be the cause of allergy development as opposed to the consequence. one of the most common comorbidities of asthma is house dust mite (hdm) allergy. it has been shown that hdm allergen der p 1 can disrupt the epithelial airway due to its protease action against cellular apical junction complexes damaging the epithelial monolayer. in the last decade, metabolomics has been successfully employed as a new approach to describe metabolic changes in biological systems. metabolomics focuses on describing and identifying small molecules to explain complex biological processes. we theorized that metabolomics could be used as a new tool to detect damage of epithelial barrier in vitro after der p 1 exposure. method: human cell line calu-3 cultured at air-liquid interphase (ali) was used as an in vitro model of bronchial epithelium. ali culture system allows establishing 2 different compartments, mimicking the conditions found in the human airways: a basolateral compartment in which basolateral surface of the cells is in contact with the culture medium, and an apical compartment where the apical cellsurface is exposed to air. after 7 days in ali, the cells were exposed to either der p 1 or pbs as a control in the apical side for 24 hours. then, apical and basolateral media were collected and processed for metabolomics analyses. results: metabolic profiles from samples were obtained, these were composed by 248 and 397 features for apical and basolateral media, respectively. of these, using mann-whitney unpaired test as statistical analysis, 108 and 15 features were found changed within the apical and basolateral compartments, respectively. specifically, in the apical compartment there were 104 signals significantly increased and 4 decreased after der p 1 exposure; whereas for the basolateral compartment, 11 signals were found to be significantly decreased and 4 increased after exposure. background: mites are one of the major causes of allergies. it is known that allergen concentration varies depending on the species of mites and the degree of allergy induction is different, but the difference in microbiota according to mite species is not known. in addition to allergen, endotoxin or bacterial dna, adjuvants of allergen derived from the microbiota in the mites, are also present in the feces. bacterial endotoxin is found in gram-negative bacteria, acting on tlr4 and acting as an adjuvant to allergies. method: three species of mites (d. farinae, d. pteronyssinus, and t. putrescentiae), known to cause allergies, are cultured in same condition(autoclaved media, 80%rh, 25°c)and analyzed for microbiota of each species. using the next generation sequencing that complements the existing sanger sequencing, we analyze the difference of microbiome according to the dust mite species and measure the level of endotoxin. method: six hundred and thirty five patients (51.8% males and 48.2% females, mean age 30.2 years old, range 3 to 82 years old) were included. all of them referred respiratory symptoms (rhinitis, conjunctivitis or bronchial asthma) and had skin prick tests positive with any pollen. patients were skin prick tested with a battery of common pollens in our area, including three species of chenopodiaceae: chenopodium album, salsola kali and salsola oppositifolia. results: three hundred and forty tree (54%) patients were sensitised to pollen of any chenopidaceae species: 255 (40.2%) to chenopodium album, 245 (38.6%) to salsola kali and 220 (34.6%) to salsola oppositifolia. the prevalence of skin sensitisation to pollen of salsola oppositifolia was 34.6% in the population studied and 64.1% in patients sensiresults: in patients aged 1-60 years of age in 80.5% of the cases ige reactivity was at least to one allergen tested. the majority of patients (more than 2/3) had a complex sensitization profile and reacted on average to more than 5 allergens. the highest frequency of sensitization in ukraine among patients who turned to the clinic among adults was found phl p1 (34.1%), amb a1(33.3%), fel d1 (33.3%), bet v1 (30.2%) and children (29.2%, 34.6%, 38.5%, 36.9%), respectively. when analyzing the results of tests for the source of the allergen, most often among house dust mites (hdm) allergens in adults and children is sensitization to fel d1 (35.9%), as well as to hdm: in adults (der f2-15.1% der p2 −15.1%, der f1-12.7%, der p1-11.9%) and in children (12.3%, 13.1%, 9.2%, 10 .8%), respectively. among fungal allergens the most common is sensitization to alt a1 and varies from 2.4% in adults to 26.9% in children. among pollen allergens in adults is sensitization to phl p1 (34.1%), amb a1 (33.3%), bet v1 (30.2%), cynd1 (23.8%), art v1 (22.2%), bet v2 (11.1%) and in children (29.2%, 34.6%, 36.9%, 19.2%, 16.9%, 21.5%), respectively. tests for food allergens in adults and children are more common on pr-10 proteins. in children, sensitization to milk and egg proteins is more common than in adults. conclusion: most patients who came to the clinic have a complex ige reactivity profile in which pollen sensitization predominates. among hdm allergens, more than 1/3 of the examined have sensitization to the cat's proteins. sensitization to mold alternaria alternata in children occurs 10 times more often than in adults. results: total 130 children were examined, aged 1-16 years (median 5 years). 72% children were sensible to two and more components 57.7%to 5 and more components. the frequency of sensitization to inhalation components was 65.4%, to food abstracts | 545 components-33.1%. among the most frequent inhalation components were feld 1-39%, betv1-37%, amba1-35%, phlp1-29%, alta1-27%, the sensitization to house dust mites (hdm) was most often observed to der p2-13%. however, the analysis of these protein by the level of isu showed that the highest levels were for der f1median 19 (iqr 9.4-47.0), whereas for fel d1-6.9 (iqr 2.6-15.0). among food allergens, sensitization was most commonly observed to pr-10 proteins -42%. children sensitized to pr-10 proteins were in most cases sensitized to -mal d1(28%), cor a1.0401(27%), pru p1 (22%).this co-sensitization was accompanied by a high correlation of isu levels among these components. sensitization to celery and kiwi was less common, the level of these proteins was also low. the frequency of sensitization to storage proteins was 38%, among which the highest level of isu was in ara h6 median 13 . sensitization to ltp proteins was detected in 22% of children, among which the most commonly detected pru p3 protein was 9.2%. the sensitization to profilins, which was evaluated at the level of bet v2, was found in 21% of children, but the levels of these proteins were not high. among the food products of animal origin, the most frequent was sensitization to egg component gal d2 −13.1%, however, isu levels were the highest to milk component bos d4 −9.8 (iqr 1.2-21.0). the most frequent causative inhalation allergens were epidermal allergens and weed pollen, however, the highest level of isu was to hdm and mould. among food allergens, the most commonly observed sensitization was to pr-10 proteins. hypereosinophilia of peripheral blood was observed in 87 children under study, which was 50% (4.7%). as a result of testing patients with a wide panel of allergens, 98% of the patients had diagnostic levels of antibodies to allergens siged1, 91.2%to allergens siged2. in 50% of cases, a significant level of antibodies to plantain allergens sige w8 was detected, 30.8% to dandelion allergens sige w9, 35.7% to evergreen trees sige t23, to maple sige t11 to 33.3%, to allergens of olive tree sige t9 -40%, to the banana allergens sige f92 -63.6%, to the egg protein sige f1 in 24.5%, in 34% to the milk allergens sige f2, to the food mixture sige f x5 -37.7%, to allergens of mold fungi mx2 −17.8%. among the leading household allergens were registered in the 1st group and in the 2nd group of the investigated children -d pteronyssinus (80.3%, 97.8%), and d. farinae results: the prevalence results are expressed in the table 1 . we have not observed any significant association in allergic rhinitis patients group with any ltp or pr-10 molecules. for atopic dermatitis only rara h 9 (or with 95% ci -10.2 (1.9-54.6) and njug r 3 (or with 95% ci -6.7 (1.6-29.5)) were associated significantly. for asthma, the most important molecules were rbet v 1, raln g 1, rcor a 1.0101, rcor a 1.0401, rmal d 1, rpru p 1 and rapi g 1 (p-values for or less than 0.05). conclusion: future studies focusing on the evaluation the association of cross-reactive molecules with allergy phenotype should be done. background: the fuzzy/green kiwifruit (actinidia deliciosa), widely grown commercially, contains various pulp allergenic molecules, including the major allergen cysteine protease actinidin. methods. this case report is about a 40-year-old male patient with house dust mite allergic persistent rhinitis and intermittent asthma, presenting a convincing history of anaphylaxis immediately after eating a kiwifruit on empty stomach, followed, a few months later, by a severe oral allergy syndrome after licking a slice of raw kiwi. previously, the patient ate kiwi without any problems and had no manifestations of pollen or latex allergy. skin prick testing was done with commercial allergen extracts, while prick-prick testing was performed with raw kiwifruit, avocado and banana. molecular approach consisted in assessment of serum specific ige to native extracts and molecular allergen components using patient-friendly allergen nanobead array multiplex test and singleplex capsule-enclosed activated cellulose solid phase fluorescence enzyme immunoassay. results. regarding kiwifruit allergy, the patient presented positive prick-prick tests with raw edible kiwifruit components: outer pericarp and inner pericarp (each 15 mm wheal) and columella/core (19 mm wheal) and negative with kiwifruit whole seeds, avocado and banana, and pollen extracts. serum specific ige to kiwifruit were detected (0.5 ku/l), but specific ige values were negative (≤0.01 fiu/ml) for actinidin act d 1, thaumatin act d 2, kiwellin act d 5, nsltp type 1 act d 10, bet v 1-like major latex/ripening-related protein act c 11, act c chitinase_iv, act d 9 cross-reactive profilins bet v 2 (birch pollen profilin) and hev b 8 (latex profilin), and also negative (<0.1 ku/ l) for pr-10 ract d 8. moreover, specific ige to avocado were nor found (≤0,01 fiu/ml). although ige against seed proteins cupin/11s globulin act d 12 and 2s albumin act d 13 were not determined, this was not considered of great importance since allergic symptoms were also induced by licking kiwi pulp, in which abundantly expressed actinidin enzymatically degrades seed storage proteins, and prick-prick test was negative to kiwifruit seeds. conclusion: in a patient with anaphylaxis to kiwifruit, positive skin tests to its pulp and detectable serum specific ige to actinidia deliciosa, a detailed molecular allergy diagnosis is necessary, including assessment for act d 3 glycoallergen or other molecules, not performed in this patient. 1049 | is pr-10 sensitization a portuguese phenomenon as well? background: bet v 1, a major allergen found in birch pollen, belongs to the pr-10 protein group. in our practice, some bet v 1 sensitized patients have been identified, residing in areas without this tree genus in its flora. our aim was to characterize a portuguese patient population with pr10 sensitization. method: a group of patients in whom immunocap isac ® (isac) study was performed, between january 2009 and june 2017, were analyzed. all subjects with one or more pr-10 sensitizations were selected, and their clinical records reviewed. a sequential sample of the last subjects (n = 80) who underwent isac study, was then used for comparison. results: out of 234 isac studies performed, only 16 were positive for pr-10 protein group. median age was 18.3 years, 68% (n = 11) were male. pr-10 sensitized individuals were more likely to live in portalegre district compared to the control group (7/16 vs 1/80; p < 0.001). 15 patients were positive for pr-10 family pollens (93.7%), frequently bet v 1 (n = 13), followed by aln g 1 (n = 10) and cor a 1 (n = 8). 14 out of the 16 patients were sensitized to pr-10 foods, mostly cor a 1.0401 (n = 13) and mal d 1 (n = 12). skin prick tests revealed birch as the main sensitizing pollen as well (14/ 16). moreover, only four patients were skin prick tested for fagaceae trees which were positive for oak (4), chestnut tree (3) and cork tree (1) . all patients were co-sensitized to other pollens, namely grass and all had respiratory allergy. nine patients were food allergic, although seven of them were co-sensitized to other cross reactive (ltp/profilin) or species specific proteins. conclusion: although pr-10 sensitization is known to be rare in our population, mostly alto alentejo inhabitants showed sensitization to this protein family in our sample, either by in vitro and/or in vivo methods. this phenomenon is consistent with the native plant species of this region, which should be taken into account when studying the allergic profile of these patients. in our sample, all pr-10 sensitized patients had respiratory allergy while this protein didn't seem to be relevant when it comes to food allergy. further studies are needed to characterize which plant species belonging to this protein family are more significant for our country's aerobiology context and to determine its clinical relevance. included. allergic asthma, rhinitis, conjunctivitis and eczema allergic symptoms were diagnosed. all patients were tested by immunocap with mugwort pollen extract and the natural components nart v 1, nart ar 2, nart v 3, and nart an 7. results: the positive frequency and sige levels of the four components in the artemisia allergic patients from southwestern china were significantly lower than that from the north. art v 1 and art an 7 were the highest recognized allergens, followed by art v 3 and art ar 2. patients from northern china were more likely to have abstracts | 549 asthma (50%) than patients from southwestern china (3%), and being sensitized to more than two allergens increased the risk of asthma. sensitization to art v 1, art v 3 and art an 7 played a significant role in the development of asthma. artemisia pollen allergic patients is helpful to assess the potential risk of asthma. conclusion: a small but significant part of the population react to ragweed pollen extract and are not identified as disease-positive by standard sige tests. there is a need for targeted tests towards a larger spectrum of allergen molecules. in ragweed allergic individuals, this allergy can be the main cause of overall sige levels and also of in vivo reactions (tested by spt). 1052 | molecular profile of pollen sensitization of tashkent residents with respiratory allergy background: in paediatric cohorts, a correlation between specific ige (sige) levels to house dust mite extract or allergen components and the occurrence of asthma has been shown. higher levels of sige to mite extract were associated with a higher risk of wheezing. moreover, asthmatic children recognized more allergens and had higher sige levels to nder p 1 as well as rder p 2, 5 and 23. we sought to investigate potential differences in sige levels or sensitization patterns between asthmatic and non-asthmatic patients in a mixed paediatric and adult house dust mite allergic cohort. method: total ige and specific ige against house dust mite extracts (dermatophagoides pteronyssinus and farinae) and allergen components (rder p 1, 2, 10, and 23) were determined in 190 house dust mite allergic patients. 35 patients had diagnosed asthma ("asthmatic", 54% females, mean age 27 ± 15 years, 31% younger than 18 years), whereas 155 had rhinitis (and conjunctivitis) without respiratory symptoms ("non-asthmatic", 54% females, mean age 28 ± 15 years, 29% younger than 18 years). results: total ige levels were markedly higher in asthmatic compared to non-asthmatic patients (315 vs. 144 ku/l, p = 0.022). positivity to rder p 1 (71 vs. 52%, p = 0.039) as well as rder p 10 (9 vs. 1%, p = 0.044) differed between both groups. specific ige levels to house dust mite extracts and allergen components (rder p 1, 2, 10, and 23) and positivity to rder p 2 and 23 did not differ between both groups. conclusion: in contrast to previously published data, sige levels to house dust mite extracts or allergen components were not statistically different between asthmatic and non-asthmatic patients in our mixed paediatric and adult house dust mite allergic cohort. only higher total ige levels and a higher reactivity to rder p 1 and 10 were found in asthmatic patients. however, larger studies are needed to confirm clinical relevance of these findings. results: prior treatments reported at baseline (bsl) included: 17.3% of pts were receiving 1 or more second-generation h 1 -ah at approved dose (recommended first-line), 23.9% were receiving them at increased dose (second-line); 8.5% were receiving omalizumab (third-line); 29.9% had no treatment. the majority of pts (78.2%) had uncontrolled csu (uct<12) at bsl (table) . treatment changes were most evident at the bsl visit, with an increase in pts receiving omalizumab (21.4%) and a decrease in those receiving no treatment (12.8%) vs. prior therapy. these changes were associated with improvements in rates of hives and/or angioedema, uct and qol scores at month 3, but only modest improvements thereafter (table) . a sub-analysis of 528 pts with uct<12 and who were receiving the approved (36.9%) or increased dose h 1 -ah (63.1%), revealed that few pts had recommended escalation from the approved to increased dose h 1 -ah (0.0-6.7%) or from increased dose h 1 -ah to omalizumab (0.0-11.1%) (table) . conclusion: poor physician adherence to guidelines was evident throughout aware. initial improvements in disease activity and qol plateaued after month 3, possibly owing to fewer changes to recommended therapies. greater physician adherence to guidelines is needed for better symptom control in pts with uncontrolled csu. results: we revealed that in russians urticaria is associated with rs20541*arg/gln genotype of the il13 gene (p = 0.02) and rs5743794*cc genotype of tlr6 (p = 0.0011) gene polymorphism. in tatars the association with disease development was shown for rs5743571*tt genotype of tlr1 gene snp (p = 0.0054). the rs5743794*c allele of tlr6 gene polymorphism is associated with acute and chronic forms of urticaria (p = 0.0209 and p = 0.0063, respectively) and rs2243250*c allele of il4 gene polymorphismwith acute urticaria (p = 0.0247). method: 100 csu patients from the urtica cohort (clinicalttrials.gov number: nct01940393) participated in the study. a questionnaire was carried out evaluating the triggers identified by the patients, the comorbidities and the treatments received. patients with a self-report of skin exacerbation by foods, nonsteroidal antiinflammatory drug (nsaid) or physical triggers were subjected to a controlled provocation test with the suspect food, medication or physical stimuli report by the patient. the levels of anti-tpo ige were measured during a period of clinical control and during two exacerbations in all patients. results: 30% of the patients had at less one inducible urticaria demonstrated by provocation tests (24% dermographism, 10% cold, 8% pressure). self-reported exacerbation for a food (60%) or medication (30%) were high, but positive provocation tests were low (1% and 14% respectively). 30 patients had (+) anti-tpo ige during the baseline period. among them, 60% presented a significant elevation of anti-tpo ige during at less one of the two exacerbations. 18.5% of patients (n = 13) with (−) anti-tpo ige, presented elevation of anti-tpo ige one of the two exacerbations. conclusion: foods, drugs and physical triggers must be verified by challenge tests to avoid unnecessary lifestyle restrictions in patients with csu, nevertheless self-report is usually greater than positive provocation tests. increase concentrations of anti-tpo ige seems to be implicated in urticaria exacerbations in some patients with csu. brzoza z 1 ; adamczyk k 2 ; wcislo-dziadecka d 3 ; zbiciak-nylec m 2 ; brzezinska-wcislo l 2 adipokines. the aim of the study was to evaluate the possible contribution of leptin to chronic spontaneous urticaria pathophysiology. the study included 48 chronic spontaneous urticaria patients and 41 healthy subjects. the leptin level in both examined groups was measured. results: no statistically significant difference in leptin level was determined between the studied subgroups. we are among the first to present the effects of exploration aimed at assessment of the possible role of adipokines in chronic spontaneous urticaria pathogenesis. in this study we did not prove any difference in leptin level. in our opinion it is valuable to perform further studies in this area. the microorganisms were inactivated with phenol, and the concentration was adjusted to 1 000 000 microbial cells/ml (labeled as a 1/ 1). dilutions 1/2 and 1/4 were made from the product labeled 1/1. the dot blot technique was used to detect the presence of specific ige to the different microbial antigens and controls (anti ige 1/1 and 2 fold dilution ½ and ¼). the dot blot images were processed with a documentation system (gel doc ez, bio-rad), and the different microbial antigens in different dilutions were compared with the positive anti-ige controls. results: all patients have specific anti ige to microbial antigens (see table below). the presence of microorganism-specific ige could explain, the relationship between the infections and / or microorganisms in ciu, as well, the urticaria control by omalizumab, even when it has not been detected ige sensitizations to common allergens. finally, these findings, showed that the bacterial allergy could be one line of research to understand the unresolved etiology of urticaria. background: dermographism is the most common form of inducible urticaria. it shows itself as hives made by scratching or rubbing on the surface where it has been produced and with the same morphology. the pathogenesis has not been clarified nor has it been associated until now with the sensitization to allergens. we have studied the relationship between the presence of dermographism and domestic mites sensitization. we have selected 95 patients older than 14 years old. all of them had symptoms compatible with dermographism at the moment of medical evaluation. at least one third of patients additionally showed rhinitis and/or asthma symptoms. we performed:: -skin prick tests with our basic neumoalergens (mites d. pteronyssinus y lepidoglyphus destructor, pollen, molds, dog, cat and horse dander, latex and anisakis simplex). -determination of specific ige levels for dermatophagoides pteronyssinus, lepidoglyphus destructor, and anisakis were measured in serum by using the immunocap (thermo fisher scientific). -blood count, serum immunoglobulins, antithyroid antibodies, serine tryptase and proteinogram. results: blood count, serum immunoglobulins, antithyroid antibodies, serine tryptase and proteinogram were normal. we divided patient in different groups. background: urticaria results from the appearance of pruritic papules and/or erythematous plaques caused by substances from mastocytes present in the skin, notably histamine. chronic urticaria is defined as flare-ups that occur at least two or three days per week over a six-week period. in addition, affected subjects are often prone to an atopic or auto-immune profile that promotes urticaria [1] . the association of polyphenols (ambora, green tea) and the soothing active ingredients slow down the itching biological process from the outset by reducing the release of pruritic mediators (e.g. histamine, cytokines, etc.) of immune cells such as mastocytes and lymphocytes, involved in urticaria. in this context, the purpose of the study was to evaluate the efficacy and the tolerance of an anti-pruritic spray containing the polyphenols and the soothing ingredient. the tested product aims to quickly calm the itching in subjects with chronic urticaria. results: on average, the product was applied 2.3 times per day with a significant decrease of 5d-pruritus scale (-35%) and sensations of itching (-58%) between d0 and d21. in terms of quality of life, a significant decrease of the skindex score was observed (-48%). the product soothed the pruritus within 60 seconds for all subjects and the anti-pruritic effect lasts at least 2 hours for 80% of subjects. the product also showed very good cosmetic properties and was well tolerated; no intolerance case was reported. showed near complete remission. in the week before omalizumab and for a few days after, her urticaria flared but on 3 of 4 weeks she was largely asymptomatic (uas7 0-5). after 3 years of successful treatment she reported an increase in csu activity. no trigger factors could be identified. add-on treatment with cyclosporine was refused, montelukast showed no, and prednisolone only transient benefit. over a period of 2 months wheals occurred almost daily and a maximal score of 42 was achieved on uas7. we replaced omalizumab with cyclosporine but this was subsequently discontinued due to side effects. 3 months later the patients' csu remained poorly controlled with up to 100 wheals occurring almost daily despite rupatadine 40 mg/d. due to the good initial response to omalizumab and lack of good treatment alternatives, a trial of re-treatment was considered. results: within 1 week of re-commencing omalizumab she once again achieved near complete remission of csu with uas7 ≤ 3 on 3 of 4 weeks. the mechanism of action of omalizumab and the development of resistance to it in csu, are incompletely understood. our case shows that some csu patients developing resistance to omalizumab may benefit from a subsequent trial of re-treatment, particularly if treatment alternatives are poorly tolerated. manipulate and store data by electronic means. this includes e-mail, sms text messaging, video chat and online social media as well as all the different computing devices that perform a wide range of communication and information functions. a rapid increase in the use icts in recent decades is an enormous contributing factor in the development of a number of novel clinical and public health intervention strategies. the aim of the present study is to assess the level of ict use and to examine patterns of preferences among patients with chronic urticaria (cu). method: we will conduct an anonymous multicentre cross-sectional study, starting from january 2018, to investigate the use of icts in patients with cu, using a questionnaire as a survey method. this questionnaire will assess the frequency of use of social media and icts in patients, and their preferences for receiving and asking disease-related information. the survey will consist of 20 items, evaluating demographical information, time with disease, medication currently used, and additional aspects of social network use. results: we will use a chi-squared test to assess the association between internet access or owning a cell or smartphone, and age, gender, type of urticaria, educational level and number of years since diagnosis. we will employ the same test to assess the association between the independent variables previously introduced and the frequency of use of each ict type (short messaging service [sms], facebook, twitter, youtube, email, internet, linkedin and skype) as well as agreement in receiving and seeking information (i.e. asking questions to the practitioner) through such icts. we will perform adjusted regression analyses between categories of age, gender, educational level, type of urticaria, years since diagnosis and the use and level of interest shown in communicating through icts. our aim is to report on remarkable findings from a registry of a large sample of patients, potentially providing clues for its approach and results: 285 patients with a median length of 14 months suffering from urticaria were registered, being 71% women; mean age 35.9 years. in 72% of patients no causal agent was identified. parasites were found in 9.3% and thyroid peroxidase antibodies in 8.9%, while autologous serum skin test was positive in 47% and igg to mycoplasma in 42% of evaluations. two thirds of patients reported wheals on uas7, with just 1/4 having concomitant angioedema. almost 2/3 reported significant affection on quality of life because of itch by cu-q2ol. just 14% of patients achieved total control on first anti-histamines provided, and less than half had good control of urticaria. cetirizine was the first choice in 44%, followed by fexofenadine (15%) and first generation anti-histamines (16%). method: cases at 18-65 years of age which were being followedup in our clinic with diagnosis of chronic urticaria and were not receiving any antihistaminic medication for last one month were included in the study. cu-q2ol, uas-7, psqi and psg results of the patients were evaluated. correlation of data with each other in regard to sleep disturbances was evaluated. results: 21 patients were included in the study. patients' mean total score in cu-q2ol was 36.25 ± 13.23. patients' mean uas-7 value was 16.71 ± 9.41. mean total psqi was 9.75 ± 3.92, the ratio of total scores ≥5 and those with poor quality of sleep was 87.5%. mean epworth sleepiness scale (ess) score was 9.71 ± 2.05, with total score ≥10 in 52.4%. in psg, mean apnea-hypopnea index (ahi) was 11.93 ± 12.6, with 44.4% of the patients having ahi ≥5. when patients having ahi<5 were compared with patients having ahi ≥5, no significant difference was determined in regard to total cu-q2ol score, mean score for questions concerning status of sleep, uas-7 and psqi. when correlation analysis was performed between cu-q2ol and total score for questions concerning status of sleep, a positive correlation was determined with psqi (p = 0.037). conclusion: it was demonstrated in our study that patients with chronic urticaria had poor quality of sleep and this disturbance was independent from ahi. omalizumab was discontinued due to absence of improvement in csu symptoms after three consecutive doses. the plasmapheresis without intravenous immunoglobulin replacement was initiated. results: the symptoms were relieved during the first procedure and the disease improved shortly thereafter. the following weeks the symptoms still occurred but with lower intensity and severity. (angioedema was gone). the second attempt with omalizumab was successful after this course (5 procedures of plasmapheresis). case report: rosacea is a chronic skin disorder associated with flushing, erythema, dryness, burning and stinging, and inflammatory papules and pustules. new treatments available or in development target the inflammatory and erythematous components of the disease. these agents include the selective alpha-2 receptor agonist brimonidine. allergic contact dermatitis to brimonidine is an unusual condition. in addition to this, urticarias due to brimonidine are rarely reported. we report on a 35-year-old woman who, immediately after apply a thin layer of brimonidine gel as preparation for a rosacea treatment on her face developed facial urticaria, which reverted in approximately four hours with systemic steroids. she had previously tolerated this product without any problems, but has not use it again ever since. skin prick-tests with brimonidine (0.03 mg/ml) and latex were realized in the patient. skin prick-tests with brimonidine were realized in eleven healthy control subjects. results: skin prick-tests with latex was negative in the patient. skin prick-tests with brimonidine were positive in the patient (9x5 mm). the prick-test with brimonidine was negative in teen healthy control subjects. we report on a case of immediate urticaria due to brimonidine and triggered by an immediate, probably ige-mediated, hypersensitivity mechanism. we highlight this case because it is the only case described in the literature with a positive prick-test. method: the study was in accordance with the helsinki declaration and was previously approved by the national comity of ethics. this was a one dose study conducted on 16 fasting young healthy volunteers, of which 11 were females and five males. the mean age was 21 ± 1 years old and the body weight 61. 13 + 9.44 background: cetirizine is a potent h1-receptor antagonist indicated in the treatment of allergic rhinitis and urticaria. cetirizine is widely used due to its potent antihistaminic effects in yielding strong and fast relief of itchy sensation, sneezy and rhinorrhea and its unlikely probability to manifest anticholinergic side effects in therapeutic doses. histamine flare and wheal inhibition by anti-h1 are widely used as a standard to test and compare the effect intensity and duration. our study aimed to test these effects of cetirizine in young healthy adults. method: this was a double-blind, single dose study in healthy young adults, previously approved by the national comity of ethics. eleven females and five males with a mean age 21 ± 1 years participated in this study. histamine skin pricks were tested before and after they received a tablet of 10 mg cetirizine as previously scheduled. twenty minutes after each test flare and wheal were drawn in a transparent paper which was then scanned and measured with a software. wilcoxon signed ranks test two-sided with significance at 5% level was used to analyze the differences. claims that the preparation relieves itch within 60 seconds of its application. we performed a simple study to verify this claim. we used irp in 20 consecutive subjects, 15 males, median age 12, range 6-49 years, whose workup implied ast. their preliminary diagnoses were "asthma" (6 subjects), "allergic rhinitis" (10 subjects), "atopic dermatitis" (2 subjects) and "food allergy" (2 subjects). all of them had refrained from systemic antihistamines for at least one week. standard skin prick tests (spt) were applied as appropriate, including histamine controls to assess the level of their skin sensitivity. subjects were asked to mark their sense of itch in the area of the skin to be tested on 100 mm visual-analogue scales (vas) starting from "0"-"no itch" to "100"-"unbearable itch". vas assessments were repeated 20 minutes after ast was done; then irp was applied according to the manufacturer's instructions, and the vas assessments were repeated after 60 seconds and 20 minutes. results: there vas assessments are shown in table format: table 1 irp did not affect the wheal and flare of the histamine control, nor did it abolish positive spt. no differences were outlined between subjects with different diagnoses. the commercially available itch relieving preparation not containing defined pharmacological antihistamine is effecting in relieving itch associated with allergen skin testing. before ast (1) 4.9 ± 2.6 vs (2) p < 0. represent the first-line treatment for osteoporosis-related mastocytosis. we report a case of sm with bone pain and with an area of osteolysis in the femur as first sign and symptom. we had to consider the risk of adverse reaction when we decided to treat the patient with bp, but the patient was under antihistaminic treatment and also we made a premedication to reduce the risk. the pk/pd model available was informed by data from 12 clinical trials. the pd endpoint data was available from two studies and used to characterize the effect of bilastine on wheal and flare. moreover, food effect had been characterized in 2 pk studies and the data was used to model the effect of food in the pk of bilastine. the pk parameters relative to the fed state were then used to simulate the temporal evolution of the wheal effect using the pk/ pd model. all analyses were conducted by nonlinear mixed effect modeling (nonmem v 7.2). using the pk model developed (food effect model) and the pk/pd model already available, monte-carlo simulations for plasma concentrations and pd over time were performed for both the fed and the fasting states. results: . a reduced bioavailability (f) and a slow absorption constant characterized the pk of bilastine when administered concomitantly with food (f = 77% relative to the fasting state and ka = 0.51 hour −1 , a 3-fold reduction compared to fasting conditions). the rest of the pk parameters remained unchanged. onset of action was 1 hour for bilastine both in fed and fasted conditions. maximum wheal inhibition occurred at 3.5 hours (fasted 78% and fed 77%). from 2 to 12 hours, the percentage reduction with bilastine for both fasted and fed was between 75% and 86% after the third day of treatment. a 50% inhibition in wheal effect was maintained during 23 hours for both conditions after the third day. the results of the simulations show that even if the pk is altered with food, the pd is maintained unchanged. conclusion: even if a significant food effect was described for bilastine at a pk level, the difference is not translated directly into the pd. therefore, the antihistaminic effect of bilastine remains unaffected by the concomitant administration with food. the results of these simulations will be further confirmed in a dedicated clinical trial. results: we also found no correlation between the different tgt parameters and other clinical and analytical parameters associated with uc (table 1) results: both cetirizine products have no differences in respect to the pharmacodynamic and pharmacokinetic parameters analyzed. the 95% confidence interval of the mean ratios of the auc 0-24 , auc 0-inf , cmax, auce 0-24 , and e max , between the test and the reference, were within the bioequivalence ranges (80%-125%) in both cases. no statistical difference was revealed when comparing the respective t max and te max too. the two cetirizine products tested were bioequivalent. the bioequivalence was evident even when tested with the pharmacodynamic parameters. there is strong evidence that supports the use of histamine skin prick test for the bioequivalence evaluation of different cetirizine products. 1089 | bradykinin-mediated angioedema associated with combination of angiotensinconverting enzyme and dipeptidyl peptidase iv inhibitors: a disproportionality analysis from the who database method: we performed a disproportionality analysis using data from the who pharmacovigilance database by a case-noncase study, until the 14/12/2017. we extracted all individual cases safety reports (icsrs) included in the high level term "angioedemas", according to the medical dictionary for regulatory activities classification. given the absence of term "bma", we selected only the icsrs of angioedema without associated symptoms evoking another underlying mechanism, such as histamine angioedema (e.g. pruritus, urticaria, rash, etc.). drug class exposure was "acei" and "dpp4i", considered suspect or concomitant, using the atc classification. we results: there was no correlation between mother's disorders such as periodontitis, rhinitis, diabetes etc. and the onset of ar (p > 0.05). a multivariate analysis showed, neonatal jaundice (p < 0.001), respiratory system infection (p < 0.001), diarrhea (p < 0.001), eczema (p < 0.001) in the first 6 months of life and home environmental factors (house decoration (p < 0.001), mold environment (p < 0.001), keeping flowers (p < 0.001), passive smoking (p < 0.001)) increased the risk of ar. besides, there was no significant difference in current height and birth weight of the participants between ar and control group. however, ar group had significantly lower current weight (p = 0.003) and age (p < 0.001) compared with the control group. paternal age and maternal age in the ar group were significantly higher than the control group (p < 0.01). conclusion: diseases in the first 6 months of life and home environmental factors increased the risk of sequential ar. the older parents increased the possibility of ar in the offspring. the data of general characteristics of participants were statistic analysis by z text analysis. *significance at p < 0.05. results: anosmia was more frequent in crs than in rhinitis (28.1% vs 3.9%, p < 0.001) and in crswnp than in crssnp (40.6% vs 13.4%, p < 0.001). lms was higher in crs than in rhinitis (8 [4-15] vs 0 [0-0], p < 0.001) and in crswnp than in crssnp (10 [6-18] vs 5 [1] [2] [3] [4] [5] [6] [7] , p < 0.001). in addition, lms was associated with loss of smell in patients with hyposmia (or = 2.66 [1.27, 5.53 clinics. patients were submitted to confirmatory exams including oral provocation test with aspirin. nasal polyps were removed by functional endoscopic sinus surgery and eosinophils in this tissue were quantitated. eosinophil counts in peripheral blood was obtained. serum periostin was measured by elisa and total ige was determined using immunocap. as control groups, 12 (9f/3m) patients with par and 23 healthy subjects (14f/9m) were selected. samples of nasal tissue and blood were collected from these subjects during elective surgery for correction of anatomical variations, and compared with the patients with aerd. results: ar symptoms were significantly improved in the treatment group compared with the control group (76.6% (36/47) vs 21.7% (10/46); p < 0.05). furthermore, the mean total vas score for patients in the treatment group was reduced from 6.21 ± 1.83 before treatment to 1.36 ± 1.51 after treatment (p < 0.05). moreover, the reduction in free ige levels was greater in the treatment group than in the control group. the results of this study suggest that the chinese herbal medicine ber may be effective for improving the symptoms of ar. a multicenter clinical trial is needed to confirm this finding. results: in patients with "eosinophilic" polypoid rhinosinusitis, mucociliary transport was 35.2 ± 0.80 minutes, ph 7.4 ± 0.01, suction-88.6 ± 6.5 minutes, excretory-57.9 ± 0.9 mlg and in patients with "neutrophilic" polypous rhinosinusitis, mucociliary transport was 34.5 ± 0.65 minutes, ph 7.3 ± 0.01, suction-76.2 ± 5.0 minutes, excretory-54.9 ± 0.8 ml. the study showed that disruption of the transport function, changing the concentration of hydrogen ions method: this prospective controlled study was carried out on crs patients underwent ess. patients participating in the study were divided into two groups-group 1: partial middle turbinectomy (n = 22) and group 2: partial middle turbinectomy and middle turbinate fenestration (n = 23). objective assessment of olfactory function using the university of pennsylvania smell identification test (upsit) and subjective assessment of symptom using visual analogue score (vas) were performed before and 3 months after surgery. results: there were significant improvement comparing postoperative and preoperative upsit in both group 1 (35.23 ± 2.96 vs 32.23 ± 2.54, p = 0.000) and group 2 (36.09 ± 2.35 vs 32.04 ± 2.64, p = 0.000). the vas were also significantly improved postoperatively compared to preoperatively in both group 1 (5.77 ± 0.75 vs 6.73 ± 1.08, p = 0.000) and group 2 (5.13 ± 0.81 vs 6.78 ± 1.28, p = 0.000). patients undergoing partial middle turbinectomy and middle turbinate fenestration were more likely to show improvements in upsit (4.00 ± 1.20 vs 3.00 ± 1.11, p = 0.014) and vas (1.59 ± 0.21 vs 0.95 ± 0.15, p = 0.000) compared to those with only partial middle turbinectomy. conclusion: partial middle turbinectomy and middle turbinate fenestration during ess is an effective method for improving postoperative olfactory function. 1109 | nasal irrigation for the alleviation of nasal symptoms in pregnant women with allergic rhinitis we sought to determine specific ige responses to bacterial pathogens in sera from cystic fibrosis patients and analyze their kinetic during disease course. genes, respectively. in contrast, most of healthy donors had normal homozygous genotype with tt-60.0 ± 8.9%(n = 18) and cc-56.6 ± 9.0%(n = 17) with low frequency of mutations; gg-16.6 ± 6.8%(n = 5) and tt-23.3 ± 7.7%(n = 7) and heterozygous genotype tg-23.3 ± 7.7%(n = 7) and ct-20.0 ± 7.3%(n = 6) for il-2 and il-4 genes, respectively. following a 2 month treatment, there was a significant reduction of cytokine levels in the il2-29.5 ± 0.5 and increased in the il4-16.6 ± 0.4, when compared to the beginning of therapy and after 2 months (p < 0.001) results: at baseline the 1st group had serum levels of il-2 (43.6 ± 0.8) pg/l; il-10 (34.8 ± 0.8) pg/l and ifn-γ (108.2 ± 1.1) pg/ l; 2nd group had il-2 (39.6 ± 1.5) pg/l; il-10 (38.6 ± 1.2) pg/l and ifn-γ (103.3 ± 1.4) pg/l vs il-2 (21.6 ± 0.8) pg/l; il-10 (50.2 ± 1.2) pg/l; ifn-γ (63.8 ± 2.2) pg/l in the control group. after 2 months, there was a significant decrease in pro-inflammatory cytokine levels in the 1st (il-2: 35 ± 0.9; ifn-γ: 75.6 ± 1.9) pg/l and 2nd group (il-2: 28.6 ± 1.3; ifn-γ: 66.7 ± 3) pg/l, respectively. conversely, il-10 increased in 1st and 2nd groups to 41.9 ± 0.9 pg/l and 46.0 ± 1.7 pg/l (p < 0.05). conclusion: prior to the study initiation patients with tuberculosis had higher il-2, ifn-γ and lower il-10 content than healthy controls. two-month chemotherapy produced significant reduction in proinflammatory cytokines and increase in anti-inflammatory il-10, with levels approaching those of healthy controls. thus, tuberculosis drugs appear to have the anti-inflammatory effect in tuberculosis patients, which was predictive of positive clinical outcome. 1114 | antibiotic resistance: ligands of innate immunity take the challenge in this work, we aimed to perform an ex vivo hrsv infection in precision-cut lung slices (pcls) from human, rhesus, and cynomolgus macaques, comparing whenever possible the response with the viral surrogate poly i:c. method: pcls containing airways were prepared from lung sections of human, rhesus, and cynomolgus macaques. the slices were inoculated with hrsv-a2 10 6 iu/ml, uv-inactivated hrsv, or vehicle control for 48 hours. macaque slices were also incubated with poly i:c 100 μg/ml with and without the immunosuppressive dexamethasone 50 μg/ml. viral replication, tissue viability, and immune response assays were assessed in supernatants, lysates, or slices. the inoculum infectivity of 10 6 iu/ml as well the uv-inactivation were confirmed by plaque-assay on hep-2 cells. immunofluorescence staining using a fitc-labeled anti-rsv showed the presence of infected macrophages in pcls, but not in mock infected samples. hrsv stimulation slightly decreased tissue viability, as seen by live/dead staining and ldh assay. the viral infection increased ip-10 production in pcls of human, rhesus, and cynomolgus macaques, reaching respectively 13.3, 3.4, and 1.7 fold-increase in comparison to the vehicle controls. poly i:c stimulation caused ip-10 response comparable to hrsv in rhesus and cynomolgus pcls. the ip-10 production ratio comparing hrsv/poly i:c was 1.1 in rhesus and 0.9 in cynomolgus pcls. conclusion: hrsv infects ex vivo pcls of human and non-human primates, inducing the release of the pro-inflammatory chemokine ip-10. this response is comparable to the viral surrogate poly i:c. in the future, these systems can be used to further investigate host response to hrsv, especially in the context of asthma development. however, a relatively small number of reports are related to the association of ebv with allergic diseases, in particular atopic ones. we found that among patients with activated ebv infection, polysensitization was found to be 2.2 times more frequent, chest syndrome was 1.32 times more common and hyper-ige syndrome occurred 1.5 times more frequently. in most of these patients, atopy was not detected in medical history. method: we evaluated the laboratory test results of five boys (45.4%) and six girls (54.6%), 11 children (6 with hbov and 5 with cov). their average age at the study time was 59.2 ± 45 months. nasal swab specimens were taken from these patients who admitted to our hospital with respiratory symptoms between 2015-2016. patients are recalled after an average of 21 ± 2.5 months. isaac questionnaire and skin prick test to common inhalated allergens were performed. results: only one patient had family history of atopy. forty percent of the patients with cov and 50% of the patients with hbov developed rhinitis. one patient with cov and one patient with hbov developed recurrent wheezing. one patient with cov developed atopic dermatitis. all skin prick tests were negative. it was noteworthy that 72.7% of the patients were passive smokers. conclusion: hbov and cov may be associated with rhinitis but there is a need for more patient groups for a clear result. rna_lig (ccg-agg-aug-cga-ggc-uug-uu) . to study chemotaxis in vitro, a boyden96 chamber was used -wellfiltrationplatemultiscreentm -mic with a pore size of 8 μm (millipore, usa). chemotaxis was studied in dynamics after 10, 60 minutes and a day using the above ligands. as control, rpmi-1640 medium without glutamine was used (paneco, russia). the statistical analysis was carried out using the computer statistical program biostat2009 conclusion: with all the data provided, a drug induced hypersensitivity was diagnosed. we present a case of immediate allergic reaction with eosinophilia due to carbapenems, with tolerance to other beta-lactams antibiotics. written informed consent of patient has been obtained in the two cases. discussion: the first case shows cutaneous immediate hypersensitivity response to infbeta1a. literature reports a few cases of urticaria and anaphylaxis but this is the first for the pegylated formulation. polyethylene glycol (peg) confers to a drug modified pharmacokinetics, solubility and immunogenicity. immediate reaction to peg (macrogol) have been described when combinated in vaccines or drug pils. dmf is a known cause of contact dermatitis related to footwear, wallets and furniture. flushig is a reported side effect of dms in ms managed with dose reduction. this case shows the possibility to immediate sensitization to dmf. as the armamentarium to treat ms now combines immunomodulatory and biologic drugs, the avaliability of diagnostic and desensitization protocols for hypersensitivity reactions must be keeped in mind. case report: drug rash with eosinophilia and systemic symptoms (dress) syndrome is an uncommon but serious hypersensitivity drug reaction, manifested with rash, fever, lymphadenopathy and visceral organ involvement. table) . drug withdrawal and prednisolone treatment leaded to attenuating of mentioned skin symptoms within 2 days, associated by occurrence of a exfoliative dermatitis. one week after admission, the patient developed fever that lasted for 4 days with enlarged lymph nodes on submandibular, paracervical, axillar and inguinal regions. a preventive antibiotic therapy is started and 2 weeks later, the lymph nodes were not palpable and the skin got the normal appearance. corticoid therapy is reduced gradually according to symptoms resolvement. case 2: a 56-year old woman presented to our department with a 6-day history of pruritic, macular rash, periorbital swelling, cheilitis and fever. she had started some weeks ago the allopurinol for asymptomatic hyperuricemia, had longer history for treatment of arterial hypertension and type-2 diabetes mellitus (olmersartan, nitrendipine, methyldopa, furosemide, regular and glargine insulin), and experienced nephrectomy and cholecystectomy. the patient was febrile, while blood tests revealed eosinophilia, increased seric creatinine/urea levels (due to nefrectomy), and severely-altered liver parameters (see table) . the allopurinol withdrawal, topical and systemic corticoid therapy, and the liver protectors attenuated serologic transaminases levels and patient's skin lesions within few days, followed by substantial improvement of laboratory findings one week after therapy start. the treatment dosage was gradually tapered and finally stopped within a period of 2 months in accordance with attenuating and complete resolvement of the clinical and laboratory abnormalities. our case demonstrated that dress syndrome is a severe drug reaction, but the immediate introduction of treatment and supportive measures can improve disease's outcome even after a temporary exacerbation or severe affection of internal organs. case report: a 40-years-old woman, diagnosed of ischemic cardiopathy, developed an anaphylactic shock 5 minutes after the administration of 2 ml sulphur hexafluoride intravenous during an echocardiogram. she was treated in emergency room with a total recovery. 2 months earlier, she had developed an extensive erythematous-maculopapular rash converging in plaques in relation with adhesive dressings which had been placed during a hospitalization due to thoracic pain. an allergic contact dermatitis was suspected and recommendations thereon were given. interestingly, an arteriogram with iodixanol (icm) was carried out one week before skin reaction with good immediate tolerance. methods: blood test: blood count and serum chemistry were done during both reactions to contrast media. serum tryptase level was not measured during the anaphylaxis, but its baseline level was quantified later. conclusions: we present a patient with a double sensitization to parenteral contrast media: an anaphylactic shock due to sulphur hexafluoride and an atypical delayed exanthema related to iodixanol, and diagnose was obtained with st in both cases. this is the first documented case with a positive immediate st to sulphur hexafluoride. with the culprit drugs mixed with 10% and 30% petrolatum resulted negative. patient was suspected to have behcet's disease, and consulted to rheumatology department. oral colchicum dispert twice a day was prescribed. afterwards, patient achieved to take oral amoxicillin-clavulanate for a week without any hypersensitivity; and has been following by oral colchicum dispert maintenance therapy since then. the reported patient had one anaphylactic perioperative reaction to morphine and another anaphylactic reaction to tramadol during her diagnostic investigation. remain the question if this patient had two allergic anaphylactic reactions with cross-reaction between morphine and tramadol, or two non-allergic anaphylaxis due to "hypersensitive" mast cells. case presentation: a 61-year-old female was diagnosed with rectal adenocarcinoma. one year after radical surgery, progression with pulmonary metastasis was shown. in first line of systemic therapy she received premedication with pantoprazole, metoclopramide, clemastine and dexamethasone, followed by cetuximab infusion. during first minutes of infusion, grade 4 anaphylactic reaction occurred. a reaction started with generalized pruritus, urticaria, rhinitis, followed by hypotension, bradycardia and loss of consciousness. she was treated with fluids, clemastine and methylprednisolone. next day she received same premedication followed by panitumumab. during first 30 minutes she had grade 1 reaction with generalized urticaria. the third day she had generalized urticaria 10 minutes after metoclopramide application. skin prick tests with cetuximab (5 mg/ml) were negative, but intradermal test were posibat response was highly positive for both cetuximab and alpha-gal, with comparable values and dose response curves. thus, we showed 70%, 63%, 58%, 35% and 4% of cd63 positive basophils for stimulation with cetuximab (500-0.1 μg/ml), and 67%, 40%, 17%, and 1% for stimulation with alpha-gal (33.3-0.033 ng/ml). bat response to panitumumab was negative (<5%; 500-0.1 μg/ml). drug provocation with panitumumab was negative and patient received treatment with panitumumab. in the operating theatre, the skin is disinfected using povidoneiodine and pupil dilation is carried out with tropicamide (showing no immediate reaction in the surgery). method: as we are dealing with a late cutaneous reaction, the study of the medicine involved is carried out by means of epicutaneous medicine testing. in order to do the study of aflibercept, we wore gowns, two sets of gloves, a mask, eye protection and in a containment hood in the outpatients hospital. the patient diagnosed himself with dermatitis when in contact with povidone-iodine and despite the fact that the cutaneous provocation was negative, it is known that when there is surgery involved, there needs to be moistness and occlusion for it to show up clinically. the application of this antiseptic seems to lose its irritation and allergic properties when it dries on the skin and therefore tends to give a negative result in these patients, but this does not mean that they are not allergic to this antiseptic. we report the case of a 60 year old man who experienced erythema and pruritus immediately after an intravenous injection of ranitidine and hyoscine butylbromide given for gastric pain treatment. results: spt and idt were performed for ranitidine (10 mg/ml and 0.01 mg/ml respectively) and hyoscine butylbromide (0.5 mg/ml and 0.005 mg/ml respectively) being exclusively positive for ranitidine at idt dose with a 15 × 25 mm papule (histamine control 23 × 35 mm). oral provocation test for hyoscine butylbromide was negative. bat for ranitidine and famotidine were carried out, being negative for both drugs. conclusion: skin tests for h2ra are the best option when studying a suspected reaction to h2ra and are also useful for assessing cross-reactivity between other h2ra. the sensitivity for bat in diagnosis of drug allergy is about 50%, and the specificity up to 93%, although these percentages make reference to the common drugs studied (beta-lactams, quinolones, pyrazolones, etc). specific studies for h2ra are still to be done. in our case we had a negative result for the bat test, although we proved ranitidine was responsible for the reaction. conclusion: gentamicin is an aminoglycoside antibiotic used systemically for septicemia and as prophylaxis during surgery. immediate type allergy (type i) to gentamicin is rarely reported. since 2016, approximately only five cases have been reported in literature. in our case, initial theories were pointed towards cefazolin as beta-lactams report a higher rate of allergic reactions. after an exhaustive allergological study, results disproved our initial theory indicating gentamicin as the responsible drug. giangrande n 1 ; bobadilla-gonzález p 1 ; garcía-menaya jm 1 ; cámara-hijón c 2 1 allergy department, infanta cristina university hospital, badajoz, spain; 2 clinical immunology department, san pedro de alcántara hospital, cáceres, spain background: polyethylene glycol (otherwise known as macrogol or peg) is a polymer with a wide application as an excipient, solvent and dispersing agent in food, cosmetic and pharmaceutical industry. it presents distinct length polymer chains with a molecular weight from 200 to 10 000 000 g/mol conferring them specific properties. macroglol with a molecular mass between 3500 and 4000 g/mol is commonly used as osmotic laxative previously to colon endoscopy and radiologic examinations. after the introduction, anaphylactic reactions to macroglol are rarely reported, considering it safe and well tolerated. we report on a 56-year-old man who, immediately after of the topical application of benzindamine in left inferior limb developed acute urticaria in this limb, which reverted in approximately 2 hours with systemic steroids. she had previously tolerated this product without any problems. skin prick-tests with benzindamine (0.06 mg/ml) and latex were realized in the patient. skin prick-tests with benzindamine were realized in eleven healthy control subjects. results: skin prick-test with latex was negative in the patient. skin prick-test with benzindamine was positive in the patient (6 × 5 mm). the prick-tests with benzindamine were negative in eleven healthy control subjects. we report on a case of contact urticaria due to benzindamine and triggered by an immediate, probably ige-mediated, hypersensitivity mechanism. some of the drug used in daily clinical practice can cause allergic contact urticaria and should therefore be borne in mind. background: the use of new oral anticoagulants which act as direct inhibitors of activated factor x is constantly increasing, due to lower rates of serious and fatal bleeding events than warfarin/acenocoumarol. rivaroxaban, the first commercialized drug in this group, is the most used for prevention of thromboembolic events. however, <10 cases of hypersensitivity reactions have been described so far, most of them delayed and severe. to present a case of delayed hypersensitivity to rivaroxaban, diagnosed by a positive ltt (lymphoblastic transformation test). a 79 year old woman with hypertension and chronic atrial fibrillation (af) was referred to our clinic for suspected drug allergy. she reported that 2 months before, for af she was started on oral amiodarone and rivaroxaban, presenting on the seventh day with both of them generalized erythema, pruritus, micropapular rash and facial angioedema. no oral or other mucosal were observed, neither pustules, vesicles or blisters. blood eosinophilia, enlarged lymph nodes, renal and hepatic injury were discarded in emergency, where the new drugs were discontinued and replaced by acenocoumarol. the rash subsided one week later, with oral antihistamines. before and after the episode the patient also has been taking losartan and hydrosalurethyl, with good tolerance. she denied other adverse reactions. in allergy department we performed skin prick tests and intradermal tests with amiodarone (0.05 mg/ml and 0.5 mg/ml) and rivaroxaban (0.1 mg/ml and 1 mg/ml), and a ltt with both drugs, 3 months after the reaction. background: patients with history of beta lactam allergy, often self-reported, are commonly encountered in the hospital setting. this frequently leads to increase use of broad spectrum and more expensive antibiotics that may be unnecessary or even less efficacious at times due to fear and concerns about potential disastrous outcomes. nonetheless, with increasing awareness, many patients are now being referred to allergy service for formal evaluation. we aim to look at patients who underwent evaluation for beta-lactam hypersensitivity and determine the number of patients that were successfully de-labelled. method: a retrospective analysis was conducted with patients referred for evaluation of questionable beta-lactam allergy to the allergy service in our institution from the years 2016-2017. initial evaluation process included a thorough history to determine the type of hypersensitivity reaction and suitability for further testing. patients underwent skin prick test (spt) and intradermal (idt) with either (a) both major and minor determinants of penicillin, benzyl penicillin, amoxicillin and ampicillin, and/or (b) the culprit drug itself. if skin testing was negative, oral or intravenous (iv) drug challenge was then performed after informed consent. clinical details and reactions were documented. patients were also contacted post challenge to ensure no delayed reaction had occurred. results: a total of 130 patients were evaluated for beta-lactam allergy in the 2 year period, of these 80 were females and 50 were males. 107 of the referred patients had presumed penicillin group allergy and 29 had cephalosporin group allergy (3 patients had both penicillin group+cephalosporin allergy). 95 cases (73%) were successfully de-labelled. beta-lactam allergy was confirmed in 26 patients (20%); identified by positive spt in two patients, positive idt in six patients and positive drug challenge in 18 patients (15 patients developed rash/urticaria, 1 had respiratory symptom and 2 patients developed anaphylaxis). 14 patients were referred before any drug allergy labelling was done, out of which 10 were confirmed not to have beta-lactam allergy. conclusion: in our study, 80% of patients were confirmed not to have true beta-lactam allergy. we were able to successfully remove beta-lactam allergy label from the electronic record for 73% of the patients. results: a total of 66% referred amoxicillin-clavulanic acid (ax-clv) as trigger for the hypersensitivity reactions (hrs), followed by ax (21%), penicillin (6%) and cephalosporins (5%). almost 80% of hrs were immediate (<60 minutes). positivity of skin tests was observed in 65% subjects, of bat in 61% and of rast in 68%. in conclusion: the label of penicillin allergy is quite often erroneous. this involves using of more expensive and less effective therapeutic alternatives, which also facilitate the emergence of multi-resistant micro-organisms. hence the importance of confirming the diagnosis of allergy. finally, we did not find differences in the study of penicillin allergy in patients older than 60 years compared with the general population. background: severe cutaneous delayed drug reactions (toxic epidermal necrolysis -ten-, stevens-johnson syndrome -sjs-, acute generalized exanthematous pustulosis -agepand drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome -dress/dihs-) among others, are a rare but potentially fatal complications of drug treatment. although its epidemiology has been described in different latitudes, it is unknown in latin america. our aim was to describe the epidemiological characteristics of severe cutaneous reactions to drugs in countries of latin america. method: an online questionnaire was designed to report new and old cases (since 2013). it was a modified and adapted version of enda questionnaire for drug allergy interesting group. sociodemographic data, type of reaction (ten, sjs, dress-dihs, agep), culprit drug (s), treatment, complications, mortality and sequelae, were described. three centers from colombia, one from argentina, one from brazil and one from paraguay were included. an excel database was created, in which cases were recorded and analyzed. results: thirty seven cases were reported. 24 (65%) were women. the median age was 47 years. 19 (51%) had dress/dihs, 6 (16%) ten, 3 (8%) sjs, 3 (8%) agep, 3 (8%) other not classified scars, and 1 (2.7%) overlapping ten/sjs. the main culprit drugs were aromatic anticonvulsants in 17 cases (46%), beta lactam antibiotics in 6 (16%), non-beta lactam antibiotics in 3 (8%) and allopurinol in 2 (5.4%). in 100% of the patients the suspect drug was withdrawn. thirty one patients (83.7%) received systemic corticosteroids. complications occurred in 17 cases (49%) and death in one patient (2.7%). seven patients (19%) had some type of sequelae. countries, dress/dihs was the most frequently reported clinical entity, and the anticonvulsants were the main triggers. complications were frequent, but mortality was low. 1155 | drug-induced cough: analysis of nationwide spontaneous reports in korea over ten years using who-adverse reaction terminology (who-art) indicative of cough. results: from 856 524 cases of spontaneously reported adverse drug event cases, a total of 9003 cases (4.5%) were identified as drug-induced cough. most cases occurred in adults (93.4% of the subjects) and females were more common than males (54.9% vs 45.1%). regarding severity, only 629 cases (7.0%) were classified as serious based on who criteria. the most common causative drug category was antineoplastic and immunomodulating agents (24.8%), followed by cardiovascular drugs (24.2%). the most common causative drugs were ace inhibitors including perindopril and ramipril. conclusion: in the nationwide spontaneous reports of adverse drug events, many cases of drug-induced cough have been reported so far. much attention is needed to find new causative drugs of cough in the future. background: allergological assessment to determine the mechanism of the perioperative reaction and to identify the agent responsible and recommendation of a range of drugs or agents likely for future surgery is essential, but it often poses a significant challenge. in this study, we analyze our experience in the investigation of adverse reactions during anesthesia in the last 4 years. method: a total of 15 patients who attended our allergy unit with suspected perioperative reactions between january 2014 and december 2017 were reviewed retrospectively. the severity of the perioperative allergic reactions was graded according to ring and messmer system. results: grade iii, ii and i reactions were observed in 9, 1 and 3 patients, respectively. in 2 patient we didn't know the reaction suffered. tryptase measurements were available for 11 patients. of those, 3 and 4 patients had elevated and normal levels respectively and suffered grade 3 reaction. ige mediated reactions was diagnosed in 9 patients (60%): 3 for ßlactam antibiotics (33.3%), 2 for patent blue (22.2%), 1 for neuromuscular blocking agents-nmbas (11.1%), 1 for latex (11.1%), 1 for colloids (11.1%) and 1 for ranitidine (11.1%) . cefazolin was the ß-lactam antibiotics causing the largest number of reactions. non-ige-mediated reactions was diagnosed in 6 patients (40%). the allergy tests were negative and tryptase levels were normal. conclusion: in our series, among the 9 patients who suffered allergy reactions during anaesthesia and the cause was subsequently identified, ß-lactam antibiotics were the most common causative agent (33.3%), followed by patent blue (22.2%), nmbas, latex, colloids and ranitidine (11.1% each agent). in contrast, data from other authors indicated that nmbas were the most common cause of anaphylaxis, followed by latex, hypnotics, antibiotics, plasma substitutes and opioids. these differences might be due to the small size of our study, which was limited to our centre over the last 4 years and thus may not be representative. diagnostic evaluation. all patients signed an informed consent. we made a retrospective analysis of their clinical records and excluded 11 patients whose records were missing or incomplete. it was analyzed each patient's medical history (focusing allergic disease) and clinical reaction to the suspect drugs. signals/symptoms at pcc were characterized. we also studied the variation of the dpt's results when it was performed after a pcc. aim: to define and quantify the ongoing pharmacy needs in sustaining a large drug allergy assessment program. method: a retrospective review of pharmacy files was used to identify and quantify the drugs and dosages most frequently used and to determine prescription trends within the allergy testing program over the last 3 years. results: initially, this reaction was thought to be a result of a drug allergy, but upon further review and the onset of fever, we determined that it met the diagnostic criteria of jhr. his twin brother was diagnosed with penicillin and betalactamic allergy. neutrophilia 83% was to be underlined in the blood test. after this, drug oral challenge with penicillin was performed, ruling out penicillin allergy. conclusion: it is not uncommon to confuse drug allergy with jhr. jhr should be an anticipated reaction to early doses of antibiotic treatment for treponemal diseases, such as syphilis. antibiotic treatment should be continued; it is not a warrant to stop treatment. clinicians should be aware and anticipate jhr as a potential complication to early doses of antibiotic for spirochetal diseases such as syphilis or lyme, leptospirosis. the patient was unresponsive in oral drug provocation tests with amoxicillin-clavulanic acid, clarithromycin and trimethoprim sulfamethoxazole for 6 months. the patient could use these drugs. results: chronic abacterial inflammation of the prostate gland was accompanied by a significant increase in concentration of slpi, il-8, tnf-α, il-17 in the seminal plasma and serum concentration, and a decrease in the concentration of il-6 and tgf-β1 compared to healthy men (p < 0.05). there was no statistically significant difference between slpi, il-8, tnf-α, il-23, il-17, and tgf-β1 in the ejaculate of patients with inflammatory and non-inflammatory forms of cap (p < 0.05). the concentration of il-6 in ejaculate of patients with inflammatory forms of cap was significantly greater than in patients with non-inflammatory form of cap (p = 0.01). the inflammatory and non-inflammatory forms of cap are pathologically similar with changes in the concentration of the studied cytokines except for il-6 in both forms with signs of inflammation. the terms "leukocytic" vs "non-leukocytic" chronic abacterial prostatitis are more correct than "inflammatory" and "non-inflammatory" when describing chronic abacterial prostatitis. results: the status of all patients after dc immunotherapy was evaluated as satisfactory. heart rate, blood pressure in patients remained within the age norm. skin had normal color without rash or peripheral edema. there were no local or systemic allergic reactions. the body temperature after the injection did not exceed 37°c. conclusion: these results show, for the first time, that among mastocytosis patients, besides the already known periodontal disease risk factors that include diabetes, age, osteoporosis and alcohol consumption, the bone marrow mast cell burden is also associated with increased periodontal disease severity. results: metformin at relatively low doses (1-10 μm) was shown to mildly suppress ige-mediated responses, including degranulation (34% reduction, p = 0.0135), tnf-α (23% reduction, p = 0.0139) and il-13 (38% reduction, p = 0.0015) secretions in bmmcs. importantly, metformin at the same doses potently inhibited mast cell responses in all parameters (100% reduction, p < 0.0001 for degranulation; 87% reduction, p < 0.0001 for tnf-α; 90% reduction, p < 0.0001 for il-13) in mast cells treated with an ahr ligand, 5,11-dihydroindolo[3,2-b]carbazole-6-carbaldehyde (ficz). mechanistically, its inhibitory effect was mediated through the suppression of ficz-induced mapk activation, intracellular calcium release and ros generation. metformin also blocked ahr-mediated pca in vivo (90% reduction, p < 0.0001). conclusion: metformin, a common anti-diabetic agent, was shown to exert inhibitory effect on ahr-mediated mast cell activation in vitro and in vivo, suggesting its potential utility as a newer form of therapy for asthma and allergic diseases; this is particularly relevant when considering the adverse effect of the exposure to environmental polycyclic aromatic hydrocarbons. gasser p 1 ; brigger d 1 ; zbären n 1 ; jardetzky t 2 ; pennington l 2 ; eggel a 1 results: in one of affected family members, we were able to identify the c.9886a>g mutation in the plasminogen (plg) gene that was recently described to be associated with hereditary angioedema. this mutation leads to a missense mutation with an amino acid exchange p.lys330glu in the 3rd kringle domain of plasminogen. there is no direct relationship between the earlier described cases with this mutation and the family we report here. in all affected members of the family, the symptoms manifested in early adulthood, with swelling of the face, the tongue and the larynx. the frequency of attacks was variable, between once in a year to once in a month. in one of the three family members, we found a slightly decreased level of coagulation factor xii and of plasminogen. icatibant proved to be very effective for the treatment of acute attacks in the affected family. the occurrence of the same c.9886a>g (p.lys330glu) mutation in the plg gene in many families with no or only unknown distant relationship suggests that the disease might have been inherited through the generations without being purged from the population. the mutated amino acid exchange appears to be significant for the function of plasmin or plasminogen. we found a decrease in plasma levels of coagulation factor xii and plasminogen, which may be beneficial markers for diagnosis and monitoring of this disease. several biomarkers are useful in the diagnosis (fibrin degradation products (fdps), d dimer (dd), and fragments of prothrombin 1 + 2). also, a correlation between the levels of biomarkers and activity phases of the disease has been detected. alterations in coagulation parameters have an etiopathogenic role in the ae attack, but have not been considered as biomarkers of activity phases. tgt is a global coagulation test which quantifies in vitro the ability of plasma to generate thrombin and estimates alterations in coagulation parameters. the objective is to assess the usefulness of the thrombin generation test (tgt) to characterize patients with hereditary angioedema (hae). method: seventeen hae patients from hospital la fe were recruited to obtain blood samples in remission and during ae attacks. none of them experienced thromboembolic events. plasma was collected in citrate tubes to obtain platelet rich plasma. hemostatic parameters were analyzed:. tgt was conducted using a calibrated automated thrombogram (cat) method and a fluoroskan ascent as a reader. results were analyzed via thrombinoscope v5. citrated plasma was incubated with calcium, tissue factor, phospholipids and a fluorogenic substrate. a thrombin generation curve is generated, obtaining parameters: latency time (lagtime), thrombin generation maximum speed (vo), maximum peak of thrombin generated (peak), time to generate the maximum peak of thrombin (ttpeak), total quantity of generated thrombin (etp), and the end time of thrombin generation (starttail). tgt parameters from 322 healthy donors were used as controls. results: thirty-eight samples were collected from seventeen hae patients (58.8% female). fifteen (39.5%) samples were collected during ae attacks. tgt parameters and fdps were significantly higher in hae patients compared with controls (p < 0.0001), although no significant differences were found in tgt between acute attacks and remission. a decrease trend in tgt is observed in ae attacks. fdps were increased during ae attacks, but normalized at remission periods. these results support the involvement of coagulation in the pathophysiology of hae, although no increase in prevalence of thrombosis is observed during acute attacks. method: the repeated measures design study included 108 patients in two groups: the slit group, 63 patients-67 follow-ups per allergen (p), and the vit group, 45 patients-54 p. the slit group had patients treated for hdm (41 p), and patients on pre-coseasonal pollen ait (grass 11 p, ragweed 10 p, birch 5 p). the vit group had 28 patients on rush protocol (18 for bee and 9 for wasp) and 18 patients on conventional protocol (9 bee, 2 wasp, and 7 for both). the ige and igg4 levels were measured by the immunocap method. the friedman test was used to compare data. results: when compared to placebo group, slit+vitamin d group therapy was more effective in the reduction of nasal symptoms (p = 0.04), asthma symptoms (p = 0.001) and combined symptommedication score (p = 0.001); there was no significant difference between groups in medication and ocular scores. we observed a significant improvement of fev1 (vitamin d group p = 0.014, placebo group p = 0.015) and fev1%vc levels (vitamin d group p = 0.004, placebo group p < 0.001), within both groups, between visits. feno results did not differentiate statistically significantly the study participants in terms of receiving slit along with vitamin d or placebo. significant increase in the percentage of cd4 + cd25 + foxp3 + and in tlr positive cells in children receiving slit+ vitamin d was observed compared to placebo group. increase in cd4 + cd25 + fox-p3 + induction, and in tlr positive cells recruitment were independently associated with better clinical effect of slit in children. conclusion: overall, ait with a high-polymerized ash pollen extract was well tolerated. as ash pollen are supposed to be an important allergen during spring time, it is recommended to include spt and npt with ash pollen in the test panel for allergological diagnostic. additionally, determination of ash pollen specific ige could be applied. furthermore, appropriate ait should be considered for ash pollen allergic patients. 1194a | impact of sublingual immunotherapy with a five-grass pollen tablet on grass pollen allergic rhinitis and asthma: a real-life, long-term analysis in france background: data on the fulfilment of prescriptions of symptomatic medications in patients with grass pollen allergy were analysed to evaluate the long-term effectiveness of sublingual immunotherapy (slit) on allergic rhinitis (ar) and asthma. method: by using data in the lifelink ™ treatment dynamics database (iqvia, paris, france), we compared two cohorts of patients with ar: a group treated with oralair® (stallergenes greer, antony, france) slit tablets (n = 617), and a matched control group having received symptomatic medications only (n = 10 990). oralair®'s effectiveness was assessed as the change in symptomatic medication fulfilments between the pre-index period (before the initiation of slit) and the follow-up period (after slit), and as the onset of asthma or the progression of pre-existing asthma (based on fulfilments of prescriptions for asthma medication). the number of fulfilments per year was calculated for each patient and each period. results: in line with prescribing guidelines, the mean duration of treatment with oralair® was 6.3 months per season for either 2 seasons or 3 seasons. the mean number of symptomatic medications for ar fulfilled per patient and per year in the pre-index period was 6.7 ± 5.9 in the slit tablet group and 9.6 ± 7.7 in the control group. in the follow-up period, this value fell for the slit tablet group (to 2.6 ± 4.2) but did not change significantly in the control group (8.6 ± 8.1). when considering individuals not taking any asthma medications in the pre-index period, asthma onset during the treatment period was observed in 12.1% of those in the slit tablet group and in 15.8% of those in the control group. the corresponding values for the follow-up period were 1.2% in the slit tablet group and 5.8% in the control group. when considering individuals already taking asthma medications in the pre-index period, the mean ± sd number of asthma medication fulfilments in the pre-index period was lower in the slit tablet group (4.7 ± 4.6) than in the control group (8.1 ± 7.9). the corresponding values for the treatment period were 4.1 ± 5.4 and 10.2 ± 9.5, respectively. in the follow-up period, the number of asthma medication fulfilments fell more in the slit tablet group (to 2.3 ± 4.1) than in the control group (7.2 ± 9.0). oralair® tablets have long-term effectiveness by relieving allergic rhinitis and slowing a progression to asthma. 1194b | a real-life, retrospective analysis evidencing slower long-term progression of asthma in grass pollen allergy patients treated with sublingual immunotherapy tablets 1195 | an examination of the reasons for treatment discontinuation and non-compliance to allergen immunotherapy background: allergic rhinitis (ar) patients treated with subcutaneous immunotherapy (scit) and sublingual immunotherapy (slit) may be non-compliant or discontinue treatment too early, which can negatively impact efficacy. therefore, understanding the reasons for non-compliance and treatment discontinuation is vital to help improve compliance, persistence and thus outcomes. this study reported reasons for treatment discontinuation to scit and slit and non-compliance to slit in patients with ar in published real-world studies. method: a literature review was conducted in embase, medline, ebm reviews, psycinfo and econlit (1998-2017) using key search terms for allergic rhinitis, scit, slit, non-compliance and non-persistence. across all studies,~20% of patients were non-compliant, and 1-year drop-out rates ranged from 23% to 74%. reasons for noncompliance and treatment discontinuation in this subset of patients were stratified according to the who dimensions for adherence (patient-related, treatment-related, or socio-economic). results: from the 428 publications identified, six studies reported reasons for non-compliance to slit (n = 3) or treatment discontinuation (n = 3) to scit or slit, and the results were grouped for analysis. the majority of patients cited treatment-related factors as the primary reason for discontinuation (66% for slit, 50% for scit). common reasons were a length of treatment for slit and frequency of injections for scit. 45% of patients discontinued scit due to patient-related factors such as travel to doctors and waiting time for administration. only 24% of slit patients discontinued due to patient-related factors. socio-economic reasons for discontinuation were low for both therapies (10% slit and 5% scit). conversely, for non-compliance to slit, socio-economic factors were the most frequently cited reasons (50%), and included taking time off work and financial concerns. conclusion: of patients who discontinued therapy, treatmentrelated factors were the most cited reasons for scit and slit, reflecting concerns with administration and treatment length. noncompliant slit patients cited socio-economic factors as common reasons for non-compliance, suggesting financial concerns over a long treatment course. differences in reasons for non-compliance and treatment discontinuation may be due to patients assigning differing importance for compliance (a day-to-day decision) compared to the long-term decision to discontinue treatment. results: 53% of patients had monosensitization to rbet v1 component. the rest 47% had combinations ige to rbet v1 and ige to one, two or even three minor allergens (35%, 10%, 2% accordingly). after 2 courses of slit by standardized pollen extracts symptoms of arc and pfas decreased in 90% and 63% patients accordingly. in group 54 patients with monosensitization to rbet v1: 49 patients had a reduction of arc (85% had 3-4 degree by ado); 41 patients had reduction of pfas. 3 patients hadn't finished treatment due to allergic reactions. among 26 patients with sensitization to rbet v1/v6: 24 patients had a reduction of arc (75% -3 to 4 degree by ado); 17 had reduction of pfas. 1 patient hadn't finished treatment due to allergic reactions. in 9 patients with sensitization to rbet v1/v2: 7 patients had a reduction of arc (57% -3 to 4 degree by ado); 3 had reduction of pfas. 10 patients with sensitization to rbet v1/v2/v6 showed the similar results: 10 patients had a reduction of arc (57% -3 to 4 degree by ado); 3 had reduction of pfas. 2 patients had sensitization to all cra, and only 1 patient who also received slit with grass allergens had reduction of arc only (2 degree by ado). as the result of the study it was identified that beneficial effect of slit is highest in patients with monosensitization to rbet v1. the increase of sige sensitization profiles to minor birch allergens caused less efficacy of slit treatment. dermatophagoides pteronyssinus immunotherapy is independent of sensitization to blomia tropicalis among children with allergic rhinitis and asthma method: 95 children (5-17 years old) with allergic rhinitis and asthma sensitised to both dp and bt received 3 years dp-scit. clinical symptom and medication scores, serum specific ige and specific igg 4 were evaluated during dp-scit. in order to investigate whether the treatment outcome was dependent on the sensitisation pattern between dp and bt, patients were further grouped into dp and bt co-sensitisation and cross-reaction, according to positive or negative ige against bt major allergen (btma) blo t 5 and blo t 21. btma+ group, with specific ige to either blo t 5 or blo t 21, was defined as the co-sensitized group; btma-group, with no detectable ige to both blo t 5 and blo t 21, was defined as the cross-reactive group in this study. results: all the recruited 95 patients completed 1 year of dp-scit, 74 (78%) patients completed 3 years of treatment. after 3 years of dp-scit, compared to baseline, all patients had significant reduction in symptom and medication scores. lung function (fev 1 ) was significantly improved as well. 65% of the patients were free of medication use and asthma symptoms, 3% of them were free of rhinitis symptom, and the fev 1 % in all patients were higher than 95% of predicted. dp-scit induced significant increases in dp and bt specific igg 4 . in 50% of patients, dp specific igg 4 increased more than 67 fold and bt specific igg 4 increased more than 2.5 fold. further investigation in btma groups showed moderate correlation (spearman r = 0.48, p = 0.004) between specific ige against dp and bt in the btma-group (n = 34), indicating specific ige cross-reactivity. no specific ige correlation (spearman r = 0.03, p = 0.82) was found in the btma+ group (n = 61) indicating co-sensitisation to both dp and bt. the two groups showed almost identical change in clinical responses. dp and bt specific igg4 significantly increased during dp-scit, no difference was found between the two btma groups. conclusion: dp-scit can induce specific igg4 cross-reacting with bt allergens. patients with specific ige sensitisations to both dp and bt may have clinical benefit from dp-scit treatment. moreover, the clinical benefit of scit was independent of ige cross-reactivity or co-sensitisation to dp and bt. method: we investigated 16 allergic rhinitis children who were basically sensitized to house dust mite and received house dust mite slit for 1 year and 6 months. among 16 patients, 9 patients were mono-sensitized to house dust mite (group 1) and 7 patients were poly-sensitized aside from house dust mite (group 2). we also assigned another 7 allergic rhinitis children who were only treated by medication as control group. nasal symptoms (rhinorrhea, sneezing, nasal obstruction, nasal itching, sleep disturbance) and anti-allergic medications use were assessed at every 6-month visit. results: the symptoms of allergic rhinitis started to improve after 6 months of slit and significantly improved after a year and a half in group 1 and group 2 compared with control group. there was no significant difference between group 1 and group 2. anti-allergic medication use in group 1 and group 2 significantly decreased after a year and a half compared with control group and there was no significant difference between group 1 and group 2. conclusion: house dust mite slit was more effective than treatment only by medication. the effect of house dust mite slit was similar between mono-sensitized and poly-sensitized allergic rhinitis children. house dust mite slit could also be recommended to polysensitized allergic rhinitis children. method: a prospective, randomized, double-blind, controlled, multicenter phase ii study was conducted with four different concentrations of cluster allergoid clustoid wiesenlieschgras (group 1: 2000 tu/ml; group 2: 10 000 tu/ml; group 2: 30 000 tu/ml; group 4: 50 000 tu/ml). out of 103 patients screened, 83 grass pollen allergic patients (18-59 years) were randomized. the cluster build-up phase was followed by four monthly maintenance injections of 0.5 ml. the efficacy was evaluated by the change of the threshold concentration step needed to induce a positive reaction in a titrated nasal provocation test (tnpt) before start and after end of the study (pre-post analysis). the safety profile was assessed for each treatment group by analyzing treatment-related adverse events. background: allergen immunotherapy relies on the consistent administration of allergen extract, therefore compliance to these treatments (subcutaneous immunotherapy (scit) and sublingual immunotherapy (slit) tablets and drops) is vital for efficacy. as scit is administered as an injection by a healthcare professional, and slit is self-administered, compliance to scit may be perceived as superior. therefore, a review of real-world studies investigating compliance to scit, slit-tablets or slit-drops was conducted. real-world studies, instead of clinical trials, were included in this review as they are more likely to reflect actual clinical practice and patient compliance. method: a literature review was conducted in embase, medline, ebm reviews, psycinfo and econlit (1998-2017) using key search terms for ar, scit, slit-tablets and slit-drops, and real-world compliance. compliance was reported according to ispor medication compliance and persistence work group definitions. results: from the 428 publications identified, eight studies (seven slit [one slit-tablets, two slit-drops, four unspecified], one both scit+slit-tablets) reported compliance rates and were included in the analysis. real-world compliance rates ranged from 80% to 81% for slit administration and 83% for scit administration. only one study compared compliance of slit to scit, with similar rates reported over three years (81% and 83% respectively). three studies reported "good" compliance (physician-reported or patients consuming >60% of allergen extract) to slit-drops or slit-tablets. the good compliance rates were higher for slit-drops (90%-99%) compared to slit-tablets (77%-80%). observed compliance to slit-drops or slittablets did not vary by country or geographical region. the percentage of patients defined as having "good" compliance to slit-tablets or slit-drops did not vary by study length or patient population. conclusion: whilst compliance to scit may be perceived as superior to slit-tablets and slit-drops, comparable compliance rates between scit, slit-tables and slit-drops were identified across real-world studies. differences between perception and real-world results may be explained by a lack of direct comparisons between scit and slit administration. limitations included discrepancies in definitions of compliance, as well as methodology between studies. however, these are common to reviews analysing compliance, regardless of therapy area. conclusion: in the allergic rhinitis patients, successful compliance for 3-year slit compared with control was approximately 52%. method: igg inhibition elisa: rabbit igg antibodies specific for grass allergen allergoids are pre-incubated with different concentrations of alum-adsorbed grass pollen allergoid. the mix is added to an allergoid coated microtiter plate. unbound igg will bind to the allergoid coat and is subsequently incubated with anti-igg hrp labeled conjugate and stained with tmb. results are expressed as percentage inhibition relative to the uninhibited value. the concentration of alum-adsorbed allergoid that is required to inhibit 50% igg is used as read-out. circular dichroism: far-uv cd spectra (190-260 nm) were recorded on a j-815 spectropolarimeter. a cuvette with a stirring compartment was used to keep the suspension homogeneous during measurement. results: the igg inhibition elisa assay is specific for grass pollen allergoids (not for other allergen allergoids), has a good inter-and intra-assay precision and is robust for assay variation. thermally stressed alum-adsorbed grass pollen allergoids were used to show that the igg inhibition assay can be used as a stability indicating method. severe thermal stressing resulted in a higher 50% inhibition value, indicating a loss of igg epitopes. furthermore, far-uv cd analyses showed that there is a close relation between the decreasing igg binding capacity (50% inhibition values) and the loss secondary protein structures by unfolding (cd-ratio 207/222 nm values). the igg inhibition assay was demonstrated to be a valuable method to determine the stability of alum-adsorbed grass pollen allergoid preparations. in addition, a relation was shown between the igg binding capacity and the change in secondary protein structures. 1205 | design of a pivotal phase iii trial of allergen specific immunotherapy (ait) using a high-dose house dust mite (hdm) allergoid in patients with allergic bronchial asthma method: 1038 male and female outpatients (age 12-65 years) asthmatics allergic to hdm are enrolled. during the baseline phase, the patient's minimal dose of ics required to achieve asthma control will be assessed. after the baseline period, approx. 446 patients will receive double-blind placebo-controlled treatment for approx. 8 months, followed by a 2nd period of 16 weeks to assess the minimal ics dose and further 2 months of observation for the assessment of asthma exacerbation. based on the results of the dose finding study regarding the efficacy endpoints and the safety profile, the optimal allergoid dose is considered to be 5400 pnu. results: competent authorities and ethic committees in all participating 12 eu countries, serbia, russia and ukraine approved the study design. the primary endpoint of the trial is the change in predefined dose steps of the minimal daily ics dose required to achieve asthma control after approximately 8 months of subcutaneous ait. all efficacy data will be determined using daily questionnaires and the acq6 by e-diary for 4 months from october to january. the aim of this clinical trial is to demonstrate efficacy and to evaluate safety of ait with an allergoid preparation of major allergens of dermatophagoides pteronyssinus in patients suffering from allergic bronchial asthma caused by house dust mites. asthma increases the burden of allergic disease and health care costs, especially when uncontrolled. with the development of a high-dose preparation we intend to treat asthmatic patients highly efficiently. romantowski j; jassem e; lata j; wasilewska e; chelminska m; specjalski k; niedoszytko m background: specific immunotherapy (sit) is the only causal treatment in patients allergic to airborne allergens. it has been proven to be widely effective in allergic populations, but individual patients vary in terms of response to the therapy. the aim of the study was to assess the factors that might affect the efficacy of sit. method: patients treated with sit for grass pollen or house dust mites were included. the efficacy of sit was assessed with the use of allergy control score (acs), performed before and at least after one year of sit. the following variables were assessed as potential risk factors for a poorer response to sit: age, gender, type of allergy, type of allergen, type of vaccine, type of sit and smoking history. background: specific immunotherapy (sit) is a suitable treatment option for asthma and allergic rhinitis (ar), but it is not commonly used in korea. in the achievement of the treatment, it is important that immunotherapy is applied with ideal dose and regular intervals and it is essential for the patient compliance. the aim of this study is to investigate evaluate compliance with immunotherapy protocols of patients who were treated with sit in clinic and their satisfaction of the treatment. we performed a multicenter, cross-sectional survey using a specially designed questionnaire that was given to allergy specialists and patient in korea. a member of the trained research group conducted face-to-face questionnaire interviews with each respondent. conclusion: this study shows that most patients are ar with asthma. in our study sit compliance and satisfy are found to be high in both groups. aim: to identify the frequency of regress claims in a dermatological setting and to assess its impact on general prescription behaviour and immunotherapy. method: all physicians of the psoriasis-praxisnetz süd-west e.v. (n = 222) were invited to participate in a web based questionnaire study on the topics of dermatology and medical law. the survey was separated into two sub-polls which were carried out after a first poll deciding whether the topic of medical law is of any interest for the dermatological practice. the topic of interest was located in the second poll. results: overall, 66 dermatologists participated in this study. most participants were form bavaria, baden-wuerttemberg or rhineland-palatinate and had more than 10 years of experience as a dermatologist. out of the 66 participating physicians 28.8% (n = 19) already experienced a previous regress claim. of these, 73.7% (n = 14) stated, that the experienced regress claim changed their prescription behaviour. half of these participants (n = 8) further stated, that the fear of a possible recourse affects their prescription behaviour, whereas only 4 out of the 47 other participants declared a possible influence. missing values excluded, this leads to a substantial hesitation in physicians who experienced a prior recourse (50.0% vs 16.7%). nevertheless, this seems not to affect the usage of allergen immunotherapy, as all 19 physicians who already experienced a regress claim, stated to use allergen immunotherapy. the fear of a possible regress can change physicians' prescription behaviour but does not seem to have an effect on the prescription of allergen immunotherapy. therefore, the topic should be addressed from another perspective such as providing trainings on relevant regulations for physicians who experienced a prior recourse claim. this approach could also improve patient centred care related to modern treatments. results: the sds were significantly reduced in patients subjected to slit (p < 0.01) 1 year after the onset it. vas also was significantly reduced (p < 0.05) with satisfied control of sar and the same time with translation from moderate-severe to mild-moderate sar, after slit. nbh was also significantly reduced (p < 0.05) 1 year after the onset slit. in patients receiving pht only, sds, vas and severity of sar did not change and significantly higher (p < 0.01) from the value obtained in the experimental group. nbh also remained unchanged and significantly higher (p < 0.05) then in experimental group. precoseasonal slit added to pht shows short-term beneficial clinical effects in polysensitized patients with sar and scuad phenotype. results: ten studies (248 children, 99 adults; median sample size, 28) met the inclusion criteria. the risk of bias was moderate to high in all but one studies. low strength evidence supports the assumption that ait is effective in reducing symptoms and medication use, with only 5 out of 10 studies reporting higher benefit in the ait group vs comparator group. subgroup analyses of studies sharing similar characteristics did not explain inconsistency. safety does not appear was not major concern for alternaria ait. conclusion: this is not enough strength of evidence to suggest that mold ait is efficacious for the treatment of respiratory allergies. high-quality studies with an adequate sample size are needed. abstracts | 627 1213 | tolerability of a two week rush updosing with modified trees, modified grasses or modified grasses/trees mixture in pollen allergic subjects in the day-to-day practice table) severe systemic reactions (grade iii and iv) did not occur. conclusion: rush immunotherapy is an effective therapeutic method for patients with allergic rhinitis. it seems that in cases requiring faster response to treatment, this immunotherapy can be considered as a substitute for conventional immunotherapy. 1217 | design of a pivotal phase iii allergen immunotherapy study to assess the efficacy and safety of subcutaneously administered tyrosine adsorbed modified birch allergen+mpl results: the design of this study, including sample size and primary and secondary endpoints, will be discussed based on prior experience gained in two dose finding studies. in addition, the number of patients screened and randomized will be presented by country, gender and/or age and screen failures will be categorized. results: the primary analysis showed an absolute difference in tcs between placebo and 12 du of 3.02 (40%, p < 0.0001). the odds of experiencing a severe day during the bps were approximately doubled in the placebo group compared to the 12 du group (or = 2.12, p < 0.0001) and the odds of experiencing a mild day were halved (or = 0.52, p < 0.0001). similar results were seen for the tree pollen season (tps), covering both alder, hazel and birch pollen seasons. the total rqlq score was improved for 12 du compared to placebo during the bps and tps (p < 0.05, except for the last week of the tps), with the most pronounced effects during week 2-5 of the bps (absolute difference: 0.47-0.58, p < 0.0001). treatment was well tolerated. the most frequent adverse reactions were mild or moderate local reactions related to the sublingual administration. no deaths were reported and no serious adverse events were assessed as related to the sq tree slit-tablet. conclusion: treatment with the sq tree slit-tablet improved arc symptoms and need for symptomatic treatment. the 12 du group had less "severe days" and more "mild days" during the pollen seasons. the quality of life was similarly improved. these findings substantiate the clinical relevance of the sq tree slit-tablet for patients with arc induced by pollen from the birch homologous group. nagaraju k 1 ; nagaraju k 2 ; katare s 3 ; kapatkar v 3 ; shah a 3 ; rathod r 3 results: total n = 57 subjects (mean age 4.6 ± 2.09 years, 61.4% males) completed entire study. the mean incidence of artis reduced from 7.7 ± 2.34 episodes at baseline to 1.4 ± 1.23 (p < 0.001), with 31.6% subjects not suffering from any episode. the mean duration of episodes reduced from 8.2 ± 3.58 to 2.5 ± 1.23 days (p < 0.001). 64% of episodes (vs 95% at baseline, p < 0.05) required antibiotics for mean duration of 2.3 ± 0.98 days (vs. 6.6 ± 1.76 days, p < 0.001). none of arti episodes in follow-up period required hospitalization as against 22.8% episodes, (mean duration 5 ± 2.06 days; p < 0.05) before pidotimod therapy. the number of school days lost & work days lost showed reduction of 3.6 ± 5.34 days(p < 0.001) & 0.1 ± 4.07 days(p = 0.871) respectively. the average expenses incurred in treatment of artis shows significant reduction of rs. 13 193 ± 1541 (p < 0.001). 11 adverse events were reported in 8 (14%) subjects, which were mild in nature. a statistically significant increase in absolute counts of t-& nk cells was seen in explorative assessment of immune markers. the study shows pidotimod to be well-tolerated effective therapy in reducing the incidence and severity of recurrent artis, thereby providing additional benefit of reduction in discomfort & healthcare cost due to recurrent artis. thus, pidotimod can be considered as potential therapeutic option for treatment of recurrent artis in children. martignago i 1 ; ridolo e 1 ; incorvaia c 2 1 department of medicine and surgery, university of parma, parma, italy; 2 cardiac/pulmonary rehabilitation, asst pini/cto, milan, italy background: two registered sublingual immunotherapy (slit) products are available to treat grass-pollen induced rhinoconjunctivitis, consisting of the 1-grass (phleum pratense) and the 5-grass pollen tablets. no study of direct comparison of the efficacy of the two products was performed. we report the case of a patient who was treated in different years with the 5-grass or the 1-grass tablets with contrasting efficacy. the patient was a 18-year old woman suffering from 3 years of grass pollen induced rhinoconjunctivitis. in 2015 slit was started with the 5-grass pollen tablets, but in 2016, due to unavailability of the product, slit was performed by the 1-grass pollen tablets. in the third year of treatment slit with the 5-grass pollen tablets was resumed. for the 5-grass tablets slit was initiated before the pollen season and stopped after 7 months of treatment, while for the 1-grass tablets the treated was prescribed to be continuous. the efficacy of slit was evaluated by symptom-medication scores as reported in diary cards by the patient during the month of may, when the grass pollen usually reach the higher concentration in the atmosphere in lombardy, where the patient lives. results: the mean symptom-medication score in the first year of treatment (5-grass tablets) was 4.35, compared with a mean score of 7.2 in the second year (1-grass tablets). the patient was unsatisfied of the symptoms control and asked to resume for the last year of slit the 5-grass tablets. the mean symptom-medication score in such year was 0.77. no clinically relevant adverse event was reported with any slit product. conclusion: based on the momentary unavailability of the 5-grass pollen tablet, it was possible to assess in a same patient the clinical outcome associated to either of the two registered slit products. a significantly different efficacy of slit with the 5-grass tablets compared with the 1-grass tablets was observed. 1222 | fusion proteins consisting of bet v 1 and phl p 5 form ige-reactive aggregates with reduced allergenic activity najafi n 1 ; hofer g 2 ; gattinger p 1 ; smiljkovic d 3 ; blatt k 3 ; selb r 4 ; stoecklinger a 5 ; keller w 2 ; valent p 3 ; niederberger v 4 ; thalhamer j 5 ; valenta r 6 ; flicker s 6 background: bet v 1 and phl p 5 representing major allergens in birch and grass pollen, occur as monomeric proteins with high allergenic activity as assessed by clinical provocation testing in patients. she did not suffer more hymenoptera stings after the last reaction. one bee sting several years before bst resulted in no reaction. she has no symptoms with honey, vegetable or other food ingestion. methods: total ige and specific ige were determined using inmu-nocap system (thermofisher, scientific inc). apis, vespula and polistes (hørsholm, denmark) were also performed. prick tests showed negative results for all extracts tested. intradermal skin tests were positive for apis at 1 μg/ml, but negative for vespula and polistes. our patient was diagnosed of anaphylaxis due to apis venom, thus bst was contraindicated and an epinephrine autoinjector was prescribed. she rejected hymenoptera venom immunotherapy. conclusion: to our knowledge, this is the first case of anaphylactic reaction after bee sting therapy. bee sting therapy should be considered a risk factor for anaphylaxis. patient reported good control of their disease, improved their quality of life, tolerating contact and exposure to numerous horses as well as contact with clothes of people who had been exposed. although ita is absolute contraindication on uncontrolled asthma with a degree of evidence ia, our case had only "transitory" con and immunocap among wasp allergen components-i3, i209, i211 were 88%; 0.5, 90%; 0.6 and 68%; 0.4 respectively and honey bee allergen components-i1, i208, i217 were 95%; 0.9, 93%; 0.7 and 97%; 0.9 respectively. agreement between polycheck and immuno-cap i1 and i3 allergen components were 85%; 0.7 and 66%; 0.3 respectively. agreement between polycheck and euroline i1 and i3 allergen component were 86%; 0.7 and 61%; 0.2 respectively. based on wasp and bee components in all three systems, sensitization pattern was analyzed. similar test results were found between euroline and immunocap systems. the comparative studies carried out showed a markedly higher compliance of results with the euroline tests compared to polycheck with the immunocap system. percent agreement was extremely high and kappa value was substantial or almost perfect in the case of bee venom allergy between euroline results: a total of 113 patients were included; 80 (71%) males, with a mean age of 38 (±15) years; 23 (21%) beekeepers, 25 (23%) were atopic, 4 (4%) had asthma, 14 (13%) rhinitis and 18 (16%) cardiovascular disease, and 14 of these patients were on ace/beta blockers. vit with honeybee was proposed in 73 (64%), wasp 38 (34%) and polistes 2 (2%). the mean duration of vit was 45 (±16) months. however, 23 completed less than 36 months. of the total, 28 patients (25%) were not treated with vit. eighty-eight patients (78%) participated in the telephone interview: 49 completed vit (56%), 15 were still on vit (17%) and 24 did not undergo vit (27%). of those who completed vit, 14 (29%) were restung and 3 went to the emergency department (er). twenty-four patients (36%) were stung while still on vit. of those never on vit, 12 (50%) were re-stung and 9 went to er. the severity of the reactions according to mueller of the patients who completed vit (mean follow-up time was 45 months (1-110 months)) and were stung again was: local reaction in 11 (79%), grade i in 1 (7%); grade iii in 1 (7%). one had a toxic reaction after multiple stings. in those who were stung during vit, 20 (87%) had local reactions, 1 (4%) grade i and 2 (9%) grade iii. of those who were not treated and were re-stung: 3 (25%) had grade i, 4 (33%) grade iii and 5 (42%) grade iv. in this series, the patients who did not undergo vit presented a greater number of systemic reactions when re-stung as well as more severe reactions (p < 0.01). conclusion: in this group with indication for vit, the reactions of the re-stings were less severe in the patients who had completed or who were on venom immunotherapy, as expected. three quarters of those who did not undergo treatment had severe anaphylactic reactions when they were stung again. this study reinforces the importance and the efficacy of immunotherapy in the treatment of hymenoptera venom allergy. method: this is a retrospective, descriptive study of cases diagmethod: data were issued from the reference centre in mastocytosis of toulouse university hospital. ms diagnosis was determined using world health organization diagnostic criteria. hymenoptera venom immunotherapy was performed with an ultra-rush protocol (table) . results: seven patients were included (4 women, 3 men), median age 47 years old. during the anaphylactic reaction, cutaneous signs missed in all cases. the reaction was most often severe: grade 2 (n = 1), grade 3 (n = 5), grade 4 (n = 1). three patients suffered from digestive symptoms and one from respiratory manifestations. basal tryptase in serum reached 10.1-41.7 μg/l. hymenoptera venom specific ige were low (0.11-1.51 kui/l) except for one patient (35.6 kui/l). ait was initiated with vespula venom in 3 patients, polistis in 1 patient, apis mellifera and vespula in 1 patient, vespula and polistis in 2 patients. no reaction was observed during ait. four restringing accidents led to increase the cumulative dose to 150 μg and 200 μg in 2 patients. in these patients, the diagnosis of mastocytosis was made due to the resting. conclusion: hymenoptera venom ait using ultra-rush protocol seems well tolerated in patients with systemic mastocytosis. specific studies are necessary to determine the real tolerance profile of this protocol. collaboration with reference centres for mastocytosis should be considered for all patients with mastocytosis associated to hymenoptera venom allergy. dose (μg/ml) results: see table. conclusion: there is a shift or immunomodulation in terms of sige to vespids. even in patients double sensitised who were receiving venom of only one of the vespids. albanesi m background: slit has been suggested as an alternative route for allergen-specific immunotherapy. aim of this study was to investigate allergen-specific antibody responses in birch pollen allergic children who had received slit for two years using recombinant allergens. method: children (n = 28; 5-12 y o) with respiratory symptoms of birch pollen and oral allergic syndromes (oas) were studied. ten children received slit with staloral, 10 were treated by slit with microgen, and 8 children received only symptomatic therapy (control group). sige and sigg levels to rbet v 1, rbet v 2, rbet v 4 were measured twice (before therapy started and after two years) using quantitative immunocap and a panel of more than 170 microarrayed allergens using immunocap isac technology. clinical efficacy of slit was evaluated by recording symptoms upon allergen contact and need of rescue medication. results: all 28 children were sensitized to the major birch pollen allergen, bet v 1 and one patient from each of the groups showed to bet v 2, no patient had sige to bet v 4. after two years of slit clinical improvement was observed in the slit patients. in the staloral group there were no respiratory symptoms in 3 patients and a decrease of symptom severity in the other 7 cases as well as a partial or complete tolerance to pr10 allergen-containing food in the 10 patients. microgen treatment had no influence on oas symptoms but decreased of pollinosis severity in 8 children. however, there were no statistically significant differences of bet v 1-specific levels measured before and after treatment in the slit and control groups (mann-whitney, p > 0.05). in this real-life study we found that birch allergic children who had been treated with slit showed a reduction of clinical symptoms but we did not find a significant induction of allergen-specific igg levels in the slit-treated group when compared with children who had only symptomatic treatment. conclusion: our study confirms the scarcity of food additives allergy. it also suggests that even when the diagnostic of allergy was excluded with a negative oral food challenge, families remain suspicious about industrials feeding products containing food additives. these results should reassure health professionals and parents who incriminate too frequently food dyes and conservators when a manifestation which mimics allergic reactions occurs. background: autumn/winter birth has been reported to be a risk factor of food allergy (fa) development. a putative mechanism is that dry/cold weather causes and exacerbates infant atopic dermatitis (ad), which is a major risk factor for food sensitization through inflamed/damaged skin. we investigated prevalence of fa among infants under well skin care in relation with seasons of birth (sob). we recruited full-term newborn infants without perinatal diseases at an obstetric/pediatric clinic. participants were followed up for skin status and food allergy symptoms until 12 months of age. sob were defined as spring (march-may), summer (june-august), autumn (september-november) and winter (december-february). ad was diagnosed based on the united kingdom working party's criteria. use of moisturizer (mo) and topical corticosteroids (tcs) was recorded. primary outcome was fa based on apparent immediate allergic reaction after ingestion of causative food. we classified infants who avoided any food because of sensitization or mother's anxiety as suspected fa. results: six hundred and thirty-one infants were screened for 12 month-period and 531 infants were enrolled in this study. of them, 277 infants were born in spring-summer (s-born) and 254 infants were born in autumn-winter (w-born). fa developed in 24 (4.5%) infants and 31 (5.8%) infants had suspected fa. there was no difference (p = 0.68) in prevalence of fa and suspected fa between s-born and w-born. multivariate analysis revealed ad at 2 and 7 months of age was a significant risk factor for fa with or=2.6 (95%: 1.1-6.0) and or=3.5 (95% ci: 1.4-8.9), respectively. prevalence of ad at 2 months of age was higher in w-born than s-born but prevalence promptly decreased thereafter and stayed low with early use of mo and tcs. prevalence of ad was rather higher at 7 months in s-born than w-born. results: 160 cases and 126 controls were included. the median age was 44 years, (q1-q3 33-53). men and women were almost equally represented (50.35% males). alcohol consumption associated with the intake of mammalian meat or innards as the trigger factor. the overall prevalence of a positive result of sige to α-gal was abstracts | 645 15.7% ic95% (11.5, 20 .0); cases _26.3% ic95% (19.4, 33.1) controls _2.4% ic95% (0.0, 5.1)_. among cases sige anti α-gal positivity rate ranged from 55.8% (rural), to 35.7% (half-urban) and 12.6% (urban). the rates of positivity were 69.5%, (northern) 1.4% (center) and 0% (mediterranean). a positive result of sige to α-gal was more frequently observed among men (24.31%) than women (7.04%) and associated with history of tick bites, practice of outdoor activities, pet's ownership and the antecedent of having eaten mammalian meats or innards previously to the development of symptoms background: a special challenge in the 21st century for allergists is allergy to food, which is considered "the second wave" of epidemics of allergic diseases. panallergens occur in unrelated organisms and perform a similar function in them. in their structure, they have highly conserved amino acid sequence regions and a similar three-dimensional structure, and thus meet the requirements for cross-recognition by ige. results: in 46 patients (92%) isac test has been shown to have specific ige for panallergen components. mostly, the presence of ige for pr-10 proteins has been shown in 41 patients. in 12 patients ige to ltp; 11 patients ige to ccd; 6 patients to profilin; 5 patients to tropomyosin; 4 patients to serum albumin, 1 person to tlp. an important aspect is undoubtedly the occurrence of simultaneous sensitization to several panallergens. analysis of data from the study group showed that isolated sensitization to one panallergen concerned only pr10 proteins (24 patients), tropomyosin (2 patients) and profilin (1 patient). in the remaining 19 patients, the analysis of the isac test results showed that two or more panallergens were allergic. in the study group, asige for the component responsible for the occurrence of real food allergy was detected in 13 (26%) patients. mostly, the presence of ige for jug r 2 has been shown in 9 patients. in the study group, panallergens were more likely to be responsible for food intolerance than specific food allergens. results: of 43 children, 14 children had peanut allergy only, 14 children had tree nut allergy only, and 15 children had both. the mean age was 3.3 ± 1.9 years in peanut allergy, 5.0 ± 3.6 years in tree nut allergy, and 4.2 ± 3.0 years in both. male to female ratio was significantly higher in tree nut allergy (78.6%) than peanut allergy (42.9%). among tree nut allergens identified, walnut (75.9%) was most frequent, followed by almond (55.2%), hazelnut (34.5%), pine nut (20.7%), chestnut (13.8%), cashew (6.9%), pistachio (3.4%), and macadamia (3.4%). mean serum total ige level was 888 kua/l in tree nut allergy and 1440 kua/l in peanut allergy. mean serum specific ige level to peanut, walnut, almond, hazelnut, and pine nut was 30.0, 21.9, 14.2, 22.4, 5.6, and 6 .3 kua/l, respectively. children with peanut allergy had higher rate of co-sensitization with soybean and higher soybean-specific ige levels than children with tree nut allergy. however, there was no difference in co-sensitization rate with tree pollen between peanut and tree nut allergy. children with peanut allergy showed significantly increased co-sensitization rate with egg white and wheat compared to children with tree nut allergy. a 42.8% of the children with peanut allergy and 28.6% of tree nut allergy showed co-sensitization with aeroallergens. a total of 75% of the children with peanut allergy showed decreased specific ige levels within 1-5 years. conclusion: prevalence of peanut and tree nut allergy is similar. tree nut allergy develops later than peanut allergy and more common in male. children with peanut allergy showed higher co-sensitization rate with soybean, egg white and wheat compared to children with tree nut allergy. 1257 | natural history of egg allergy in a large cohort of infants with food allergy shows its high prevalence but also its transient nature in a 36 months of follow-up background: the cohort of 80 infants (55 boys,25 girls,3-36 months) with the food allergy has been followed for 36 months. as more than 70% of infants manifested atopic dermatitis (ad), a condition closely linked to egg sensitisation, we focused our attention on egg allergy, following its natural history as well as a development of atopic march. method: the diagnosis of food allergy was based on a personal history, clinical examination, skin prick tests and/or atopy patch tests with native foods. laboratory tests were performed within 1 year of age the latest. the specific ige levels against food allergens were measured using immunocap or immulite. patients with ad were scored according to scorad system. the oral food challenges (ofcs) with cooked/baked egg were done in children at the age of 12 months except for children at risk of anaphylaxis. results: within the whole cohort the allergy to cow milk proteins was confirmed in 70 pts (87.5%), to egg in 35 pts (43.7%), to wheat in 8 pts(10%), to lentil in 3 pts (3.75%) to banana in 3 pts (3.75%), to soya in 2 pts (2.5%) and to potatoes in 1 pt (1.25%). in a cohort of 35 egg allergy patients we found out that: 83% of pts presented the early onset of allergy-up to 3 months of age, 80% of pts presented severe ad (scorad >50), 46% of pts showed cosensitisation to peanuts, 34% of pts had early sensitisation to inhaled allergens, and majority 54% of pts presented with early onset allergic rhinitis and/or asthma. we proved that egg allergy is closely linked with the early onset of allergy symptoms, with severe forms of ad, co-sensitization to peanuts, early sensitisation to inhaled allergens and an early onset of allergic rhinitis and/or asthma. we also proved that the egg allergy in infancy is transient. the tolerance to baked/cooked egg was achieved in about 75% of pts at the age of 3 years, unlike previously published results claiming the reach of tolerance in 75% of pts at the age of 7 years. in these patients we studied: sex, personal history, type of reaction they presented, time of onset of symptoms and food involved. results: out of a total of 1479 patients over 60 years of age (from 60 to 99 years old) who have been attended the consultation for the first time during these period, 70 patients (4.7%) ask about possible allergic food allergies. of these patients who came for possible allergic pathology, 28 patients (40%) presented positive results. these are the other item we have studied: 1. sex of patients: 55% of the patients are women. these patients because of that, it is important to remember that food allergy can also appear in old people. the food that is mainly involved in our population is fish and seafood. a much higher percentage than in other populations, probably due to the mediterranean diet of spain. the symptoms mainly involved are itching and skin lesion, which is the characteristic symptom of a mild allergic reaction. in our population, there was 3 patients with a anaphylactic shock, a much higher percentage than in other studies. the experience with this group of patients is still limited. more studies are needed to know better this patient profile. background: cow's milk allergy (cma) is the first atopic disease in children. diagnosis suspicion in the emergency room (er) is increasingly frequent, however, further assessment by an allergist is often difficult to schedule. therefore, screening for cma through a blood test (specific ige) while the infant is still in the er has gained momentum in recent years. we set out to analyse (a) symptoms which had led the emergency physician to prescribe specific ige, (b) the prevalence of confirmed cma among infants screened in the er, and (c) the long-term outcome of the screened infants. method: a retrospective study of medical records and laboratory results was performed. patients were infants under 6 months, without a previous diagnosis of cma, attending one of the two pediatric er of the university hospitals of marseille, france. allergy blood tests were specific ige to cow's milk extract (immuno-cap, thermofisher, sweden). in infants with specific ige to cow's milk extract of 0.12 kua/l or higher, ige directed to the main three individual proteins (casein, alpha lactalbumin et beta lactoglobulin) were also measured. results: 482 infants were included from december 2011 to june 2016. the sex ratio was 1.45. 40% of infants were atopic et 48% were currently or had been breastfed. the most prevalent symptoms were vomiting and reflux. one third of infants were hospitalized after the er visit. following the er visit, 25% of infants attended a specialized consultation with an allergist. 15% of infants with a follow-up visit were diagnosed with an ige mediated cma. 18 infants with cma developed further food allergies (egg, nuts, cashew…). it is difficult to diagnose it. the emergency pediatrician are increasingly confronted to infant with symptoms evoking cma. thus they prescribe sige and extensively hydrolysed proteins because they know that ige-positive infants can be ige-negative during the interval between the er visit and the follow-up one. after bad results interpretation of blood assay after er visit, cma was probably over diagnosed without prick test for ige positive allergy and no eviction/ reintroduction test for non ige. the lack of allergist is probably leading to over prescription of blood assay in er to diagnose cma and prolonged eviction of milk. results: a total of 96 patients were included (59% female) aged from 18 to 82yo with an average 33.9 ± 15 years. 77% of patients had history of atopic disease: 60% rhinitis, 30% asthma, 9% prior food allergy, 8% eczema, 6% drug allergy, 5% eosinophilic esophagitis (ee) and 3% chronic urticaria. mean serum total ige was 441.9 ui/ml. sensitization to aeroallergens was present in 63% of patients, the most common were dust mites (22.9%), pollen (15.6%) or both (25%). in 69(72%) patients, first symptoms of fa appeared ≥18 yo, with an average age of 35 ± 15.4 yo. in this group, 4 were diagnosed with ee, 1 with eosinophilic colitis and 2 with eosinophilic gastritis. from the remaining 62 patients, 20 had history of reaction with more than 1 food group (fg). cutaneous reactions were referred in 60% of patients followed by anaphylaxis (20%) and gastrointestinal symptoms (10%). the fg most commonly implied were: fresh fruits (n = 26), seafood (n = 19) and tree nuts (n = 6). fa diagnosis was confirmed in 66% of patients, the remaining had negative ofc. in 27(28%) patients, their symptoms started under 18 yo, with an average age of 11.5 ± 5yo. from this group, 10(44%) were diagnosed ee. from the remaining 17 patients, cutaneous complaints were the most frequent (47%) followed by gastrointestinal (35%) and respiratory symptoms (17%). the most common fg implied were: fresh fruits(n = 9), seafood(n = 4) and tree nuts(n = 3). only one anaphylaxis was referred. fa was confirmed in 82%, the remaining had negative ofc. in patients with history of anaphylaxis 13 of 14 had positive st and/ or sige; one had negative sp and sige, with ofc positive. the 401 blood donors were classified based on their clinical symptoms related to possible as contact via fish intake: allergic to as (1%), chronic urticaria (0.5%), unspecific dyspepsia (2.8%) and asymptomatic (95.5%). the prevalence of sensitization (anti-as ige >0.35 kua/l) were 12.7% (ic: 9.6-16.4%; mean 0.69 kua/l; median 0.03 kua/l) with a maximum value of 40.70 kua/l. raw fish consumption was the only variable associated with statistical significance (p < 0.05) to as sensitization (20.4% vs 9.5%, respectively). albacore and codfish were the most consumed species associated to seropositive results (15%), followed by hake (10%). coastal population (13.6% vs 9.3%), non-previously frozen fish consumption (13.7% vs 9.2%) and >3 times per week fish consumption (51.2%) were other seropositive associated factors. background: oral allergy syndrome (oas) is an ige-mediated allergy caused by raw fruits and vegetables in patients with pollen allergy, which is known as the most common food allergy in adults. however, there has been no nation-wide study on oral allergy syndrome in korea. the aim of this study is to investigate the prevalence and clinical manifestations of oas in korea. method: twenty two investigators from 19 hospitals and 2 private clinics participated in this study. the patients with allergic rhinoconjunctivitis and/or bronchial asthma with pollen allergy were enrolled to the survey. the questionnaires include demographics, a list of fruits and vegetables, and clinical manifestations of food allergy. pollen allergies were diagnosed by positive results of one or more pollen allergens including birch, alder, hazel, beech, oak, willow, poplar, bermuda, meadow, orchard, rye, timothy, mugwort, ragweed, hop japanese on allergy skin prick tests (allergen/histamine ratio ≥3+) and/or serum specific ige levels using multiple allergen simultaneous tests (mast ≥2+) or immunocap (≥0.35 ku/l). conclusion: this is the first nation-wide study for oas in korea. the prevalence of oas in korea was 41.7%, in which substantial proportion had anaphylaxis. these results will provide useful information for clinicians to apply in clinical practice. we conducted a self-administered, questionnaire-based survey in 2013-15 during the 18-month checkup. children were considered to have food allergies if they were diagnosed by a physician or if they had been instructed to avoid a causative food after medical examination by interview. we divided the year into three periods. the months of march-june were considered spring, july-october as summer/fall, and november-february as winter. while the season of onset for the 4095 boys occurred in 8.2%, 12.7%, and 15.3% in spring, summer/fall, and winter, respectively, it was 6.9%, 10.5%, and 12.2%, respectively, for the 3922 girls. thus, the onset rate was the highest in winter for both genders. in boys whose mothers did not consume folic acid (fol − ), the food allergy onset rate was significantly higher for boys whose mothers ate no eggs and for boys whose mothers ate 2-5 eggs per week than for those whose mothers ate eggs daily according to the dunnet multiple comparison test. however, no relationship was observed with egg intake if the mother had consumed folic acid (fol + ). on the basis of seasons, fol − and egg intake by mothers affected only children born in winter, with a significant difference in the dunnet multiple comparison. among mothers who did not eat eggs, fol + was 15.2% and fol − was 28.2%; for mothers who ate 2-5 eggs per week, fol + was 16.5% and fol − was 12.9%; and for mothers who ate eggs every day, fol + was 17.9% and folwas 4.9%. thus, consumption of folic acid seemingly annulated the effects of eating eggs. however, for girls, neither folic acid nor eating eggs had any effect on the onset rate. conclusion: since this effect varied according to the birth season, consumption of folic acid, a methyl group donor, appeared to affect the allergy onset in children. results: skin prick test with commercial extracts of tuna (7 mm), cod (5 mm), rooster (8 mm), hake (6 mm), salmon (4 mm), trout (7 mm) and anisakis (7 mm ige to shrimp, lobster, crab and mixed seafood were all undetectable. dermatophagoides pteronyssinus 10, to assess for tropomyosins was negative. outcome: the patient continues to react to both hdm and shrimp, despite undetectable ige levels to tropomyosin associated components. this is the only testing available in south africa currently and hence we are unable to look at other proteins. the relationship between tropomyosins in shellfish allergy and mite allergy has been well documented and investigated, but other allergens are now also being implicated in cross-reactions. we also established the level of ige specific to allergen components using the immunocap isac method. allergen-specific ige was not elevated to any shrimp allergens available in immunocap isac: n pen m1 (tropomyosin), n pen m2 (arginine kinase) and n pen m4 (calcium binding sarcoplasmic protein). the patient was diagnosed with a shrimp allergy. the molecular diagnostics used did not explain which allergen component is the patient allergic to. it is possible that the patient is allergic to hemocyanin, which can also cross-react with house dust mite allergens, but confirmation of this diagnosis requires further investiresults: the groups were identical in terms of the age and sex (table 1) . ara h 2 ige correlated (spearman test) with the cumulative protein dose (threshold dose) r = −0.439 (p = 0.023) but not with reaction severity r = 0.091 (p = 0.348), or the use of adrenaline r = 0.300 (p = 0.093). patients with ara h ige < 10 ku/l had higher threshold doses (644 vs 71 mg) than children whose ara h 2 ige was ≥10 ku/l (p = 0.016). there were no significant differences in severity of the reaction or in use of adrenaline (table 1) . the level of ara h 2 ige is relevant in predicting the threshold dose at peanut exposure. a low reaction threshold dose increases the risk of reaction at an accidental exposure leading potentially to a severe reaction. flaxseed allergy is uncommon and most of the cases reported involved anaphylaxis. cross reactivity has been described with other seeds. case report: a 9-year-old atopic girl diagnosed with egg allergy and rhinoconjunctivitis and asthma due to pollens. when she was eight, she presented two reactions consisting of conjunctival, periorbicular, malar erythema and abdominal pain after eating egg free french toasts cooked with flaxseed. she was treated with oral antihistamines. the allergic workup included prick-by-prick test with flaxseed which was positive and skin prick tests with mites, molds, cockroach, cat, dog, profilin, ltp and pollens with positive results for olive and grass pollens. the serum total immunoglobulin (ig) e was 476 u/l, and specific ige to flaxseed was 7.23 kua/l. the flaxseed extract was resolved with sodium dodecyl sulfate polyacrylamide gel electrophoresis (sds-page) and an ige immunoblotting was performed under nonreducing conditions. the patient's serum showed specific recognition of a 18-kda band in the immunoblot. proteins were identified using mass spectrometry (maldi-tof) that showed results highly consistent with conlinin, a 2s storage protein of flaxseed. we described for the first time a patient with allergy to flaxseed due to conlinin, a 2s storage protein of flaxseed. background: cyperus esculentus is an herbaceous plant that has edible tubers called tiger nuts. in spain, they are used mainly in the elaboration of the well-known "horchata" or tiger nut milk, which is obtained by macerating tiger nuts with water and sugar. tiger nut allergy has rarely been reported, despite of its widespread consumption. case report: we present the case of a 19-year-old male with a history of oral syndrome allergy with several fruits (peach, melon, banana, kiwi, apple, pear and plum) and seasonal allergic rhinoconjunctivitis due to grass pollen. he reported oral pruritus, vomiting and cutaneous itching in both arms and hands immediately after drinking tiger nut milk. he became asymptomatic without treatment after 3-4 hours. the allergic workup included skin prick tests with profilin, ltp, latex and fruits that were positive to melon and watermelon and negative to profilin, ltp, latex and the rest of the fruits. prick-by-prick tests with melon, banana, kiwi, apple, pear, tiger nut and tiger nut milk were positive. the serum total immunoglobulin (ig) e was 68.7 μg/l, and specific ige was negative to profilin, ltp, bet v1 and all the tested fruits. background: specific blood ige tests for food allergens are mainly used to confirm a suspect food allergy than to diagnose such an allergy. this is due to the low positive predictive value and the high negative predictive value they have. nevertheless, they are very helpful when they are interpreted in the context of medical history by an experienced allergist. we analyzed the prevalence of sige in children with suspected food allergies. we retrospectively analyzed the all the consecutive laboratory tests of sige for food allergens during the two-year period (2015) (2016) (2017) . tests were of children diagnosed or suspected to have food allergies. a quantitative immunoblot assay was used to measure the circulated 30 different sige. t-test, wilcoxon signed rank test, and chi-square were used to make comparisons. results: fifty-six (55.4%) men and 45 (44.6%) females, 3.4 + 3.2 years old with a maximum of 16 years and a minimum of 2 months old were part of 101 children whose tests were analyzed. one-third of the tests (30.7%) reveals more than one sige present and 55.4% of the tests resulted negative for the sige for the 30 allergens tested (table) . only 3 (3.0%) children have very high concentrations (>100 iu/ml) of egg whites sige, and 2 (2.0%) have egg yolk sige. concentrations of 79.27% of sige positive cases were 0.35-3.5 iu/ml. in our study more than half of the children suspected of food allergies resulted negative for sige for 30 most common food allergens. seventy-nine percent of the positive cases had relatively low sige. only a few positive cases have higher sige than 100 iu/ml. our data support the recommendation that sige couldn't be decisive in food allergic diagnosis, but they may help if they are interpreted cautiously. method: seven patients with a mean age of 61.4 years and female to male ratio of: 3:4, with a background history of hypertension treated with an acei presented with oro-pharyngeal irritation (itch, tingling), face and tongue angioedema and laryngeal constriction, on ingesting fresh fruits (cherries, apples, plums, peaches, apricots, strawberries, grapes), vegetables (parsnips) and/or nuts (peanuts, hazelnuts). two patients required admission to emergency department and three received adrenaline auto-injector. six out of seven patients underwent skin prick testing to common aeroallergens and the index foods. in five cases, immunocap/isac testing was undertaken. in one case the diagnosis was based on the history and in one other case it was based on history and skin prick tests. results: a diagnosis of pfas was confirmed in all patients through the clinical history, spt and/or specific ige serology to the offending food confirming predominant sensitisation pr-10 allergens. primary food allergy and spontaneous angioedema was excluded in all patients. in the cohort studied, the pfas symptoms were unusually severe. we therefore postulate that this was secondary to concurrent use of acei. the management of these patients to sensitization to a β-casein with high homology between only the first 3 milks. more precisely, the allergen candidate could be γcasein, which is derived from β-casein by proteolysis, whose abundance increases during cheese production from fresh milk, and which is absent in cow's milk. a lactoglobulin specific to buffalo's milk may also be responsible. in case of ewe's and goat's milk allergy without cow's milk allergy, sensitization to buffalo's milk should systemically be seeked out. we recommend inclusion of all mammalian milks in the list of the 14 mandatory allergens for declaration on food products. method: prick tests with fruit battery, ltp and profilin was made. analytical with blood count, immunoglobulins, triptasa, total ige and specific ige to banana, apple and orange. finally, open oral provocation with fruits was performed. the diagnostic key was given by the mother of the patient who attended consultations because the infant had erythema in the temporary zone after drinking sea water on the beach. associated with salivation, the patient presented erythema in the malar area lasting a few seconds many times. the prick tests with fruits, ltp and profilin were negative. hemogram: 100 eosinophils/μl, total ig e: 4.9 iu/ml, specific ige to fruits were negative. triptase: 5.1 μg/l. method: here we describe a variety of cases of nsltp allergy presenting to a tertiary allergy centre in the north west of england. results: nsltps have been found to be major allergens in various foods and they are likely to produce severe and systemic allergic reactions. this is reflected in the cases we present here. these proteins are highly cross-reactive due to extensive sequence homology and are panallergens. nsltps are remarkably heat stable and retains its allergenicity in processed foods. it is assumed that nsltps may sensitise both by inhalation and ingestion. an intriguing aspect in nsltp hypersensitivity is the extreme variability of its clinical expression. co-factors are often needed for the clinical expression of nsltp hypersensitivity. conclusion: patients regardless of where they are from, presenting with multiple severe/systemic food allergies need to be investigated for nsltp allergy. these patients require specific dietary advice on foods to avoid and a tailored management plan on how to deal with their allergic reactions. cow's milk as well as cow's milk products are tolerated. material and methods: skin prick tests with different sorts of milk, cheese and milk proteins were performed, specific ige antibodies were measured, a basophil activation test with cow's and goat's milk was performed and an oral provocation test (opt) with cow's milk, cow's milk cheese, raw milk and raw milk cheese was conducted. results: skin prick tests were positive for sheep's milk, goat's milk, goat's milk casein, feta, pecorino and parmesan cheese. elevated specific ige against goat's milk (12.7 ku/l) and sheep's milk (11.7 ku/ l) were detected. activation of basophil granulocytes after incubation of the patient's blood with cow's milk and goat's milk was measurable but also in the non-incubated control blood. all cow's milk products were tolerated in the opt. conclusion: despite consistent homologies between whey and casein proteins of mammals and high cross-reactivity between cow's, goat's and sheep's milk an isolated goat's and sheep's milk allergy with tolerance of cow's milk is possible. skin testing and specific ige help to distinguish from allergy against cow's milk proteins. diet counseling is possible after opt. introduction: salmon roe's allergy, without concomitant fish allergy, is rarely described in western countries. there are few studies on its allergenicity. objective: to report of a case of salmon roe allergy without concomitant fish allergy in a western country. case report: a 26-year-old male with house dust mite allergic rhinitis and asthma, describes for the 1st time, in 2015, an acute episode of dyspnoea, rhinorrhoea, ocular pruritus, epigastric pain and nausea, a few minutes after the ingestion of a sushi meal with rice, salmon, salmon roe, wasabi, soy and ginger. these complaints motivated observation in the emergency room, where it was still documented uvular oedema. he was prescribed intramuscular adrenaline, intravenous steroids and anti-histamines with complete symptoms resolution. the patient declares not had eaten other foods, taken any drugs including nsaid, been infected or practised exercise. skin prick tests with food extracts (salmon and other fish, shellfish, soy, rice, egg total, egg white, egg yolk, ovalbumin and ovomucoid) were negative. skin prick-prick tests were positive for salmon roe (17 × 10 mm) and negative for egg (white and yolk), ginger, salmon, flying fish roe (tobiko), sturgeon roe (caviar) and black scabbard fish roe. specific-ige (sige) to salmon roe extract was 0.28 kua/l (immu-nocap-phadia) and negative against extracts from salmon fish and other fish (<0.1 kua/l). sds-page immunoblotting with salmon roes extract showed a 20 kda-ige binding band, that may correspond to a lipovitelin. after the allergic reaction the patient have tolerated abstracts | 659 salmon fish and other fish roes (tobiko, caviar and black scabbard fish). no oral provocation test with salmon roes was performed given the severity of the reaction. conclusion: this report is an example of a severe allergic reaction to salmon roe without concomitant fish allergy, where the clinical history and the in vivo and in vitro tests were important to an accurate diagnosis. the authors believe this is the first report of a salmon roe anaphylaxis in our country and highlight the importance of this allergen in the western countries, given the increase of sushi consumption in these countries. case report: the prevalence of food allergy is increasing worldwide and consumer habits are changing. pomegranate (punica granatum) was commonly consumed in the mediterranean area but in the last few years became also popular in the different parts of europe. a 5-year-old boy was admitted to our emergency department suffering from allergic reaction within 10 minutes after consumption of pomegranate. he presented with skin pruritus, generalized urticaria and eyelid edema. symptoms resolved within an hour after oral intake of cetirizine. prick-to-prick test with pomegranate was positive (wheal diameter 13 × 7 mm). he had a history of anaphylaxis with egg (urticaria and wheezing) at the age of 9 month, meanwhile consumption of egg is well tolerated. an episode of anaphylaxis with unknown origin appeared at the age of 4 years (urticaria, wheezing and abdominal pain). skin prick tests with aeroallergens revealed birch pollen allergy and he was diagnosed with allergic rhinoconjunctivitis. dietary elimination of pomegranate was suggested and adrenaline auto-injector was provided. we have analyzed omalizumab effectiveness and safety in patients with csu from our database. clinical response was categorized as: no response, partial or complete response by using the urticaria activity score 7 (uas 7). furthermore, the dosage, administration frequency and any side effects were recorded. results: effectiveness: 23 out of 25 patients (92%) achieved complete response. 15 (65.2%) after a single dose of 300 mg (8 patients) or 150 mg (7); 5 patients (21.7%) after two doses of 300 mg (4 patients) or 150 mg (1) results: multi-ethnic adolescents accounted for approximately 1.2% of the total sample of adolescents. prevalence of asthma was significantly higher in multi-ethnic group than non multi-ethnic group. we examined if maternal or paternal foreign born status had a differential effect: in multi-ethnic family with foreign-born father, prevalence of asthma was significantly higher. parental region of country at birth had a significant influence on the prevalence of asthma. adjusted logistic regression analysis was used to determine risk factors for occurrence of allergic disease. residential area, perceived household economic status, parental region of country at birth, and body mass index (bmi) had a significant effect on prevalence of asthma. conclusion: population admixing appears to have significant effect on the prevalence of asthma. further study will be needed to clarify the effect of population admixing on prevalence of allergic disease. several studies have aimed to explore the possibility of mirs as biomarkers for various diseases. in our study we examined six different mirs, previously shown to be involved in eosinophil development and other immune responses, in serum from non-allergic and allergic asthmatics and healthy control subjects in order to determine their potential ability to be used as biomarkers for varying forms of asthma. method: serum from healthy individuals as well as age matched non-allergic asthmatics (naa) and allergic asthmatics (aa) were utilized. additionally, the naas and aas subjects had high eosinophila (≥0.4 × 10 9 cells/l) compared to healthy controls (≤0.1 × 10 9 cells/l) and eosinophil cationic protein (ecp) in serum was measured. asthmatic subjects were included irrespective of inhaled corticosteroid usage. rna was extracted from serum, reverse transcribed and subjected to qpcr analysis. expression changes in six candidate mirs, mir-126, -145, -146a, -155, -223, and -374, were investigated. results: two mirnas, mir-155 and mir-146a, were significantly upregulated in aas as compared to naa or healthy subjects. additionally, mir-223 was upregulated in naa, but not aa or healthy subjects. furthermore, the expression change observed in the aa mirs appeared to correlate with the use of inhaled corticosteroids, but not in the naa mirs. finally, mir-223 and mir-374 expression levels were altered based on the number of eosinophils, which correlated to ecp levels, in naa subjects. conclusion: using six mirs found in the literature to be involved in eosinophila or immune responses, we were able to detect expression changes in the serum of healthy and asthmatic individuals. moreover, were able to distinguish between healthy individuals, aas, and naas on inhaled corticosteroids or with differing eosinophil levels, leading to the possibility that these mirs may be valuable future biomarkers for asthma. background: some studies report that certain sensitization profiles may increase the risk of a more serious allergic respiratory disease. the aim of this study was to describe the sensitization patterns to major allergens of dust mites in our area and investigate the association of these patterns with a specific clinical picture. method: multicenter study performed in 3 hospitals for 4 months. we recruited 133 patients older than 5 years with rhinitis and/or bronchial asthma, with a history of allergy to dust mites and both skin test and specific ige to d. pteronyssinus, d. farinae or l. destructor positive. der p1 and der p2 were determined to all of them. we analyzed 133 patients with an average age of 28.25 years, 60.9% women, 9.7% smokers, 69.9% rhinitis and asthma, 17.3% only rhinitis and 12.8% only asthma. 94% of patients presented sensitization to d. pteronyssinus, 83.5% to d. farinae and 63.2% to l. destructor. the detected sensitization patterns were: both der p1/der p2 positive 73.9%; der p1 positive 8.4%, der p2 positive 11.8% and both der p1/der p2 negative 5.9%. it was observed that patients with higher specific ige levels had more severe forms of respiratory disease, with isolated asthma or associated with rhinitis. for d. pteronyssinus, d. farinae, der p1 and der p2 > 50ku/l there is a greater number of cases of asthma associated with rhinitis, while for l. destructor >3.5ku/l greater number of cases of asthma. no relationship was observed between a specific sensitization pattern and an increased risk of asthma. conclusion: 1. specific ige values greater than 50 ku/l for d. pteronyssinus, d. farinae, der p 1 and der p 2, were significantly associated with a higher probability of asthma and this association was significant for l. destructor>3.5 ku/l (class 3). 2. there are four well-defined sensitization patterns in our population that are influenced by geographic location, being the double sensitization to der p 1 and der p 2 the most prevalent and allowing the correct characterization of 94% of the cases. none of them increased the risk of asthma. kobori t 1 ; nagao m 1 ; ekenkrantz t 2 ; borres m 2 ; sjölander a 2 ; fujisawa t 1 1 national mie hospital, tsu-city, japan; 2 thermo fisher scientific, uppsala, sweden background: reliable biomarkers for diagnosis and management of asthma in young children are needed since pulmonary function test and exhaled no measurement, good biomarkers for asthma in older children and adults, are difficult to perform in young age. we have developed a sensitive and stable assay system to measure eosinophil-derived neurotoxin (edn), an eosinophil granule protein, that is released upon activation, and that may serve as a marker for eosinophilic inflammation also in young children. method: volunteer children from 0-6 years old were recruited and an isaac-based questionnaire was filled out by their caregivers. venous blood was obtained to measure serum and plasma edn and eosinophil count. edn was measured with a research assay developed on the immunocap ® platform. conclusion: blood edn may be a reliable biomarker for diagnosis of asthma in preschool children. conclusion: feno measurement as an add-on option in asthma management to identify asthma patients with th2 driven airway inflammation is less costly than the use of standard diagnostic methods. new biologics may have an additional impact on overall asthma treatment costs. our model demonstrates that incorporating feno measurement may help to optimize asthma medication and reduction in physician visits as well hospitalizations due to severe exacerbations. 1294 | peripheral airway inflammation assessed by fractional measurement of the exhaled breath temperature is a leading feature of asthma background: airway inflammation is considered to be a hallmark of asthma. the potential clinical benefits of assessing it non-invasively has led us to develop a method and device for measuring the temperature of the exhaled breath (ebt=exhaled breath temperature) reflecting the thermal state of the airway mucosa. studies have demonstrated that ebt is increased in asthma, proportionately to the level of control of the disease. in an attempt to further increase the usefulness of this approach, we have further developed a device to allow the assessment of the relative contribution of the central and peripheral airways (caw and paw). now we present the frebt data gathered from patients with suboptimal control of their asthma and from healthy subjects. method: in this cross-sectional study we included 120 volunteers: 71 patients with suboptimally controlled asthma of mild to moderate severity (median age 44, range 18-68 years, 31 men) and 49 nonsmoking subjects without respiratory disease (median age 49, range 18-70 years, 17 men). we measured the fractions corresponding to caw and paw sampled with a fast reacting inflatable balloon valve system operated by a computer during a single breathing cycle. it allows steering of the expired airflow through channels with sensitive temperature sensors. during an initial deep inhalation, the inspired volume is measured and the sequence of valve openings is adjusted so as to yield volumes of air characteristic of caw or paw during expiration. the ratios between [pawebt-cawebt] over the total ebt [%] measured during the same manoeuvre (fractional ebt, frebt) were calculated and compared between asthmatics and controls. results: there was high statistically significant difference between the frebt ratios of asthmatics and controls: 16.25 ± 0.51 (mean ± sem) vs 12.66 ± 0.28, p < 0.001. as the magnitude of the ratio depends on the difference between pawebt and cawebt, higher values of the frebt ratio point to bigger contribution of the peripheral lung tissues, presumably indicative of peripheral inflammation. multiple regression analysis with frebt ratio as dependent variable identified only asthma diagnosis as significant predictor (p < 0.001) and excluded all other anthropometric indices. conclusion: peripheral airway inflammation assessed by frebt measurement appears to be a leading characteristic in asthmatics compared to healthy subjects. method: we examined 142 outpatients (30% male, aged 18-82 year, mean age 54.7 years) with severe asthma according to ers/ ats (2014) definition treated with high dose of ics/laba± tiotropium, antileukotrienes and omalizumab. some patients (n = 21) had orally steroid-dependent asthma. they referred to our secondary care center by gps. pulmonary function tests were measured by dry spirometer (2120, vitalograph ltd., uk). skin prick tests or serum specific ige to common inhalant allergens (house dust mite, animal dander, pollen) were used to assess atopic status. results: seventy five percent (n = 107) of patients with severe asthma had fao in 50% of those was diagnosed concomitant copd. duration of asthma was 14.6 years in patient with reversible airway obstruction (rao) and 14.5 years in those with iao (p > 0.05). early (before age 12 years) onset of asthma was established in 13% of patients with rao and in 9% of patients with fao (p > 0.05). prevalence of atopy did not differ between both groups (81% vs 81%, p > 0.05) but total ige level in serum was higher in severe asthmatics with rao than fao (924 me/ml vs 330 me/ml respectively, p < 0.01). most of atopic patients with severe asthma both with fao (91%) and roa (83%, p > 0.05) were sensitized to house dust mites (d. pteronyssinus and d. farinae). hypersensitivity to pollen was diagnosed in 36% patients with foa and in 17% with rao (p > 0.05), to cat and dog dander in 49% and 25% respectively (p < 0.05). the majority (75%) of patients with severe asthma had fao. hypersensitivity to house dust mites was most common in severe atopic asthmatics with foa and roa where as sensitization to animal danger was associated with presence of foa. 1296 | loss of smell as a clinical marker of severe asthma and its association with upper airway inflammatory diseases background: asthma is frequently associated with rhinitis and chronic rhinosinusitis (crs) while severe asthma is more associated with crs with (crswnp) than without (crssnp) nasal polyps. loss of smell (los) is associated with crs, mainly with crswnp. we aimed to assess loss of smell as a clinical marker to discriminate crs from rhinitis and severe from non-severe asthma. method: in a cross-sectional multicentric study, asthmatic patients (n = 383) were evaluated by pulmonologists and ent specialists using gina, aria, and epos definitions. los was evaluated by severity [vas scale, 0-100 mm, median (iqr,inter-quartil range)] and by prevalence of anosmia (hyposmia vas >0-70 mm, anosmia vas>70 mm). results: los was present in 55.4% of asthmatics (hyposmia 41.5%, anosmia 14.9%). los was more severe [22 mm (0-75), p < 0.001] and anosmia more frequent (26.4%, p < 0.001) in severe persistent asthma than in moderate [10 mm (0-50); 11.4%] mild [0 mm (0-28); 10.7%], or intermittent [0 mm (0-45); 8.6%] asthma. in addition, los was more severe [38 mm (2-76) vs 0 mm (0-20), p < 0.001] and anosmia more frequent [28.1% vs 3.9%, p < 0.001] in crs than in rhinitis patients. in those asthmatic patients with crs, los was even more severe [50 mm vs 20 mm (0-56) p < 0.001] and anosmia more frequent (40.6% vs 13.4%, p < 0.001) in crswnp than in crssnp. conclusion: loss of smell and specially anosmia may clearly discriminate severe from non-severe asthma and crs (specially with np) from rhinitis alone in asthma patients. thus, los may be considered a significant clinical marker of severe asthma and its association with upper airway inflammatory diseases. 1297 | last station in the eosinophilic asthma with chronic rhinosinusitis and/or nasal polyposis march: eosinophilic asthma with radiological findings associated with blood eosinophilia yilmaz i 1 ; nazik bahçecioglu s 2 ; türk m 3 ; tutar n 1 ; oymak fs 2 ; gülmez i 3 1 erciyes university school of medicine, kayseri, turkey; 2 department of chest diseases, kayseri, turkey; 3 division of immunology and allergy, kayseri, turkey background: eosinophilic asthma with chronic rhinosinusitis and/or nasal polyposis (eacrs/np) is a subphenotype of adult-onset eosinophilic asthma. blood eosinophil levels are shown to be highly elevated in patients with ea-crs/np and have potential for tissue infiltration. we aimed to demonstrate the clinical features of the patients who have a blood eosinophil level above 10% and have thorax computed tomography findings due to blood eosinophilia. results: we identified 36 patients who met the above criteria. we defined this group as "eosinophilic asthma with chronic rhinosinusitis and/or nasal polyposis with radiological findings related to blood eosinophilia" (earr). the mean age was 44.9 ± 11 years and 64% was female. nasal polyps, aspirin exacerbated respiratory disease and atopy was present in 81%, 47% and 25% of the patients, abstracts | 665 respectively. the mean blood eosinophil count was 1828.6 cells/mm 3 (19%). the majority of earr patients had upper lobe dominant ground-glass opacities. the mean follow-up period was 3.2 ± 2.5 years. earr patients did not evolve into eosinophilic granulomatous polyangiitis in the follow-up. method: we aimed to identify features more probably associated with asthma in a unselected group of patients with diagnostic criteria for aco. we consecutively selected the first 10 consecutive patients with diagnostic criteria for aco. all patients were evaluated by accurate clinical history interview, assessment of asthma control test (act) and copd activity test (cat), lung function and exhaled nitric oxide (fe no ) measurements, sputum cytology, blood eosinophil count, serum total ige and periostin levels, methacholine and adenosine-mono-phosphate (amp) bronchial challenges. all these measures were repeated after an oral corticosteroid (ocs) trial of methylprednisolone 32 mg/day for 14 days. we defined 9 parameters that we expected improved after the ocs trial, and therefore considerable as markers of asthma: fev 1 , fef 25-75 , fev 1 /fvc, fe no , act, sputum and blood eosinophilia, methacholine and amp challenges. patients with improvement of at least 4 of these parameters after ocs trials were defined as "responders" to the treatment, and therefore more likely to be asthmatic than copd or aco. results: five (50%) patients were classified as responders and they were characterized by having basal higher fe no values (102.8 ± 34.2 vs 13.6 ± 3.5 ppb, p = 0.032), greater bronchial reversibility basal values of serum periostin and total ige, and blood eosinophils were higher in responders but without reaching the statistical significance. conclusion: fe no and the degree of bronchial reversibility (and possibly also the degree of response to an amp challenge) are reliable biomarkers to distinguish asthmatics among those with suspect aco. method: the preliminary case-control study included 52 obese persons with asthma who were matched for age and sex and 48 nonobese asthma subjects. non fasting serum levels of adiponectin, and leptin were measured by commercially available immune assay kits, and routine biochemical parameters were analyzed in both the study groups. the results show statistically significant lower levels of serum adiponectin and higher serum leptin levels in obese asthma subjects with respect to non-obese asthma patients (p < 0.001). moreover, an inverse correlation was also observed between serum adiponectin and serum leptin in obese asthma subjects (p < 0.05). our results indicate the association of these hormones might act as a significant predictor in the progression of asthma. moreover, the role of serum adipokines is promising and might potentially act as a meaningful drug target in the pathogenesis of asthma. background: overweight/obesity is known to be a possible factor for poor asthma control. the aim of the study is to determine the serum concentrations of leptin in atopic asthmatic patients and its relationship with body mass index (bmi), asthma severity defined by medical treatment and asthma control defined by the asthma control test (act). method: we randomly selected 33 adult patients previously diagnosed with allergic asthma based on gina (global initiative for asthma) guidelines, returning for follow-up to an outpatient allergy/ immunology clinic during november 2017. following an informed consent, the patients were asked to fill act, their bmi was recorded, and elisa blood assays for leptin were drawn. exploratory data analysis, spearman's correlation (95% ci by bootstrapping), and partial correlations were performed. results: female/male ratio was 24/9, mean bmi was 27.2 ± 4. conclusion: leptin was significantly associated with overweight/ obesity in asthmatic subjects, and showed higher values for women. leptin inverse correlation with act did not reach statistical significance, likely owing to underpowered estimates, in a small sample characterized by an elevated mean bmi and severe allergic asthma. background: immunoglobulin lowering may be associated with recurrent wheezing symptoms and clinic by increasing the tendency to viral respiratory tract infections. in this study, it was aimed to investigate the frequency of immunoglobulinemia in preschoolers with wheezing. the study was conducted between 01.01.2013 and 01.01.2016 between. university of health sciences, ankara child hospital, the children allergy and immunology clinic included patients who had been followed up and treated for at least one year with recurrent wheezing attacks within younger than 48 months. the immunoglobulin (g, a, m) values of the patients were retrospectively analyzed. immunoglobulin levels were determined to be normal and low according to age limits. the study included 585 patients (65.6% male, 34.4% female) under the age of 6 years with a mean age of 26.9 months. the mean follow-up period of the patients is 2.2 years. in 33.7% of these patients, at least one immunoglobulin was found to be low. none of these patients had any signs or symptoms of immunodeficiency. immunoglobulin a was low in 21% of the patients, immunoglobulin g in 18%, and immunoglobulin m in 7.5% of all patients. conclusion: immunoglobulin was found to be low in these patients when there was no immunodeficiency and preschool wheeze was diagnosed. this should be etiologically investigated as to whether if this is a special group in preschoolers with recurrent wheezing and hypogammaglobulinemia combination. method: asthma severe unit is formed by allergists, pneumologists, pediatricians and otorhinolaryngologists. hematologists and immunologists make specific collaborations. we present the partial results of our data collection, which include 75 patients with severe asthma according to ers/ats task force, selected by peripheral eosinophils >220 according to wagener et al. we followed them up to assess control for 1 year. we obtained cellularity in sputum using induced sputum technique. values of il of th2, th1, th17 pathway, periostin and ilc were not yet available. results: median age was 36 ± 24, feno 45 ± 34, exacerbations previous year 1.8 ± 2.4, act 17.7 ± 5, fev1 75% ± 21 and dose of inhaled corticoids (budesonide equivalent) 1235ug ± 618. most of the patients were sensitized (78%) and 15.9% were polysensitized. the most frequent sensitization was dust mites (81%). 27% had received immunotherapy of whom 35.3% with lack of response. not sensitized patients were older. sputum cell analysis of 54 patients was performed, 37% had sputum eosinophils>3%, mean sputum eosinophil value was 4.1 ± 4.7 and peripherally 518 ± 384. correlation among sputum and peripheral eosinophilia was 0.097 (p = 0.485). the peripherally eosinophil value >220 had a sensitivity of 80% and a specificity of 54% for the detection of sputum eosinophils >3%. no differences were observed in sputum cell count depending on allergic sensitization. 64% had an uncontrolled asthma. presence of polysensitization, rhinitis or polyposis were not statistically related with the control. different patterns were observed in function of cause of poor control: patients with obstructive pattern (fev1 < 80%) were older and received more inhaled treatment. patients with high rate of exacerbations had more sputum eosinophilia and neutrophilia. both groups had worse act and received more oral steroids. patients who received oral steroids were more often sensitized to fungi in some follow-up visits. not significant differences were observed in control according to the act. asthma had more sputum neutrophilia, were older, received higher inhaled steroids dose and had adult onset asthma. the only control variable related with sputum eosinophilia was exacerbation. fungi sensitization was more frequent among patients with oral steroids. method: a randomized, double blind, placebo controlled study with 80 patients from the de la salle university medical center with a mean age of 44 with partly or uncontrolled asthma. they were assigned to either cm glucan or placebo group for two months. act score and %fev1 postbronchodilator were assessed at the 1st visit, 4th week follow up, and 8th week follow up visits. an independent and paired t-test were used to determine mean changes in act scores and %fev1 between the groups. results: in the two treatment groups, those in the cm glucan group had a greater % fev1 mean change of −6.95 compared to placebo which had only −14.1, a mean difference of −7.15, and a trend toward significance with a t-test p value of 0.061. in terms of changes in act score, those in the cm glucan group had a mean change of 10.12 and 9.75 for placebo, a mean difference of 0.37 and was not significant at t test p value of 0.718. the result of the emanuel trial showed a trend of improvement among patients on both groups in terms of act score and %fev1 postbronchodilator. however, it was not statistically significant. 1306 | lung function improvements with tiotropium in patients across all ages: impact of episodes of asthma worsening during phase 3 trials vogelberg c 1 ; casale tb 2 ; bleecker er 3 ; goldstein s 4 ; szefler s 5 ; engel m 6 ; el azzi g 6 ; dewberry h 7 ; hamelmann e 8 method: post hoc analyses involved 6 phase iii, randomized, double-blind, placebo-controlled trials: 4 in patients aged 6-17 years (rubatina-/canotina-/vivatina-/pensietina-asthma) who received tiotropium (5 or 2.5 μg) or placebo, as two puffs once-daily via the respimat, as add-on to ics ± other controllers; and 2 in adults (pri-motina-asthma replicate trials) who received once-daily tiotropium 5 μg or placebo, as add-on to ics/laba ± other controllers. we analyzed change from baseline for peak fev 1(0-3h) and trough fev 1 at week 12 in vivatina-and pensietina-asthma, and week 24 in pri-motina-/rubatina-/canotina-asthma, comparing patients with and without episodes of asthma worsening during the trials. asthma worsening was defined as an episode of progressive increase in dayto-day asthma symptoms (recorded by patients and confirmed by the investigator) or a decrease of patient's best morning pef ≥30% from mean for ≥2 consecutive days. as a post hoc analysis, p values are nominal. results: there were no differences in baseline disease characteristics between those who experienced episodes of asthma worsening and those who did not, within specified age and asthma severity groups. placebo-adjusted lung function improvements were observed with tiotropium 5 μg in patients who experienced episodes of asthma worsening and those who did not during the trials (table 1) . there was some variability in subgroups with low numbers of patients. conclusion: once-daily tiotropium add-on had a similar efficacy in adult and pediatric patients with symptomatic asthma, irrespective of whether they experienced episodes of asthma worsening or not during the trials. these data support the broad efficacy of tiotropium and show largely consistent improvements in lung function even in patients who experience episodes of disease worsening. 1307 | cochrane review of the use of antibiotics for acute exacerbations of asthma method: we searched the cochrane airways trials register, trial registries and reference lists of primary studies. we extracted outcome data and assessed risk of bias in duplicate and used current cochrane methodology throughout. our primary outcomes were intensive care unit (itu) admission, duration of symptoms/exacerbation and adverse events. we included six studies, including a total of 681 adults and children. trials were of varied methodological quality and we were able to perform only limited meta-analysis. one study reported a single itu admission but no other studies reported admissions to itu. two studies investigating macrolides reported diary card symptom score and showed antibiotics improved symptoms (md −0.34, 95% ci −0.60 to −0.08). one study including 40 participants reported more symptom-free days in the macrolide group than usual care. one study of a penicillin including 69 participants reported asthma symptoms at hospital discharge; the between group difference was reported as non-significant. serious adverse events were rare; 10 events were reported across the three trials (n = 502). the pooled effect estimate for all adverse events from three studies was imprecise (or 0.99, 95% ci 0.69-1.43). no deaths were reported. conclusion: our results confirmed that omalizumab significantly improves disease control and is a safe add-on therapy. also in appropriate patients with controlled disease over time, efforts to stepdown other asthma medications will be appropriate. (45) aerd: aspirin exacerbated respiratory disease; sd: standard deviation. data are n (%), mean ± sd or n/n (%). c-act: asthma control test for children, fev1: forced expiratory volume in one second; fev1/fvc: the ratio of forced expiratory volume in one second to forced vital capacity, pef: peak expiratory flow; feno: fractional exhaled nitric oxide, vas: visual analogue scale *these included allergic rhinitis, asthma, eczema, atopic dermatitis, food allergy, etc. **there were 11, 13 and 18 missing data in treatment a, b, and c, respectively. this study examines the potential treatment effects of sq ® hdm slit-tablet on qol measured by sf-36v2 in people with aa and ar. the analyses are based on data from the mt-04 trial (eudract no. 2010-018621-19) and utilize data from the 12 sq-hdm treatment group (282 subjects) and the placebo group (277 subjects). throughout the trial, qol was measured at each of visit 3-13 via sf-36v2. this yielded psychometrically-based physical and mental health summary measures, as well as a sf-36v2 total score. according to trial design, the use of inhaled corticosteroid (ics) was reduced by 50% for a three months period (visit 10 and 11) and completely withdrawn for the last three months of the trial (visit 12 and 13). results: by estimating a simple regression on differences in sf-36v2 total score from baseline measurements (visit 3), a positive and statistically significant treatment effect on the overall qol of the 12 sq-hdm treatment compared to the placebo group in visit 9 and 10 was found. further analyses show that the qol improvements are mainly driven by increases in the general mental health score, which are carried through to visit 12. in particular, the mental health and role emotional domains show statistically significant improvements. the results show that the sq ® hdm slit-tablet improves qol measured by sf-36v2 in patients with hdm induced aa and that this effect is driven by improvements in the mental health domains. 1315 | impact of treatment prescription, adherence to treatment and use of inhalers in asthma control-results of the efimera study method: cross-sectional multicenter observational study conducted with patients who use any type of medication with inhaler devices. patients referred from primary care and seen by a pneumologist or allergist for the first time were evaluated. the following data was collected in a single visit: adequate prescription according to gina2015 guidelines (gina); specific and general treatment adherence using morisky-green questionnaire (mg) and inhaler adherence test (tai); disease control with asthma control test (act) and assessment of inhaler use technique were measured with the extended tai. results: patients included in this study (n = 1682) had a mean age of 45 ± 17 years, an average disease evolution of 14.9 ± 14.1 years, 64% of which were women. according to gina recommendations, 35.9% of patients have insufficient or inadequate prescription. when measured by the mg test the 68.5% of patients showed bad adherence, meanwhile measured by the tai test adherence was 76.8% measurements of inhaler use technique resulted in 17% of patients having one or more mistakes regardless of whether the device was a mdi or dpi. several factors showed to be related with bad asthma control: inadequate prescription (or: 8.05 [5.74-11.27 background: it is well known that the constant and prolonged tobacco smoking affects the natural history of asthma. vaping is the act of inhaling and exhaling the vapor produced by an electronic device called e-cigarette (e-cig), whose basic structure includes a power source and an atomizer. two types of vaping are the most popular ("mtl" and "cloud chasing"). we have created a web-survey with questions concerning epidemiological data, quality of life and symptoms worsening in asthmatic vapers. the survey has been advertised through various social networks and local press. 2403 people responded, including 437 asthmatics (18%). the asthmatics were: males 88%, under 18 3%, 18-25 years 36%, 26-30 years 19%, 31-65 years 42% and over 65 0%. 70% used ecig-only, 30% smoked and vaped together, 0%. those who preferred mtl-type of vape were 43% and "cloud chasing" were 57%. results: to the question: "has vaping ever worsened asthma symptoms?" 90% answered no, 10% yes. to the question: "as asthmatic, would you suggest to an asthmatic smoker to start vaping instead of smoking?" 1.3% answered no, 98.7% yes. to the question: "how much nicotine do your vaping liquids have?" 15% answered 0 mg/ml, 4% 1.5 mg/ml, 62% 3 mg/ml, 11% 6 mg/ ml, 6% 9 mg/ml, 1% 12 mg/ml and 0% 18 mg/ml. to the question: "do you take medications for your asthma?" 57% declared to use a drug as needed, 0% used a single drug daily, 16% used more than one drug daily and 27% declared "i don't take any asthma medication". we related (χ2 test) the worsening of asthma symptoms with the nicotine content (p = 0.313), the type of vaping (p = 0.305), the current therapy (p = 0.123) and we did not find a statistically significant correlation. vaping has undoubtedly shown an advantage in terms of improvement of symptoms compared to cigarette smoking (p = 0.016), in particular 82.5% subjects who smoke and vape did not have a worsening of symptoms, while 17.6% of them had a worsening. the vaper-only users who never worsened were 271 (90.6%) and 28 (9.4%) had a worsening. conclusion: despite the limits related to the online survey as a data source, e-cigs seem to be a useful tool in the pathway to quit smoking. in fact, 98% of the asthmatics who smoked traditional cigarettes would recommend switching to e-cig and 90% did not worse their asthma symptoms. background: despite the success of pharmacotherapy, more than half of patients with persistent bronchial asthma (ba) do not achieve disease control. in recent years, the issue of approaches to treatment based on the identification of phenotypes of the disease has been increasingly discussed. this approach becomes the key to optimizing therapy for asthma, allowing the personification of treatment. anti-ige-therapy using omalizumab is one of the most researched variants of phenotype-specific treatment. method: aim of our study was to investigate of the causes of uncontrolled predominantly atopic asthma, the frequency and effectiveness of the personalized therapy in real clinical practice. 54 patients with uncontrolled severe atopic asthma were examined in outpatient department of the city hospital during 2017. all patients underwent physical examination, pulmonary function testing, and total serum ige evaluation. results: 35% of patients had uncontrolled asthma due to inadequate basic therapy of the disease. the change in therapy allowed them to achieve control of the disease. obstructive sleep apnea syndrome (osas) was revealed in 11.1% of patients. these patients underwent cpap (continuous positive airway pressure) therapy. 13% of patients had gastroesophageal reflux disease (gerd). 25% of patients had an elevated level of serum ige level and needed anti-ige therapy. in 7.4% of cases, the initial serum ige level was more than 1500 iu/ml which was a contraindication to therapy of omalizumab. 8 patients received omalizumab therapy. this therapy led to relief of symptoms and decreased frequency of asthma exacerbations. results: it was found that the prevalence of obesity among the 367 patients with asthma and being treated in inpatient conditions in 2013-2015 was 44.9% of patients, which is comparable to the prevalence of obesity among the population in general. the data of the patients suffering from asthma and obesity treated both in inpatient and outpatient conditions, was analyzed and it is set that obesity does not affect the severity of the clinical course of asthma. it is shown that obesity does not affect the control of symptoms of asthma. thus, the control of asthma symptoms depends on timeliness of diagnosis, the adequacy and terms of appointment of basic asthma therapy, the presence, severity and adequate treatment of concomitant diseases, psychoemotional background of patients, their compliance and adherence to therapy. results: the causes of smoking in asthmatics were not significantly different from the control (p > 0.05). patients most often used smoking as "support for emotional stability". the motivation to smoking cessation was higher in the asthmatics group (58%) than in the control group. the main reason for smoking cessation was a deterioration in health -60%. the majority of smokers -85%, performed attempts for smoking cessation. low level of br was revealed in 90% asthmatics (27% non-smoking asthma patients and 18.5% of cases in the control group, p < 0.001), cf had low values and was lower in asthmatics group in compare to the control group (p < 0.05). the pac values correlated with the level of br: a low level was determined in 100% in smoking asthmatics, in 50% in nonsmokers with asthma and 7.4% in smokers of the control group obstructive sleep apnea (osa). all of the patients were on regular treatment with low dose inhaled corticosteroids for at 12 months and start treatment with continuous positive airway pressure (cpap) .to assess quality of life, we used asthma symptom control tools (asthma control test) .patients performed daily peak flow meter and spirometry (once a week) during period of 4 weeks after start using cpap. results: during the study, 47 of the followed patients had no exacerbation of asthma. four of patients during this period had exacerbation, due to upper airway infection so they were excluded from study. results of following showed that there was improvement in quality of life in all 47 patients included in study but there no statistically significant improvement in pulmonary function tests fpt. huang y 1 ; yao t 1 ; huang y 1 ; chiu c 1 ; tsai z 1 ; kao p 1 ; lu k 1 ; fang h 1 ; lin c 1 ; gau c 1 ; lee w 1 ; tsai h 2 results: the rate of preterm birth among the study subjects was 18.2%. the prevalence of physician-diagnosed rhinitis was 50.6%. there was no significant association between preterm birth and physician-diagnosed rhinitis (p = 0.43). when stratifying by atopy status, we found that preterm birth was associated with physiciandiagnosed rhinitis among children without atopy (adjusted or [aor] = 0.33, 95% ci = 0.12-0.93, p = 0.04), but not among children with atopy (p = 0.77). when further classifying by gender, greater protective effect of preterm birth on rhinitis was only found in boys without atopy (aor = 0.12, 95% ci = 0.03-0.56, p = 0.007). the results suggest that preterm birth may have a protective effect against the development of childhood rhinitis in our study population. the protective effect is only observed in boys without atopy. further investigations will be merited to confirm these findings and to investigate underlying mechanisms. background: folic acid supplementation (fas) during pregnancy has been suggested due to its protective effect against neural tube defects. at present the effect of fas during pregnancy on childhood rhinitis has remained unclear. we aimed to investigate the relationship between fas during pregnancy and childhood rhinitis. logistic regression analysis with covariate adjustment was performed. adjusted covariates included sex, age, number of older siblings, breast feeding duration, maternal smoking during pregnancy, maternal allergy, maternal education level, maternal age and socioeconomic status results: the prevalence of physician-diagnosed rhinitis was 55.3%. there is a significant association between fas and physician-diagnosed rhinitis (adjusted odds ratio [aor] = 2.07; 95% confidence interval [ci] = 1.25-3.43 for fas ≥3 months) compared to the group of never use. in the stratified analysis by atopy status, maternal fas during pregnancy was significantly associated with physician-diagnosed rhinitis in the atopic group (aor = 1.91, 95% ci = 1.07-3.40 for fas <3 months; and aor = 2.34, 95% ci = 1.19-4.58 for fas ≥3 months), but not in the non-atopic group. when further stratified by gender, significant association between maternal fas during pregnancy and physician-diagnosed rhinitis was only found in boys with atopy (aor = 3.23, 95% ci = 1.39-7.50 for fas <3 months; and aor = 4.02, 95% ci = 1.51-10.72 for fas ≥3 months). the results demonstrate that maternal folic acid supplementation during pregnancy might increase the risk of childhood rhinitis, especially among boys with atopy. further investigation will be needed to validate our findings and to understand potential underlying mechanisms. according to sequence data 13 from 16 detected adv (in all groups of patients) belongs to species f 41 type and 3 samples to species c 1 type (rei group). bv type 1 was identified in 3 strongly positive (ct ≤ 25) swab samples in ari group. conclusion: simultaneous testing of respiratory and stool samples together shown that at least 6.6%/7.9% of 151 study subjects had dual/mixed infections, respectively, including 11%/9.5% of 63 respiratory disease patients, 3.6%/7% of 56 gastroenteritis patients and 3.1%/6.2% of 32 patients with combined respiratory/enteric infections. we found no virus combination specific for different groups of patients. 1327 | neonatal respiratory supports and future asthma-like presentation in prematurity with bronchopulmonary dysplasia results: of all the tests analyzed 54.4% were males and 45.6% females with a mean age 5.7 ± 4.8 years old. half of the tests (49.2%) reveals positive specific-ige to more than one allergen and 38.6% (66) have no serum specific-ige for the tested allergens (table 1) . sixteen patients (9.4%) have very high concentrations (>100 iu/ml) of derm. pteronyssinus specific ige, 13 (7.6%) of derm. farina, 7 (4.1%) of rey pollen and 6 (3.5%) of oak and timothy grass pollen. further studies are needed in order to elucidate the effect of these cytokines on allergy development and protection. shinohara m 1 ; matsumoto k 2 1 department of pediatrics, ehime university hospital, toon, japan; 2 department of allergy and clinical immunology, national research institute for child health and development, tokyo, japan background: probiotics consumption during perinatal and postnatal periods reportedly reduces the risk of atopic dermatitis in the offspring, whereas such probiotics consumption did not affect ige levels or the risks of other allergic diseases; the precise mechanism how probiotics consumption reduces the risk of atopic dermatitis remains unknown. we hypothesized that probiotics consumption may reduce skin hypersensitivity to histamine. to test this hypothesis, we investigated whether perinatal/postnatal consumption of yogurt associates with skin hypersensitivity to histamine or not. method: this was a cross-sectional study enrolled 256 motherinfant (≥6-months-old) pairs. physician-diagnosed allergic diseases and food consumption, such as milk, fermented drinks, and yogurt, by mothers during the third trimester of pregnancy and by infants during the first 6 months of life were assessed using self-questionnaires. skin prick tests (spts) to saline and 1 mg/ml histamine were performed using bifurcated needles, and wheal sizes were measured 15 minutes after the puncture. the spt wheal sizes in infants with eczema/atopic dermatitis (n = 44) were significantly larger than those in infants without eczema/atopic dermatitis (n = 156; 4.6 ± 1.9 mm vs 3.8 ± 1.8 mm, respectively, p = 0.015), and thus these infants were excluded from the further analyses. the spt wheal sizes to histamine in infants with daily yogurt consumption during the first the aim of this study was to evaluate the prevalence and clinical relevance of sensitization to profilins in atopic patients with food allergy. the study was performed on a group of 43 children age 2-14 years with sensitization to at least one plant-derived food allergen (ige > 0.7 ku/l). the included patients had never been treated with allergen immunotherapy before the study. the presence of ige to recombinant (r) rbet v 2, rart v 4 and ramb a 8 in serum was evaluated using elisa method as previously described (jbc 2016; 291:15447) . in addition serum level of igg4 to rbet v 2, rart v 4 and ramb a 8 was also evaluated. results: sensitization to profilins was found in 8 out of 43 (18.6%) patients (p+). sensitization to all 3 studied profilins was demonstrated in each p+ patient. the remaining 35 children, with pollenfood sensitization, were not sensitized to any of the studied profilins and they served as a comparator group (p−). analysis of the clinical status revealed that asymptomatic patients in regard to plant-derived food hypersensitivity were found more frequently among p+ (75%) than p− (37.1; p < 0.01) patients. sensitization to profilin was associated with positive ige to the same food allergens as in the control group. clinical manifestation of pollen-food sensitization expressed as allergic rhinitis, bronchial asthma and atopic dermatitis was comparable between groups, except of oral allergy syndrome, which was not seen among p+ children. similarly, history of anaphylaxis to plant-derived foods was registered only among p− (11.4%) patients. interestingly, all patients with sensitization to profilins had also elevated level of serum igg4 against rbet v 2, rart v 4 and ramb a 8. results: no significant difference of physician-diagnosed eczema (p = 0.88) or current eczema (p = 0.82) was observed between children born full-term and preterm. after stratifying by atopy status, we found that children born preterm had a more than three-fold higher risk of having physician-diagnosed eczema (adjusted or (aor) = 3.92; 95% ci = 1.25-12.29; p = 0.02) and current eczema (aor = 3.16; 95% ci = 1.06-9.41, p = 0.04) than their counterpart in the non-atopic group. no statistical significance was observed for the association between preterm birth and eczema in the atopic group. no association between preterm birth and eczema was found when stratifying by gender. our results reveal that non-atopic children born preterm have a higher risk of developing eczema. the results suggest potential modifiable effect of atopy on the association between preterm birth and eczema. further studies with a larger sample size are needed to validate the findings in this study. background: there is a need for more knowledge about factors of importance for a successful transition from childhood to adulthood among adolescents with allergic disease and especially those with severe allergy. therefore the aim of this study was to describe experiences of living with severe allergy from the adolescents and their parent's perspective and thereby identify factors of importance for transition from pediatric to adult care. method: a qualitative study was performed based on six focus groups interviews, two with adolescents and four with their parents. in total 11 adolescents (age 10-16 years old) and 21 parents participated. the interview guide contained questions about experiences of living with severe allergy. the transcribed data was analysed using systematic text condensation. results: in total four themes were presented, two themes occurred in both the adolescent and the parent's focus groups, to be special and to be prepared. for two themes there was a difference between the adolescents and their parents. the theme, the importance of the parents, only occurred in data from the adolescents and the theme the meetings with health care only occurred in the parent's data. the adolescents felt that they had low priority in the class and several stated they were teased at school and their parents felt that focus on their child often was in a negative way. the adolescents described that they took responsibility for their diseases while their parents expressed a need to protect. the adolescents stated that one of the parents were always present or had been during the years, the reason being safety and security. only the parents mentioned experiences from healthcare. parents who described that they had continuity in healthcare meetings and where met by high competence and with a professional approach were more satisfied with the support from the health care. one factor that was felt to be important was whether the doctor involved the youth in the conversation or not. the teenagers in this study relied on their parents while also taking responsibility for their illness at the same time. parents, on the other hand, showed a tendency to overprotect their adolescents. for healthcare professionals it is important to involve the adolescents in the care to facilitate the transition. results: 50.9% of the children used antibiotics currently and 21.0% out of them used antibiotics ≥3 times yearly. current wheeze (w) was established in 6.5%, sleep-disturbing w in 3.6%, exerciseinduced w in 1.7%, dry night cough apart from a cold in 12.2%, and asthma in 2.3%. current antibiotics use ≥3 times yearly was positively associated with current w (aor: 13.37; 6.14-29.11; p < 0.001), sleep-disturbing w (aor: 7.87; 3.34-18.57; p < 0.001), exercise-induced w (aor: 5.44; 1.89-15.61; p = 0.002), dry night cough (aor: 3.80; 2.29-6.29; p < 0.001), and diagnosed asthma (aor: 5.68; 1.96-16.50; p = 0.001) while antibiotics use <3 times yearly was positively associated only with current w (p = 0.003) and dry night cough (p = 0.011). the results suggest an aggravating role of antibiotics use on asthma in school age thus further supporting the recommended restriction of antibiotics exposure. results: after questioning 31.6% 95% ci, 23.2-40.9 were suffering from respiratory diseases, having symptoms of chronic disease: cough-86.1%, wheezing-41.66%, tightness in the chest-27.7%. the risk factors (passive smoking, open fire house warming and no air conditioning) were commonly met in major cases at ill children rather than healthy ones (68.4% 95% ci, 59.1-76.8). as a result of studies made of the equal to 17.5 ± 0.3, comparative the end of lessons equal 19.2 ± 0.2 (p ≤ 0.05); air relative humidity varies during lessons equal with 62.9 ± 1.4 (norma toilet 30%-60%); co2 concentration exceeds allowable limits −0.3 ± 0.02 (mac −0.1%). conclusion: respiratory morbidity in high school examined has a tendency to increase. we noticed deviations from the hygienic norms: the indoor temperature and relative humidity was lower and the co 2 level was twice higher than the normal one. the "asthma ever" outcome was reported in 32 cohorts. 28 cohorts defined this as parental reported asthma (with or without specifying that it was doctor-diagnosed), 2 cohorts used gp records as the only source of diagnosis, and 2 used parental report or gp records. the "current asthma" outcome was reported in 40 cohorts. there was little consistency with how current asthma was defined or worded, with 23 different definitions used. the most common definition of current asthma, reported 16 times, was "asthma ever and either asthma symptoms in the last 12 months or asthma medication in the last 12 months". other criteria included in asthma definitions were bronchial hyper-responsiveness, reversible airway obstruction, positive exercise test, and asthma symptoms reported at a previous questionnaire. only one "current asthma" definition was based exclusively on prescription data: "dispensed two asthma medication during the past year". nine cohorts reported asthma outcomes without specifying how it was defined, and were categorized as "asthma unspecified". conclusion: "asthma ever" and "current asthma" are two main asthma outcomes used to define asthma in child cohort studies. definitions of asthma vary substantially across cohorts. case report: thereby we present two case reports of two children with impairment verbal communication as part of asd and allergic diseases. the first patient was a 3 year old boy with sneezing, rhinorrhea night cough and eye redness. he had been suffering for almost 2 years from the above mentioned symptoms. he had family history for atopic diseases and was for 7 month breastfed. specific ige revealed sensitization to birch, alder, hazel, oak, mugwort pollen and dog epithelia and dermatophagoides farinae. specific ige resulted positive for nuts and rye flour. the second patient was almost 3 year of age in the tame that he presented in our hospital. he cried and screamed all the time because of severe atopic dermatitis and typical symptoms such as itching all over the body and his impairment of verbal communication. specific sensitization showed sensibilization to egg white and egg yolk, to nuts, rye and wheat flour. the food specific ige leaded to positive results to alder, birch, hazel and oak pollen, but also to grasses, ragweed and mugwort. prick by prick test showed positivity to egg white and egg yolk. atopy patch test to pollens resulted negative. results: the first patient symptoms were well controlled after treatment with antileukotrienes. his verbal communication was also improved after a year or more. the second three year old patient after required a combination of specific treatment with antihistamines, corticosteroids, immunosuppressive drugs and diet recommendation. afterwards he had a reduced level of itching and anxiety but compared to other children he had a severe eczema. erythema multiforme (em) is an acute, immune-mediated, mucocutaneous condition that is most commonly caused by infection and drugs. it is characterized by targetoid lesions, sometimes accompanied by oral, genital or ocular mucosal erosions. there was no pediatric patient that had previously been reported in the literature with development of type 4 reaction after omalizumab treatment. we presented a case who developed em to omalizumab therapy. an 16 year-old female patient was admitted to pediatric allergy clinic with complaints of fever and rash. she had been diagnosed with chronic spontaneous urticaria (csu) 8 years ago and she was planned to treat with omalizumab (75 mg, subcutaneously every 2 week) because of the inadequate response of antihistamines at a medical center. her complete blood counts, liver, renal, thyroid function tests and serum c3,c4,c1 esterase inhibitor protein levels introduction: celiac disease is an autoimmune disease triggered by exposure to gluten in genetically predisposed individuals and characterized by chronic inflammation of the small intestine. chronic urticaria is a skin disease, characterized by the appearance of pruritic wheals with or without angioedema, whose underlying mechanism cannot be identified. objective: to report a sporadic case of an 11-year-old boy with chronic urticaria associated with celiac disease. methods: an 11-year-old boy(weight 31 kg, 3rd-10th percentiles) was admitted to our clinic with a 6-year history of chronic urticaria. during the first three years, he was under antihistamine treatment(of incremental doses)and occasionally received preparations of cortisone according to the eaaci guidelines. he was asymptomatic for 2 years until treatment was discontinued. eight months earlier, after a viral infection, a recurrence of urticaria, involving the trunk and extremities without angioedema was noted. subsequently, he was under antihistamine treatment with cetirizine but had an uas-7 score of 11. total laboratory investigations were performed. results: laboratory control was negative except for positive antibodies to celiac disease(anti-transglutaminase >200 u/ml, anti-endomysial, gliadin antibodies).further control with colonoscopy and biopsies (from duodenum and stomach) were obtained. the histopathological findings along with the clinical findings indicate celiac disease, type 3b marsch-oberhuber and grade b1 corazza-villanacci. in the past, similar cases have been reported. efforts have been made to associate chronic urticaria with celiac disease, although the mechanism remains unclarified. evidence suggests that the duration of gluten exposure, among otherwise asymptomatic patients with celiac disease, is related to the development of other autoimmune mechanisms. this can be explained by resolution of urticaria manifestations after the onset of gluten-free diet. in our case, three months after gluten-free diet, an improvement of urticaria with decreased uas-7 score of 5 was observed. conclusion: he specific case of subclinical diagnosis of celiac disease in a child with chronic resistant urticaria further reinforces the suggestion that screening for celiac disease should be included in the diagnostic approach of chronic urticaria. 1350 | allergy to gingival balm in an infant with cow's milk protein allergy we report a case of an infant with a diagnosis of cmpa with an allergic reaction to a gingival balm caused by the presence of cmp in its constitution. furthermore, it is important to reinforce that milk proteins were labeled in an unusual form which might increase the risk of misunderstanding. these findings illustrate the difficulty in implementing total avoidance of common food allergens as well as the need to improve their labeling, particularly in non-food products. bakiri ah results: after specific treatment with corticosteroids, antihistamines, emollient creams, disinfectants and antileukotriens he was feeling better, he was smiling again and wished to have the chance to play with his classmates again. conclusion: this case report shows an association between level of stress and risk for atopic dermatitis. as previously showed children with low educational level parents and boys with higher stress have increased risk of having severe atopic dermatitis as compared to "no stress" boys. so early treatment and diagnoses are key important factors improving the children`s social life. results: the data cover 69 immigrants (mean age 39.0, range 8-62) and 232 locals (mean age 40.8, range 9-80). a slight difference in male prevalence (30.4% vs 47%, p = 0.01), and pet possession (20.2% vs 41.8%, p = 0.01) were found between immigrants and locals, respectively. no differences were find in term of age and symptoms at presentation. the pattern of sensitization to the different allergens showed no statistically significant differences between migrants and controls. the rate of monosensitization resulted slightly higher in migrants (27.5%) than controls (21.1%). pollen-only sensitization was statistically higher among migrants than control (39.1% vs 22.4%, p < 0.01). monosensitization was more frequent among patients who have been living in italy for less than 4 years (52.6% vs 20%, p = 0.05). the opposite phenomena can be seen among polysensitized patients. conclusion: migrants are more frequently monosensitized than locals and tends to cluster towards either a pollen or dust mite sensitization. sensitization to house dust mite tends to appear early (< 4 years of stay). pollen or mixed sensitization is more frequent the longer the residence time. 1353 | allergenonline.org: update of comprehensive allergen and celiac protein searchable databases for risk assessment of novel food proteins goodman re 1 ; baumert jl 1 ; taylor sl 1 ; ebisawa m 2 ; ferreira f 3 ; bohle b 4 ; van ree r 5 ; kleine-tebbe j 6 ; abdelmoteleb m 1 ; koning f 7 ; amnuaycheewa p 8 conclusion: allergen and cd databases have been updated following a described review process. they can be used to identify proteins that might represent risks of food allergy or cd for affected consumers. han dh 1 ; lee jw 1 ; yim hj 1 ; ko yk 1 ; kim d 1 ; rhee c 2 1 seoul national university hospital, seoul, south korea; 2 seoul national university bundang hospital, seoul, south korea background: stress can change the immune response and aggravate various allergic diseases. we already demonstrated in previous allergic rhinitis cohort (arco) kids study that stress might be a risk factor for pediatric allergic rhinitis (ar). the aim of this arco study is to investigate relationship between stress intensity, symptoms severity and quality of life as well as allergic markers in adult ar patients. results: as stress intensity increased, the proportion of moderatesevere ar patients was significantly increased. ar patients in high stress group was likely to belong to moderate-severe group (or, 1.60; 95% ci, 1.01-2.50). global vas of ar symptom was 7.0 ± 1.9 in high stress group and 6.7 ± 2.0 in low stress group, respectively. the each 7 rqlq domain score was significantly higher in high stress group than in low stress group. total rqlq scores were 75.3 ± 35.5 in high stress group and 57.4 ± 36.0 in low stress group, respectively. however, as the level of stress increased, there were no significant changes in serum levels of allergic markers. our results suggest that stress may affect ar symptom severity and quality of life in ar patients. 1355 | skincare and synbiotics for the prevention of atopic dermatitis or food allergy in newborn infants: a 2 × 2 factorial randomized non-treatment controlled trial dissanayake e 1 ; tani y 2 ; sahara m 2 ; mitsuishi c 2 ; nagai k 3 ; sato y 4 ; suzuki y 5 ; nakano t 1 ; yamaide f 1 ; shimojo n 1 (n = 118). the skin care group was advised to apply an emollient 2-3 times/day especially on cheeks and peri-oral area. the synbiotics group consumed a mixture of fos (1 g) and bifidobacterium bifidu-mol6378 (7 × 10 9 )/day. the last group received both. emollient application was not prohibited in the no-intervention group. interventions were carried out from birth to 6 months of age. the development of ad was assessed at 1 month, 6 months and 9 months by a pediatrician and at 1 year by a questionnaire. ad was diagnosed using guidelines of the japanese society of dermatology. sensitization to food allergens was assessed by allergen-specific ige levels at 9 months of age. results: skin care and synbiotics, alone or in combination, did not prevent the development of ad at 1 year of age or the sensitization to food allergens at 9 months of age. conclusion: our data suggest that skin barrier protection using emollients may be insufficient to prevent the development of ad as other factors affecting skin barrier integrity and trans-epidermal water loss such as the method of skin washing may have an additional effect. the probiotic bacterial species used may also affect the outcome as lactobacilli have been shown to be more beneficial. more studies are required to confirm the effects of skin care and synbiotics on ad. results: in the population number of girls exceeded the one of boys (p < 0.001), especially within the age group from 4 to 15 years. questioning, for 12 months, symptoms of allergic rhinitis (rhinorrhea, sneezing, nose itch, nasal obstruction and eyes' itch) were identified in 19.5 (p < 0.05); symptoms of bronchial asthma (wheezing (14%), episodes of cough at night (8.3%), intolerance to physical load (2.5%), indoor and outdoor (13.6%), coughing and rales in response to stimulus (7.2%)) in 9.8% of the population; atopic dermatitis (dermatitis, itch, revelation in early age, involvement of large areas in early age, damage of extremities bending and stretching surfaces in adults)-5.7% (p < 0.01); food allergy-3.7% (p < 0.001) etc. at the second stage of clinical studies, on the basis of prick-testing, average ige, in our case, was 3-5 times greater than normal level. results of study of allergens showed sensibilization to domestic dust (d.f. and d.p.) (64, 43%) (p < 0.05). in 25.46% of cases there was stated sensibilization conditioned by cat and dog epidermal allergens results: among the 2624 women with available serum, 39.3% were sensitized of whom 12.5% were monosensitised, and 25.3% polysensitised (to two or more allergens). sensitisation to inhalant allergens dominated (38.9%), with grass being most common (25.5%). only 4.0% were sensitized to food allergens, most often to peanuts (2.6%), while among the 11.4% who reported ddfa, ige reactivity to foods were identified in 17.5%. compared to women with no asthma, women with dda (14.9%) were in a significantly higher background: regular exercise has been known as beneficial that it reduces the risk of chronic diseases including allergic diseases. however, little has known regarding the relationship between exercise and allergic diseases in korean adolescents. we analyzed the national data whether exercise is related to the prevalence of allergic diseases in the population of korean adolescents method: data from sixth korean national health and nutrition examination survey (2013-2014) that included 1272 adolescents from 12 to 18 years old was analyzed. we defined regular exercise according to physical activity guidelines for americans. multivariate regression analysis was performed to find whether lack of exercise could be a risk factor for allergic diseases. results: the prevalence of asthma, allergic rhinitis (ar) and atopic dermatitis (ad) were 1.3%, 9.3% and 5.2% in korean adolescents, respectively. after adjusting for factors, lack of exercise was not associated with asthma and ar, but was significantly related to ad in korean adolescents (adjusted odd ratio 3.254, 1.202-8.810 , results: it was found that over 43% of ch up to 14 y.o. having the ad within allergic disease (ads). the most significant symptom was a long-lasting itchy rash lasting for 6 month in 12.42 ± 0.56% of 1g and 9.23 ± 0.49% of 2g. the first morbidity of ad was noticed at the age of up to 2 y.o. among 56.29 ± 1.27%. at the age of ch 2-4 y.o. and older than 5 y.o. the skin ads onset was noticed for 31.12 ± 1.11% and 12.58 ± 0.57% accordingly. the ad sl was determined as follows: 52%moderate (mo), 12%severity (s), 36% were 13 ± 10 kua/l, 344 ± 132 iu/l respectively. skin prick tests were positive in 43.4% of the patients (61.7% multiple allergens). grass pollens (53%) and dermatophagoides (45.2%) were the most common allergens. average vitamin a and d levels were 469.8 ± 108 μg/l (257-832), 54.8 ± 21.3 (13-187) respectively. thirty percent of the patients vitamin d levels were mildly low, 8.6 percent was low. in control group 20% was mildly low, vitamin a levels was low in 6.7% of the patients. none of the children in control group had low vitamin a levels. we didn't find any statistical significant difference for both vitamin levels between patient and control groups. vitamin a deficiency was mostly found in asthma patients whereas vitamin d deficiency was mostly in allergic rhinitis and asthma groups. passive smoking and vitamin d deficiency was significantly related (p = 0.09). there wasn't any relation between asthma attacks and vitamin levels. conclusion: in conclusion vitamin a and d levels weren't found significantly related with allergic diseases but was found lower than control group. patients having chronic diseases are one of the population groups that are chronically exposed to drugs. this study aims at evaluate the impact of this factors in developing drug allergies in the medical staff. method: this was a cross-sectional study that included 639 nurses from the uhc "mother theresa" of tirana. they were asked to fill up a questionnaire where questions about chronic diseases and drug allergies were included. 92.18% were females and the mean age was 43.28 (+10.71) years old. relative risks with 95% ci were calculated for different groups. results: 40.69% (260) nurses reported to have at least a chronic disease. the most common non-atopic disease was hta followed by the groups of autoimmune and thyroid diseases. nurses who had one chronic disease have a rr of 1.82 (95% ci = 1.03-3.21, p < 0.05) to develop a drug disease higher than those who didn't had any chronic disease, and those who have more than one chronic disease have a rr of , p < 0.05) to develop a drug disease. the presence of chronic diseases can be a risk factor to develop a drug allergy probably through the increased risk to drug exposure. these patients may be exposed to drugs not only through therapy but also through hospitalizations and other forms of health care. lapeere h 1 ; oosterlinck p 2 ; vermeir p 3 ; vermeire i 2 ; coppens m 3 ; gevaert p 3 1 ghent university hospital/ghent university, ghent, belgium; 2 ghent university hospital, ghent, belgium; 3 ghent university hospital/ghent university, ghent, belgium background: the key to managing latex allergies in healthcare professionals and patients lies in correct recognition and appropriate action. 7.7 million people are employed in the health care sector. while there are no overall statistics on the prevalence of latex allergy in that work force, studies do indicate that 8%-12% of health care workers regularly exposed are sensitized, compared with 1%-6% of the general population. latex allergy is defined as an immune mediated reaction to latex products (e.g. balloons, contact dermatitis for gloves, condoms, surgical catheters); these encompass immediate and delayed hypersensitivity reactions. method: based on the experience of the belgian dutch pathway network, a 7-phase method to develop, implement, evaluate and continuously follow up a care pathway for latex allergy was designed and implemented. the purpose of the study was to develop and implementation of latex allergy clinical care pathways to provide all staff at ghent university hospital with appropriate knowledge and skills to identify and manage patients who have a known latex allergy or those at risk of developing latex allergy. results: care pathways, also known as clinical pathways, are used all over the world to implement and monitor patient-centered care processes in a transparent way. care pathways are defined as a complex intervention. 7 -phase method consists of: 1) screening phase; 2) project management phase; 3) diagnostic-and objectification phase; 4) development phase; 5) implementation phase; 6) evaluation phase and 7) continuous follow-up phase. this phased approach is based on the deming cycle, better known as the "plando-study-act" (pdsa)-cycle. conclusion: this method can offer support to multidisciplinary teams (re)designing and implementing safe, efficient, effective, person-centered, timely, equitable, continuous and integrated care processes. however, the method is no guarantee to success. the key to success is the collaboration and critical attitude of the entire multidisciplinary team when implementing pathways. background: cord blood ige (cb-ige) were considered to be a useful predictive tool for allergic symptoms especially in early childhood. there is only sparse knowledge about their importance for health in later life. the aim of our work was to determine the importance of cb-ige for allergic symptoms in young adults. we also studied the possible modifying factors for cb-ige concentration. results: resutls shown as daily mean, pollen grains/m³: table 1 . the daily means of pollen concentrations of cupressus arizonica, platanus acerifolia and plantago lanceolata in our area differs from other sites in madrid city. although cupressus arizonica and platanus acerifolia counting were lower, plantago lanceolata counts were higher, representing a relevant pollen in our area. the clinical relevance of these findings is under evaluation by our group. method: grass pollen counts were performed since 1979-2016 using a burkard 7 days spore trap located in our allergy center in madrid. the beginning of the algid period of pollination was considered the first of three consecutive days with more than 10 grains/m 3 and the end, the last day of three consecutive days with more than 10 grains/m 3 . madrid, barajas meteorological station data, was used. skin prick tests (pt) to grass pollen was also studied in comparison conclusion: total grass pollen concentration did not suffer any increase or decrease in its counts despite the dramatic increase of the temperature. an advance at the beginning and the end of the season was seen. these changes significantly correlate with the temperature increase during may and july. discrete decrease in the sensitization prevalence. since several years, the reference method to monitor the biological particles concentrations has been the hirst method: a volumetric pollen trap, located on the roof of building for background measurements, sucks continuously 10 l of air per minute, particles depositing by impaction on a coated tape. the tape is then analyzed by optical microscopy. the hirst method produces accurate but past data. nowadays, many researches are focused on the development on new devices to get real time information. method: rapid-e from plair sa is a device using red laser beam to determine the size and the shape of sucked particles and an ultraviolet ray to measure the fluorescence of these particles. the results: the correlation coefficients got between rapid-e and hirst trap are higher than 70% for most of calibrated pollens, this correlation reaching 86% for all pollen taxa: • plane 99% • pine 99% • birch 96% • oak 82% • plantain 75% • dactylus 73% • urticaceae 55% conclusion: new calibrations are planned for 2018 and a real time information will be set up. results: the quinquennial media concentrations since 1979-2016 were 3.866; 4.903; 6.610; 13.454; 9.501; 7.248;11.027 and 19.406 grains/m 3 . the quinquennial media temperatures were 14.2; 13.8; 14.3; 14.9; 14.2; 14.7; 14.9 and 15.8°c. increase of 1.4°c (r s = 0.9 p < 0.05). the beginning and the end of the actual season advanced 5 days respectively in regard to the period from 1979 to 1983. the annual prevalence of positive pt to platanus in 1979 was 2% an 52% in 1994. the quinquennial media from 1999 to 2016 was 50, 38, 26 and 29%. conclusion: platanus pollen counts had a dramatic increase that meaningfully correlates with the dramatic increase of the temperature. a discreet advance at the beginning and the end of the season was seen. these changes did not influence in a longer duration of the season. we observed a significant increase in platanus pollen sensitization prevalence whiting madrid pollinosis patients. results: the quinquennial media concentrations since 1979-2016 were 1963, 4813, 5455, 6948, 6985, 5976, 6727 and 9298 grains/m 3 . the quinquennial media temperatures were 14.2; 13.8; 14.3; 14.9; 14.2; 14.7; 14.9 and 15.8°c. increase of 1.4°c (r s = 0.9 p < 0.05). the actual season beginning advanced in 51 days and the end has results: over 60% of house dust samples collected between april and may from central european countries were found to contain bet v 1 allergen at levels well above the limit of detection of 0.0039 μg/g for elisa 2.0 ep kit and 0.001 μg/g on maria. samples were found to have much higher levels of bet v 1 allergen from midto-late april, particularly those that were collected in germany, belgium and hungary. samples taken from outside of the pollination season were tested and found to be negative for bet v 1. in conclusion, we found that bet v 1 allergen can be detected and quantified in house dust samples. these data suggest that household dust is a source of pollen allergen and could therefore be contributing to asthma and allergic rhinitis symptoms in individuals affected by pollen allergy. household dust may also be considered as a source of bet v 1 allergen which could contribute to allergic sensitization. 1383 | cupressaceae pollen in the atmosphere of alentejo: disruption of pollen grain during air transport spring, depending on the temperature. despite being considered moderately allergenic, it might be responsible for winter allergic outbreaks. as ornamental trees, they are found scattered throughout the territory but are more abundant in pockets of wild forest, outside alentejo. despite being more common in mountain, this pollen type is captured in considerable amounts in alentejo, portugal, where its aerobiological features and allergenic impacts are poorly characterized. the aim of this work is to characterize the aerobiology of cupressaceae pollen, to evaluate the effect the meteorological conditions and the source of this allergenic pollen type in the atmosphere of evora, alentejo. method: pollen were collected using a hirst type 7-day pollen trap and pollen was identified following standard methodology. background: allergic rhinitis caused by pollen is one of the most common allergic diseases. the presence of pollen in the air is currently centrally monitored at roof top levels, and not in the direct living environment of sensitized subjects. in the current project we aimed to develop a handheld pollen sampler, called pollensniffer, that can collect pollen in the living environment of the allergic subjects. as a first step this device was validated against the standard burkard pollen sampler and used to monitor local pollen concentrations at street level in the city of leiden. method: rooftop level pollen were monitored routinely by a hirst type pollen sampler (burkard, uk). the pollensniffer ( 1385 | does the allergy risk due to pollen exposure information is useful for the allergy sufferers? sindt c; oliver g; thibaudon m background: in france the information for the allergy sufferers is not made with pollen counts, which have not a real signification, but with the allergy risk due to pollen exposure. method: since more than 20 years, rnsa (réseau national de surveillance aérobiologique), the french aerobiology network, has measured the pollen exposure in the main cities of france, using background: the effect of environmental factors on allergic sensitizations is still unclear. rural areas vs cities have different exposure levels to pollutants and aeroallergens. these differences could give clues on the causes of higher allergic sensitization rates in children exposed to city air. method: two studies with children aged 5 years old were initialized to analyse the airborne drives of allergic sensitization: seal (günzburg, 350 children) and ae2r kids (munich, 200 children). capillary blood was collected and the parents filled in a questionary. sensitization rates were quantified using the immunocap ® isac sige array. pollen data were measured at both locations. results: in günzburg more children were sensitized to aeroallergens, however munich children showed significant higher sensitization to phl p 1 (p < 0.05), despite the lower concentration of pollen. in günzburg 66% children had no sensitization at all compared to 58% in munich. 80% of the children in munich spend at least 1 hour per day outside and 91% of the total have no animals at home. 23% felt symptoms of hay fever in the last 12 months, the majority between march and june, which correlated with the pollen flight. results: the total rate of atopy in crd patients was 36.1%, and asthma patients was the highest (45.9%). the positive rate of phadiatop in urban asthma patients (56.0%) was significantly higher than that in rural areas (25.0%, p < 0.05) and the phadiatop positive rate of office staff (62.5%) was significantly higher than that of outdoor workers (37.5%, p < 0.05). the total rate of atopy in copd patients was 32.7%, and in patients with acute exacerbation was 42.9%. beside, atopy is a risk factor for dyspnea (or = 1.22, p < 0.05), and the fvc levels in copd patients with atopy were significantly lower than those without (2.06 l vs 2.63 l, p < 0.05). optimal scaling analysis show that, there were a correlation between the tige and smoking coefficient (cronbach's alpha = 91.1%). in addition, the correlation between the level of tige and phadiatop sige was so strong in the patients with mild to moderate asthma (r s = 0.709, p < 0.001), but it was weak in severe asthma patients (r s = 0.486, p < 0.001), and up to 35.0% of the gold iii iv patients with low phadiatop level (≤10 ku/l) had a high level of tige (≥1000 ku/l) compared gold i ii (5.5%). conclusion: the rate of atopy in patients with crd is high, and atopy is an important factor affecting the process of crd. the patients with severe copd or asthma is likely to has high serum tige level but the level of common allergen sige is low, so the allergy screening strategy should be adjusted and we should pay attention to those patients, therefore, it is necessary to screen the sensitization situation of crd patients at first, and the results can guide the treatment, management and prevention of crd. background: due to a limited amount of epidemiological data [1] it has been thought that many severe allergic asthmatics in germany remain unidentified and are therefore not adequately treated. a pilot project demonstrated that more than 50% of patients, having been mean total ige (sd) was 366.4 (692.2) ku/l. 26.5% of the patients had no sensitization towards any of the specific iges tested, whereas 24% were positively tested on 5-10 allergens and further 23.5% showed sensitizations towards >10 allergens. conclusion: approximately 75% of 392 online recruited (severe) asthmatics had a total ige level of >30 ku/l and ≥1 sensitization (allergen-specific ige) towards atopic allergens. this further supports the high prevalence of atopy in asthma. results: 875 patients (mean age: 26 ± 11.9 years, range 2-64 years, m/f ratio: 0.89) who suffered from allergic rhinitis or allergic rhinoconjunctivitis enrolled in this study. highest rate of skin sensitivity was for weeds/grasses pollen including salsola kali, amaranthus retroflexus, chenopodium album and compositae family (74.3%, 62.5%, 50.9% and 39.3% respectively). among tree's pollen; ash (49%), walnut (46.9%) and mesquite (29.3%) were the most common. less than 20% of patients showed skin reactivity to indoor allergens and storage mites, mix of cockroaches and house dust were the most common (17.6%, 17.3% and 9.8% respectively). the results of current study confirmed the importance of weed/grass and trees pollen as the major source of allergic sensitization in our area. interestingly the rate of sensitization to indoor allergens was low which can be explained by geo-climatic situation. background: there are few studies of cutaneous sensitivity to gramineae in our region. mostly of them use allergens of foreign species. the study aims to estimate the prevalence of skin sensitivity to widespread grasses in our region. method: this is a retrospective observational study of 894 patients with seasonal allergic rhinitis. patients were studied using skin tests with pollens extracts from pooideae, chloridoideae and panicoideae grass species. results: the prevalence of positive reaction to pollen from pooideae subfamily was 86.8% (ic: 84.4%-88.9%). in turn, prevalence of allergy to panicoideae subfamily pollens was 69.6% (ic: 66.5%-72.5%) and positive reaction to chloridoideae subfamily reach 48.1% (ic: 44.8%-54.1%). cochran test suggests that prevalence in those three groups is different (χ2 = 319.11, p < 0.01). when comparing just the groups of allergens from pooideae and panicoideae differences are also significant (χ2 = 71.43, p < 0.01). in particular, 52.5% (ic: 49.2%-55.7%) of patients were allergic to paspalum notatum. regarding cross-reactivity between subfamilies, we find a no crosscorrelation between pooideae and panicoideae (χ2 = 2.197, p = 0.138). conclusion: in bahia blanca, patients with seasonal rhinitis are sensitive to pooideae, chloridoideae and panicoideae. paspalum notatum, belonging to panicoideae, has a significant prevalence, high reactivity and low cross-reactivity within the group of species studied. this last species is relevant because it is a native grass from the northwest region of our country, paraguay and the south of brazil. prevalence of grass positive skin tests in patients with seasonal rhinitis by species. allergen frequency percentage 95% ci results: correlation analyzes were performed between sige and spt and area results. the concentration with the highest correlation by diameter and area for blo t was 30 μg/ml and for der f of 400 μg/ml. in the case of der p the concentration with the highest correlation for the diameter was 30 μg/ml and for the area of 3 μg/ml. when evaluating the reproducibility of the results according to the area and the greater diameter of the spt, a strong agreement was observed for blo t in the concentrations of 3 μg/ml and 0.3 μg/ml. results: among the 94 patients, the majority of allergens-positive was t20, accounting for 60.6%, followed by f14 (59.6%), f13 (58.5%), ds1(57.4%) and ccd (56.4%). the prevalence of plant-related allergens (t20, w1, f14, f13, w6 and u80) in ccd-positive patients were significantly higher than those in ccd-negative patients (all results: with our new point-of-care methods using a selected recombinant protein e other markers, we were able to detect the disease early as 10 days post-infection and more than 95% of positive cases from chronic and low endemicity areas (which are characterized by hard to detect patients with extremely low parasite load, <10 eggs per gram of feces) were obtained. plus, chromatography poc-cca ® test was improved by our group with a urine concentration step that turned its sensibility from 6% to 56%. conclusion: monoclonal antibody and recombinant protein technologies allowed superior detection methods when comparing it to the conventional ones. in conclusion, data showed 100% of sensitivity of chronic patients and 98% of acute patients. marton c county hospital, oradea, romania background: allergic rhinitis is a disease that affects about a quarter of the population, a disease with an important negative impact on daily activities, both on learning and working ability, as well as spending leisure time or sleeping. in the western part of romania, the most popular and blamed allergen is ambrosia, in the late summer months. it is a plant of the compositae/asteraceae family, along with goldenrod, sunflower, dandelion, cocklebur, chamomile, wormwood, daisy, etc. allergen identification is important for applying prophylactic measures, but especially for determining the allergen to be desensitized. considering the possible cross-reactivity within the compositae plant family, as well as the possibility of co-sensitization, as well as the number of patients sensitized to these pollens, which is steadily increasing, i considered is necessary a broad screening for a more precise identification of the allergen and increase chances for a successful desensitization. method: the observational study includes 37 patients who presented on october for testing with standardized allergen extracts, as recommended. criteria for inclusion: patients with specific symptoms of rhinoconjunctivitis in august and september, with or without asthma symptoms, who returned for allergic prick test after the end of treatment. criteria for exclusion: patients who disagreed with cutaneous testing, who did not discontinue antihistamine treatment or who had been treated for other diseases with drugs that influence skin testing. background: in recent years, cationic liposomes are thought to be the most effective and non-toxical nucleic acids`transport system, so most of gene therapy drugs are developed on their base. however, lipoplexes are quickly captured by reticuloendothelial system cells after the injection and taken out of a blood stream. there are many modification methods of liposomal surface for liposomes with prolonged pharmacokinetic properties production. addition of hydrophilic polymers (peg) is seemed to be the most promising approach, that is able not only to create steric barrier on the particle`s surface and prevent the interaction with blood plasma lipoproteins, but also inhibits the protein adsorption, opsonisation and subsequent degradation in human body. the aim of this study is the evaluation of liposomal surface modification by hydrophilic polymers influence on nucleic acids`lipoplexes conjugation and on their physico-chemical and biological properties. method: liposomes preparation (including peg-modified liposomes), size determination by photon-correlation spectroscopy, examination of transfection efficacy by luciferase assay. (c16h33)2) were obtained. also the modified liposomes were produced by addition of 5% of peg (by mass) during thin lipid layer preparation step. the size distribution was analysed by photon-correlation spectroscopy. it was shown that peg addition does not increase the parconclusion: it can be noted that addition of peg can change the lipoplex formation but the cationic liposomes still remain an effective rna delivery system. and peg modification will be able to impart prolonged properties for the vehicle in bloodstream. foundation (grant № 17-74-10111). ory c4 may cause a cross reaction with fel d4 (cat), can f6 (dog), equ c1 (horse), mus m1 (mouse) and rat n1 (rat). february 2017 eight patients that were treated at our institution were diagnosed with rabbit allergy. results: all eight patients with the diagnosis of rabbit allergy presented with signs of upper respiratory involvement. two patients had itching teary eyes, watery nasal discharge and sneezing while feeding farm rabbits. one of those also presented with dyspnea. four patients developed problems whenever in contact with domestic rabbits. one patient developed allergic rhinoconjunctivitis whenever she was home-her parents own a rabbit, but while away in her college room she had no problems. another patient had dyspnea whenever visiting his girlfriend's house. she owned a rabbit. two patients developed asthma-like symptoms, one also presented with angioedema. the other two had developed allergic rhinoconjunctivitis. two patients have problems in contact with cats, one of them also with cows, however skin prick tests were also positive to rabbit. three out of eight patients developed allergic asthma with a positive methacholine test. six patients had a positive house dust mite prick test. all patients were diagnosed with a positive prick tests to rabbit allergens. all were treated with a nasal steroid and antihistaminesic. they were also advised to avoid contact with the animal. conclusion: domestic rabbit-induced asthma and/or allergic rhinoconjunctivitis is possible, however it is still rare in our environment. it is very important to always ask the patient about their pets in general, not just focusing on cats or dogs. only with a thorough examination and history we can find the true cause of the patient's allergy where pets play an important role. korea. changes of protein and major allergen concentration were measured over one year by bradford assay, two-site elsia, and sds-page after reconstitution of the lyophilized allergen extracts in various buffer (normal saline, 0.3% phenol saline, and 10 or 50% glycerol with saline) and stored at room temperature (rt, (18) (19) (20) (21) (22) (23) (24) (25) (26) or refrigerated (4°c). results: more than 90% of the initial protein concentration in all four extracts examined was detected over one year when 50% glycerol was added and refrigerated, whereas 57.9%-94.5% remained in the extracts at rt. the addition of 50% glycerol to the storage buffer was found to prevent protein degradation at rt. all four extracts were found to be stable when reconstituted in 50% glycerol. amb a 1, a major allergen of ragweed, was almost completely degraded in 9 weeks at rt when reconstituted in a buffer without 50% glycerol. however, 55.6%-92.8% of amb a 1 content was detected after one year of incubation at 4°c in all buffer conditions except 0.3% phenol. conclusion: addition of 50% glycerol as well as refrigeration was found to be the important to increase the shelf-life of allergen extracts from pollens of allergenic importance. results: this is the first genetic study of the bulgarian hae patients. genetic defects were identified in 10 hae families are: 3 nonsense, 2 splice-site defects, 2 frameshift mutations, 1 indel non frameshift, 1 missense, and 1 large deletion of exon 4. novel mutations, not previously reported in human gene mutation databases were discovered, and were predicted to be deleterious due to the expected effect on dna transcript and protein. descriptive statistics were used to summarize the eq-5d-y descriptive system responses and vas scores by treatment and visit. results: twelve patients with hae type i and a median (range) age of 10.0 (7) (8) (9) (10) (11) years were enrolled, 7 (58.3%) of whom were female. during bop, treatment with 500u c1 inh, and 1000u c1-inh, ≤33.3%, ≤22.2%, and none of the patients, respectively, reported having problems with mobility, self-care, doing usual activities, pain or discomfort, and feeling worried, sad or unhappy. the mean [sd] eq-5d vas scores increased from 78.3 (13. results: overall, the model-derived median exposure and peak concentration across all weight ranges in paediatric patients is predicted to be higher with 5 wb vs weight-based dosing (table) . the effect was most pronounced in patients aged 2-5 years, where the 5wb dosing achieved approximately 30% higher values than weight-based dosing for median auc 0-6 (1251 ng hour/ml vs 853 ng hour/ml, respectively) and c max values (777 ng/ml vs 529 ng/ml, respectively). the 5wb levels are closer to those in adults receiving 30 mg icatibant (median auc 0-6 2975 ng hour/ml; median c max 1254 ng/ ml) but never exceed them. results: samples from 124 patients were analysed. lanadelumab concentrations in plasma increased with higher doses and dosing frequencies. steady state was reached around week 10 (range week 8 to week 14 as evaluated by predose concentrations). at baseline, mean (sd) chmwk levels were 49. 9% (28.8), 47.7% (27.1), 53.7% (24.5) and 48.4% (30.0) for patients in the placebo and lanadelumab 150 mg q4 wks, 300 mg q4 wks and 300 mg q2 wks treatment arms, respectively. by week 14, mean (sd) chmwk levels decreased to 24.0% (13. 3), 28.7% (17.2), and 22.4% (11.5) following treatment with lanadelumab 150 mg q4 wks, 300 mg q4 wks, and 300 mg q2 wks, respectively, and remained reduced throughout the treatment period. conversely, chmwk levels remained elevated at 52.3% (28.1) at week 14 in patients who received placebo. patients in the placebo group had the highest attack rates over the 26-week treatment period (mean 2.46 attacks/month), whereas the rates were markedly lower in patients treated with lanadelumab 150 mg q4 wks (0.48 attacks/month), 300 mg q4 wks (0.60 attacks/month) and 300 mg q2 wks (0.31 attacks/month). dose-and frequency-dependent manner. exposure to lanadelumab was associated with decreased chmwk levels (indicating inhibition of plasma kallikrein activity) and lower hae attack rates, corroborating the efficacy findings and utility of chmwk as a bioactivity marker in the help study. with cyklokapron (tranexamic acid) since she was 9 years old and took the medication very irregularly due to lack of efficacy. one year before presentation at our clinic, she married and moved to vienna. we started a treatment with the bradykinin-2 receptorantagonist icatibant sc at the beginning of the menses and if needed a second time at the time of ovulation. she responded well until she got pregnant. during pregnancy, she developed weekly attacks with increasing severity. therefore, a weekly treatment with humanplasma-derived, pasteurized, nanofiltered c1-inhibitor (inh)-concentrate, 1000 units iv once a week was started and had to be increased to twice per week after one month of therapy due to increasing number and severity of attacks. results: with this treatment attack frequency and severity attenuated. in january 2016 she had a normal delivery at term and gave birth to an otherwise healthy son. treatment had to be continued during 1 year of lactation period and also thereafter due to persistent attack severity. conclusion: there are only limited data for the use of humanplasma-derived, pasteurized, nanofiltered c1-inh concentrate during pregnancy and lactation period. this case confirms the safety and efficacy of the named drug during these periods. wheals are yet classified. the best characterized stem from hereditary or acquired c1 inhibitor deficiency (c1-inh-hae and c1-inh-aae) . last year, the french angioedema network (creak) joined the registry of angioedema without wheals (cloud-r hae). here we present the contribution of the grenoble alpes university hospital (chuga) to this disease registry. the study population is composed of patients with a proved diagnosis of c1-inh-hae/aae. the following items are collected: patients' personal-demographic data, clinical/laboratory/genetic characteristics, major comorbidities, treatments (prophylaxis/acute attacks). data from existing registries at chuga are merged into cloud-r hae and missing data obtained at follow-up visits. as from cloud-r hae structure, patients can directly provide information on angioedema attacks and their treatment through a dedicated electronic app, web connection or paper support, which is then transferred into the registry at chuga. method: in a retrospective study, we included a total number of 48 patients, suffering from a chronic skin disease, whose lesions did not improve or even worsened under immunosuppressive treatment (18 chronic ulcers/pyoderma gangrenosum, 21 bullous autoimmune diseases, 9 skin lymphomas). ffpe tissue was examined for the presence of cmv dna by pcr. next, within the framework of a small prospective study (n = 29) we analyzed the seroprevalence of cmv as well as the presence of cmv dna in lesional skin in patients that had been diagnosed with a chronic skin disease and in whom longterm immunosuppressive therapy had been initiated. results: in the retrospective study cmv dna could only be detected in 1/18 chronic ulcers/pyoderma gangrenosum (5.6%), but not in bullous autoimmune diseases and skin lymphomas. 21/29 patients (72.4%) of the prospective study group were seropositive for anti-cmv-igg, as compared to 55/87 patients (63.2%) in an ageand sex-matched control group. anti-cmv-igm could be detected in method: in this study, we aimed at testing the diagnostic potential of skin function measurements in ss. sixteen patients with conformed diagnosis ss were enrolled in the study. skin fibrosis was assessed by conventional rss and involvement of inner organs and serum inflammation parameters were determined. four objective criteria, namely transepidermal water loss (tewl), corneometry, ph and elasticity, were assessed at nine predefined sites of the body. results were compared to patients with atopic dermatitis (n = 19) and acne vulgaris (n = 22). method: a multicenter prospective observational study was conducted to investigate the clinical significance of serum scca2 in children as a biomarker for ad. patients with ad younger than 16 years old and age-matched healthy children without any allergic disease were enrolled in this study. the severity of ad was evaluated using the objective scorad (o-scorad). the serum levels of scca2, tarc and total ige were also measured. results: in total, 176 patients with ad and 159 non-allergic healthy children were recruited. the serum levels of scca2 had the strongest significant correlation with o-scorad, compared with tarc and ige (r = 0.622, 0491 and 0.407, respectively). after standard treatment with topical steroids and emollients resulting in an improvement of symptoms, the serum levels of scca2 and tarc decreased significantly. the area under the curve (auc) for the roc curve was higher for scca2 (0.929) than for tarc (0.871) or ige (0.820). the difference in aucs between a single cut-off value and age-dependent cut-off values was not significant for scca2, compared with that for tarc (0.042 and 0.064, respectively). conclusion: scca2 is a more reliable biomarker than tarc for the diagnosis of ad and for determining the clinical severity of ad in children. challenges in predicting severity of atopic eczema patients results: before modeling, we checked for significant differences between patients and controls. these were detected for the levels of ccl17, ccl22, cxcl10, ige and ldh. next, we assessed whether single serum proteins already explain disease severity by calculating correlations. twelve of the proteins, namely gcsf, il-5, il-13, il-22, ccl22, il-1ra, cxcl8, ifng, ccl3, il-1ß, ccl17, and il-6, significantly correlate with severity (r 2 range: 0.3-0.45). finally, we built a model for the severity of ae based on all measured serum proteins. ten of the proteins are included in the best-fit model (adjusted r 2 =0.47). the overall correlation between original and predicted severity scores is high (r 2 =0.759) nevertheless the cross validation prediction error is substantial with 19%. conclusion: applied in daily practice, a prediction error of 19% translates to a possible miscalculation of 19 scorad points in both directions and therefore the model is of no practical use. aside from using model-based quality measures like cross validation prediction errors to infer the usefulness of predictive models, testing them in independent cohorts could validate these models. collaborations among scientists working on similar approaches would lead to an increase in statistical power and ideally to more robust models. only robust and validated models are going to have the chance to take the step forward from being a result of computational modeling to being applied in the clinical practice of assessing disease severity in patients. jargosch m 1 ; lauffer f 1 ; pätzold k 1 ; krause l 2 ; garzorz-stark n 1 ; schmidt-weber c 3 ; eyerich s 3 ; eyerich k 1 preclinical studies in cell cultures, mice, guinea pigs and rabbits, comprising sterility, cytotoxicity, systemic toxicity, skin irritation, delay contact sensitization and phototoxicity tests, demonstrated safety of this therapeutic agent. we next conducted a single-blinded, intra-individually controlled, 2phased clinical trial on patients with keloids. the aim was to determine the effects of 1-month therapy on keloid volume and symptoms of pain and itch. two similar keloids on each subject were selectedone was treated with once-daily, self-administered application of triamcinolone-loaded (0.015 mg/patch) microneedles for 4 weeks, while the other served as control with no intervention. outcome measures were (a) keloid volume using a 3-dimensional high-resolution (0.1 mm) scanner and (b) pain and itch scores on 0-10 numerical rating scales. evaluations were performed at baseline, 4 and 8 weeks. in phase 2 of the trial, the whole process was repeated using microneedles loaded with a higher dose of triamcinolone (0.1 mg/patch). case report: a 15-year-old girl was admitted to our department with a single round-shaped lesion in the popliteal fossa which spread to extremities, trunk and face and persisted for several weeks and then faded slowly to residual hyperpigmented patches. courses of antihistamines, antibiotics, cyclosporine a, fluconazole, hydroxychloroquine, prednisolone and topical steroids were ineffective. also patient has had history of itchy urticarial rash and angioedema since 5-year-old, suffered from the flares triggered by physical exertion, stress, cold air and water, spicy food, which resolved within 3-4 hours. the patient's father and 7-year-old brother also had chronic urticaria induced by the same stimuli. the physical examination revealed multiple pink-to-red non-scaly, non-pruritic papules coalescing into annular, arcuate, polycyclic plaques (4-5 cm) with central clearing, centrifugal spread, indu1448 | the role of humoral immunity in the pathogenesis of psoriasis results: we found significantly increased levels of iga in the serum of treatment-naïve psoriasis patients correlating with disease score. however, iga was only observed in dermal vessels of skin sections. we next performed in-depth analysis of peripheral b cell subsets using flow cytometry. among all investigated subsets, we only found a moderate positive correlation of cd138 + plasma cells with iga levels and disease score in untreated psoriasis patients. however, in the group of treated psoriasis patients, neither did iga levels drop nor did plasma cells correlate with iga levels and disease score, rather hinting at an epiphenomenal finding. confirming our hypothesis that psoriasis can develop in the absence of proper humoral immunity, we present a patient who suffered concomitantly from both psoriasis and a hereditary common variable immune defect (cvid). conclusion: here, we provide new insights in the immunology of psoriasis, demonstrating the clear dominance of t cells over shifts in b cell subsets. conclusion: allergic diseases show an increasing incidence in geriatric age. this is partly due to the growing emphasis on a more accurate and careful diagnosis of the aging population. we must also take into consideration the influence of other factors, besides comorbidities and therapeutic regimens in elderly that might affects the immune response, such as environmental pollution as well as food contamination and changing dietary habits of elderly such as easy access to exotic food. one of the challenges in the decades to come is recognizing and fulfilling the need for accurate and timely diagnostics of allergic manifestations in elderly patients, as important part of achieving the best possible quality of life for this growing age group. method: sixty-eight patients with various forms of psoriasis and 30 healthy subjects (healthy control group) were assessed after informed consent was obtained. all subjects were asked to complete a questionnaire including age, gender, duration of psoriasis, concomitant diseases and medications. in the group of patients psoriasis was with only skin involvement with skin plus joints involvement ranging from moderate to severe. psoriaticplaques were evaluated by a specialized medical team using the psoriasis area and severity index (pasi). all patients were seen by a dermatologist and clinical immunologist, who collected data considering the demographic, health status and any other relevant details. blood samples included serum levels of 25-hydroxycholecalciferol and tnf-α using an elisa kit (germany). method: 30% ethanolic extract of sp (sp etoh ) and its five major chemical constituents are prepared. to elucidate whether human orai1 modulated by sp etoh and its chemical constituents, conventional whole-cell patch clamp performed in horai1-overexpressing hek293t cell. we also assessed whether sp etoh and its constituents could inhibit mast cell degranulation and t cell activation. results: in jurkat t lymphocytes, we found that 3 mg/ml sp etoh inhibited orai1 current (i orai1 ) by 81.0 ± 11.1%, while one of its constituents (compound v (com v ); 100 μm) inhibited i oria1 by 48.9 ± 8.71%. investigation of human primary t cell proliferation induced by co-stimulation with antibodies to cluster of differentiation 3 and 28, and of rbl-2h3 mast cell degranulation following ige-antigen complex stimulation, revealed that 100 μm com v inhibited both t cell proliferation (by 34.8 ± 6.08%) and mast cell degranulation (by 36.7 ± 0.07%); these effects were concentrationdependent, and no cytotoxicity was observed. conclusion: considering that most regional plants have not been investigated chemically or pharmaceutically, they remain as untapped potential sources of topical agents for drugs and other application. our findings suggest that com v , which derived from sp etoh , represents a promising candidate compound for the development of therapeutic agents for the prevention and treatment of allergic diseases. results: the cohort consists of 14 caucasian patients. eight of them (57%) are women. the mean age (and range) at the clinical presentation of disease was 33 years (4-51 years). the mean age at diagnosis for men was 23 years and 48 years for women. all patients have a positive history of recurrent and/or persistent lip swelling, 3 of them (21%) report oral ulceration, 5 cases (36%) have history of previous or current facial palsy and 4 patients (28%) present tongue fissuring. concurrent cd has been diagnosed in one patient. biopsy reports were available for 10 patients (71%); in 6 cases (60%) non-caseating granulomas were seen. various therapeutic approaches have been described: intralesional corticosteroids had a good response in 6 patients, infliximab was partially effective in 3 cases; oral corticosteroids and/or methotrexate seem to cause a partial symptoms improvement. conclusion: this is the first attempt, in our knowledge, to (a) centralize all data of patients with ofg in a national registry with the aim of carrying out epidemiological data and (b) develop italian guidelines including a diagnostic-therapeutic flow chart, shared by the participating centers. the registry will guide the clinicians in the identification and management of the ofg patients, reducing the diagnostic delay and hopefully improving quality of life. case report: a 10-year-old girl without personal history of atopy, got a temporary tattoo with henna. after three days, she developed a local exudative, erythematous eruption with painful blisters lesions that followed the contours of the tattoo. she had neither fever nor other lesions. she was treated with topic methylprednisolone-gentamicin showing an important improvement 10 days after. as a liquenoid scar remained in tattoo area, trofolastin ® (centella asiatica, αtocopherol, hydrolysed collagen, elastin) patch was prescribed to be placed on the scar. forty-eight hours later, the patch was removed and was newly observed an exudative, erythematous and painful wound that required oral treatment with amoxicillin-clavulanic. after three days, the girl developed on a maculopapular, generalized and itching rash. she was treated with dexchlorpheniramine and methylprednisolone with a complete resolution in 4 days and she was referred to our allergy unit to be studied because of a suspicion of drug allergy to amoxicillin-clavulanic acid. an allergy workup was performed after obtaining an informed consent. case report: it may be sometimes difficult to find the causing allergen in allergic contact dermatitis. face is a region on which various materials contact. in this manuscript a woman case is presented who shows patch test positivity to her husband's shaving product. a 35 years old woman applied because of allergic contact dermatitis on her face. it is learnt that lesions have been continuing for a long time, occasionally getting well with corticosteroid creams; but continuing again. patch test was performed with european standard series and cosmetic products she was using. negative result was observed. following, patch test was performed for the products her husband was using. 2 positive results were obtained for the shaving cream of her husband was using. in detailed anamnesis, it is learnt that the lesions developed approximately 1 month after her husband started to use this cream. it is advised not to use this product to her husband. the disease did not repeat again. it should not be forgotten that cases with allergic contact dermatitis could get in touch with allergenic materials via individuals in close contact. gül ü akdeniz university faculty of medicine, department of dermatology, antalya, turkey case report: tnf-alpha plays role in etiopathogenesis of allergic contact dermatitis (acd). in mice which lack tnf-alpha, the response of late type hypersensitivity is spoiled. in addition, tnfalpha blocker are also used in some cases with acd. in this poster the results of european standard patch test is given in which acd is observed and tnf-alpha blocker are used without dermatological indication. 3 cases who use tnf-alpha blocker applied because of acd: there was lesion in one case on face, in other case on face and hand, and in the last case only on hand. european standard patch test was performed to patients who were continuing to use tnf-alpha blocker. in one case no positive response was observed, while in two cases positive response to more than one allergen were obtained. in conclusion, tnf-alpha blockages cannot suppress the response of delayed type hypersensitivity. 1459 | case of allergy to nickel on the background of its intake in food peredelskaya m case report: nickel is one of the most commonly used metals; it is used for the manufacture of jewelry, plates and dishes, and medical products. a patient n, 32 years old, female, complains of pruritic rash on the body skin with the itch intensity up to 8-9 points and the number of lesions more than 50. allergic background: for quite some time now the patient noted occasional eruptions on her skin after a contact with jewelry made of non-precious metals. previously patch skin tests with nickel showed a positive reaction. the patient sought emergency medical care with complaints of a number of itchy lesions erupted on her whole body during the last 24 hours. on admittance: state of moderate severity, the patient was emotionally labile, focused on her body sensations, tearful. on the skin of face, upper and lower extremities and torso a punctuate purpura with lesions up to 0.5 cm diameter, prone to confluent. a physical status was within normal limits. in order to control the itching, as well as to sedate the patient, antihistamines of the first generation were administrated parenterally; but the eruptions kept to progress and to intensify; lesions were spread throughout the whole body, merged in gigantic areas. system glucocorticosteroids therapy was administrated, with 120 mg of prednisolone, but then new lesions kept appearing in a large number, including after-meal rash. water, tea, bakery products, thin yoghurts did not impact the skin condition, whereas the intake of pasta, cereals, and similar products provoked intensifying of eruptions. the patient observation revealed a sharp increase in the rash after such manipulations as intravenous injections or blood sampling from the vein, the process spreading from the injection site to the entire arm. a detailed anamnesis of the disease: on the eve of the start of hives, the patient purchased a coffee machine (with metal nickel-plated parts) and started to use it. diagnosis: a systemic contact dermatitis. an allergy to nickel. the injection treatment was discontinued and a therapy with per oral gcs and antihistamines of the second generation was administrated. a recommendation was given to cook and to eat food using ceramic or wooden utensils. three days later marked positive dynamics of the skin process has been noted. the episode of systemic contact dermatitis has developed due to exposure to nickel from ingestion in food, as well as during the parenteral treatment. background: anaphylaxis reactions during anesthesia can have a mortality of 3%-6%. 2/3 of the anaphylaxis in the operating room are due to the use of neuromuscular blockers. rocuronium is frequently involved because is oftenly used. we present a case of a 41 years old man with an anaphylaxis shock due to the administration of rocuronium. method: 41 years old man with no personal history of interest that is going to undergo vertebral surgery. minutes after anesthetic induction with fentanyl, propofol and rocuronium he started with lowering of oxygen saturation. orotracheal intubation is performed and, with the suspicion of anaphylaxis shock, adrenaline, antihistamines and corticoids were administered. after 20 minutes without improvement, 500 mg of sugammadex was administered, given the possibility that the condition was secondary to the use of rocuronium. tryptasa level was 63. results: skin test to fentanyl, propofol, látex and rocuronium were done 6 weeks after and only rocuronium test was positive. conclusion: in summary, the occurrence of anaphylactic shock after neuromuscular blockers is widely described in medical literature. there are conflicting data about the use of sugammadex as coadjutant treatment in case of anaphylaxis due to the use of rocuronium. we believe is a good option when conventional treatment is not useful. case report: a 31-year-old woman with past history of allergic rhinitis and hypertension was admitted to the obstetrics service in labor of first child in april 2016. epidural anesthesia with ropivacain and sufentanil was administered. as there was no labor progression, eighteen hours later she was admitted to undergo cesarean section and epidural anesthesia was re-administered. metoclopramide, ampicilin and ranitidine were given intravenously. during ranitidine perfusion, the patient presented general cutaneous erythema and pruritus, tongue, lips and eyelids angioedema and dyspnea. perfusion was suspended and hydrocortisone and supplementary oxygen administered. she denied any type of previous adverse reaction to drugs and any symptoms with use of latex-containing material. allergic evaluation revealed negative latex skin prick test (spt) and negative penicillin, amoxicillin and ampicillin specific ige assay. skin prick and intradermal tests with sufentanil, ppl, mdm, amoxicillin and ampicilin were negative. oral amoxicilin and metoclopramide provocation challenge were negative. spt and subcutaneous provocation challenge with ropivacain were negative. spt with ranitidine was negative but skin intradermal test proved to be positive. the patient was taught to avoid histamine h2 receptor antagonists and use as a safe alternative proton pump inhibitors. conclusion: anaphylaxis during anesthesia is an unpredictable, severe, and rare reaction. the identification of responsible drugs is a complex task. we report a case in which a commonly used and generally safe drug caused a severe reaction, which demonstrated that even the least obvious culprit should not be disregarded. epidemiologic data suggest that the number of cases of chx allergy appears to be increasing. background: chlorhexidine is a synthetic chemical with excellent antiseptic and disinfectant quality frequently used in everyday products and medical devices. the prevalence of allergic reactions towards chlorhexidine is rare, though there is increasing evidence for its allergenic potential. in this case we report about a patient with serious perioperative anaphylaxis. next to multiple potential allergens that he was exposed to, a chlorhexidine containing lubrication gel has been used for urinary catheterisation. within minutes post-exposure, the patient developed generalized urticaria, bronchospasm, tachycardia and hypotension. material and methods: we performed skin prick tests and intradermal tests with all substances documented in the anaesthesia chart, further we analysed specific immunoglobulin e (sige) antibodies and performed oral provocation challenges for exclusion. results: in the skin tests all substances except for chlorhexidine (spt: 7 mm wheal diameter/31 mm erythema) were negative. a sensitization for chlorhexidine was further corroborated by chlorhexidine-specific ige antibody (4.08 ku/l) in the patient's serum. in addition, the challenges for the drugs without sensitization (cefuroxime, lidocaine) were tolerated. considering all potentially relevant allergens that the patient was exposed to and the proof of specific sensitization, we diagnosed an immediate-type allergy towards chlorhexidine. conclusion: with the ubiquitous use of chlorhexidine an increase in hypersensitivity reactions including immediate-type allergic reactions is observed. anaphylactic reactions are rare, but potentially life-threatening, the diagnosis is crucial. as a warning declaration in medical devices is missing, the diagnosis of chlorhexidine allergy might be easily under-recognized or misdiagnosed. unfortunately, until now validated provocation tests are not existent, but the evaluation of combined skin tests and sige is sensitive and specific. 1464 | an approach to incidence of death due to anaphylaxis in spain (1998 spain ( -2011 background: reports about death due to anaphylaxis are still scarce because of its rarity and limited information to few countries. also, data source analysis is usually not included. we report incidence of death due to anaphylaxis in spain using two databases. method: we used a hospital series of anaphylaxis deaths from the spanish hospital system and a series from the national institute of toxicology and forensic sciences (intcf) predominantly formed by extra-hospital deaths. deaths from the spanish hospital system were extracted using codes from icd-9-cm, related to anaphylaxis among all deaths occured in the 1998-2011 period. for extracting deaths due to anaphylaxis at the intcf in the same period, two allergist researchers identified these deaths among cases with suspicion of anaphylaxis cause. a regression logistic was run to discriminate the probability of anaphylaxis death belonging to each database. incidence rates were calculated for the different groups (age, sex) using the spanish population as the denominator. temporal trends were calculated from the hospital database using poisson regression models with the number of cases of anaphylaxis detected each year as the dependent variable, and age and sex as covariates. results: there were four positive predictors of fatal anaphylaxis after the logistic model (usual allergen, positive specific ige, suggestive symptoms and previous reaction to the same allergen case report: we were informed that a girl was admitted to the pediatric endocrinology department due to early breast development. she had been diagnosed as central precocious puberty (pp). later, triptorelin acetate (ta) therapy had been started monthly. within 20 minutes after first sc injection of ta at home, she had developed shortness of breath, decreased air entry, and coughing for ten minutes and lastly she had developed vomiting for 15 minutes. her symptoms were accompanied by a pruritic blanchable maculopapular rash on her ears, cheeks, lips, and eyelids approximately for two hours. although they had applied emergency department of the local hospital. based on the diagnosis of anaphylaxis she was immediately treated with adrenalin. she was subsequently hospitalized for possible recurrence and discharged next day without any further events. treatment with another preparation, leuprolide aseptate(la-lucrin), as an alternative treatment was started with premedication against anaphylaxis risk only at first time and the patient did not develop any reactions. the patient is still on this treatment with no complications. anaphylaxis is diagnosed in the presence of a detectable allergen accompanied by symptoms of two systems. our patient had symptoms of the three systems as described above, that is, dyspnea with coughing, hives, nausea, and vomiting. main treatment of anaphylaxis is the epinephrine use. early usage maximizes the likelihood of survival. diagnostic tests with culprit drug were not performed in our hospital if the patient had the anaphylactic drug reaction and grouped as "physician diagnosed anaphylaxis". there has been only one report regarding anaphylaxis to ta treatment in cpp in turkey. in the literature, anaphylactic reactions against ta have been reported only in few pediatric cases. gnrh analogues are important to ensure the physiological growth in precocious puberty. because anaphylaxis can be lethal, and gnrh analogues are similar structure; the present case suggests that one should bear in mind the possibility of anaphylaxis in all patients who receive gonadotropin-releasing hormone and anologs and monitor such patients carefully as needed. furthermore, we must provide sufficient information of adverse reactions, including anaphylaxis, to patients. hence, managements against anaphylactic shocks should be recognized and treatment should be given immediately. 1467 | an anaphylactic shock induced by the rocuronium anesthesia: a case report cabrera v; barrios j; callero a; gonzález ce; pérez e; martínez ja hospital universitario nuestra sra de la candelaria, santa cruz, spain background: the anesthetic act is a unique pharmacological situation, where the patient is exposed to a multitude of substances.among them, neuromuscular blocking agents are the leading cause of preanesthetic anaphylaxis, with a frequency of between 50%-70%.followed by latex in second place and antibiotics in third place. among the neuromuscular relaxants, most reactions are due to suxamethonium or succinyl-choline in 60.6%, followed by atracurium, rocuronium and verocuronium.the one that produces the least reactions is cisatracurium. method: a 61-year-old woman presented a type iii anaphylaxis of the brown classification during the anesthetic induction in a surgery scheduled for laparoscopic cholecystectomy. for which adrenaline, dexchlorpheniramine, hydrocortisone, ranitidine and sugammadex was administered and was transferred with orotracheal intubation to the anesthetic resuscitation room. due to good evolution of the patient, she was extubated within three hours. the drugs involved in the reaction were: rocuronium, amoxicillin-clavulanic, fentanyl, propofol, midazolam, lidocaine and atropine. there was a high suspicion by the anesthesiology and resuscitation service that the abstracts reaction could have been due to the neuromuscular relaxant used, in this case rocuronium, since the reaction was reversed with sugammadex. the patient had undergone surgeries under general anesthesia previously without incidents. a specific allergy study was performed with laboratory tests with tryptase, skin tests with drugs and basophil activation test for rocuronium, sugammadex-rocuronium mixture and cisatracurium. • serial measurement of serum tryptase: 12.9 u/l, 10.9 u/l y 3.42 u/l there is no activation of basophils for sugammadex-rocuronium mixture and cisatracurium. the patient is diagnosed with rocuronium allergy. sugammadex not only acts as an antidote to reverse the neuromuscular block against rocuronium, but also has antiallergic properties by inhibiting mast cells. as an alternative for future interventions, the patient can use cisatracurium, as the skin tests and the basophil activation test are negative. unal d yedikule chest disease, istanbul, turkey case report: tetracycline hydrochloride may rarely cause hypersensitivity reactions. (hrs). immediate type reactions are at the level of case presentations and anaphylaxis is reported. we report a patient with late onset anaphylaxis caused by tetracycline. a 47-year-old woman referred to our allergy outpatient clinic because of urticaria due to an antibiotic that she does not remember the name of. the patient reported that many years before she had presented urticaria on her arms and legs one hour after taking the drug. to confirm drug allergy invivo and invitro testing have to performed. for many drugs there was no validated skin test. for all that invitro tests are often less sensitive and more expensive. therefore single blind placebo controlled drug provocation tests (sbpcdpt) is the gold standard in the diagnosis of drug hypersensitivity reactions. we did not know which group of antibiotics were allergy to the patient. because the patient had history of asthma and atypical pneumonia we were performed the allergy tests with clarithromycin and she had tolerated. it was necessary to use tetracycline because of patient had vaginal infection. skin tests have not yet been validated for tetracyclines. for skin prick tests of tetracycline that is only available as tablet, not in a soluble form. therefore, the tablet was smashed and diluted with 0.9% nacl. it was also tested. 10 healthy controls to exclude irritation. because of skin prick tests with tetracycline negative. sbpcdpt was planned. sbpcdpt was performed by progressively increasing four divided doses at 30 minute intervals. two hours after last dose the patient experienced dyspnea, palpitations, and hypotension. as the reaction was considered to be anaphylaxis, she was given 0.5 mg of intramuscular epinephrine, intravenous 45 mg of pheniramine, and 40 mg of methylprednisolone. the reaction resolved within 3 hours. blood tryptase level was 14.9 ug/l taken at the 2nd hour of the reaction approximately 2 months after the anaphylaxis, serum tryptase level was 1.59 ug/l the serum tryptase level and the patient's clinic confirmed anaphylaxis due to tetracycline. we had proved late onset anaphylaxis due to tetracycline with the patient's clinic and serum tryptase level. anaphylaxis due to tetracycline is limited to case reports and small series but to our knowledge, there is no previous report of late onset tetracycline anaphylaxis. 1469 | case series of ige mediated anaphylactic shock due to polysorbate case 2: an 86-year-old male patient with hypertension, hypothyroidism and episodes of sustained monomorphic ventricular tachycardia (smvt), developed an anaphylactic shock after the administration of injectable amiodarone due to smvt. serum tryptase levels reached 34.8 μg/l during the reaction (baseline 6.59 μg/ l). skin tests were positive to injectable amiodarone (prick 50 mg/ ml, intradermal 0.5 mg/ml) and polysorbate 80 and 20 (prick-prick). skin prick-prick to amiodarone and dronedarone tablets were negative. the patient tolerated oral amiodarone. we report an anaphylactic reaction during the first intravenous administration of amiodarone in a female patient being treated for supraventricular tachycardia. bat was positive, suggesting a direct effect on basophil activation, as the patient was not previously exposed to the drug. 1472 | anaphylaxis during labor: don't forget to think of an amniotic fluid embolism case report: a 32-year old primigravida (40 weeks of gestational age) was admitted with signs of pre-eclampsia and labor was induced. benzylpenicillin and ropivacaine (epidural anesthesia) was administered >3 hours before the event. eighteen minutes after starting an infusion with oxytocin (15 ml/h) and a vaginal toucher, the patient developed a decreased level of consciousness, generalized edema/erythema and thoracic pain, followed within 3 minutes by fetal bradycardia and maternal collapse. after resuscitation, an urgent sectio was performed, and a baby girl was born. patient was extubated the same day. serum tryptase, 1 hours after the event, was 11.2 μg/l (basal tryptase level 3.4 μg/l). allergy workup demonstrated negative specific ige and skin tests for latex and chlorhexidine, negative skin and provocation testing for ropivacain. however, skin testing was hampered by dermographism: intradermal (idr) testing of benzylpenicillin (10 000 iu/ml, 1/1000-1/1) and oxytocin (10 ie/ml, 1/10 000-1/100) showed extensive erythema. idr testing of oxytocin in healthy volunteers showed pallor around the injection site (n = 3). intravenous provocation with benzylpenicillin was uneventful. a basophil activation test with oxytocin (patient and control) was negative. an additional bone marrow evaluation showed no evidence for mastocytosis. although clinical criteria for anaphylaxis were fulfilled, a diagnosis of an amniotic fluid embolism (afe) was concluded. no drugs were prohibited. patient gave consent for publication. conclusions: afe is one of the most devastating conditions in obstetrics, occurring typically during labor and delivery or immediately postpartum. the pathogenesis remains incompletely understood, however, it has been suggested that afe involves an anaphylactic reaction to fetal tissue exposure associated with breaches of the maternal-fetal physiological barrier, supported by transiently increased serum tryptase levels. the diagnosis is primarily clinical, and generally one of exclusion. no specific antemortem diagnostic tests are available to confirm afe. postmortem identification of fetal squames in the maternal pulmonary circulation gives final diagnosis. differential diagnosis includes drug-induced anaphylaxis or mastocytosis, which were ruled out in our case. method: the patient presented after hymenoptera stings dyspnoea, generalized erythema with pruritus, edema of the face that required emergency therapy in 3 episodes. results: an angio-ct was performed at the inferior limbs with optiray and 5 minutes after the end of the investigation, the patient presented an anaphylactic shock requiring admission to the icu for 4 days. conclusion: the patient's progression was slowly favorable. results: thirty seven cases were reported. 24 (65%) were women. the median age was 47 years. 19 (51%) had dress/dihs, 6 (16%) ten, 3 (8%) sjs, 3 (8%) agep, 3 (8%) other not classified scars, and 1 (2.7%) overlapping ten/sjs. in 100% of the patients the suspect drug was withdrawn. thirty one patients (83%) received systemic anti-inflammatory treatment. twenty six patients (70%) received intravenous (iv) corticosteroids alone, 3 (8%) iv corticosteroids plus ivig, 1 (2.7%) iv corticosteroids plus ivig, infliximab and colchicine, and 1 (2.7%) iv corticosteroids plus infliximab and cyclosporin. there were complications in 17 cases (49%), and death occurred in the patient with overlapping ten/sjs who had received corticosteroids plus immunoglobulin. in this study, our aim was to evaluate severe ihr to icm. method: we retrospectively analysed patient who consulted to our allergy unit between july 2011 and july 2016 reporting symptoms within 1 hour after icm administration. from a total of 109 patients, we selected eight that had suffered an anaphylactic reaction. a written informed consent had been obtained for diagnostic procedures. introduction: immediate type hypersensitivity reactions to pemetrexed have been reported as very rare case reports. as limited availability of alternative therapies in chemotherapeutic allergy, desensitization plays an important role in ensuring reuse of the culprit drug. we report a case of pemetrexed anaphylaxis and successful desensitization. case: 43 years old female patient with lung adenocarcinoma had been treated with cisplatin-pemetrexed as second-line therapy. during the 5th cycle within 5 minutes after the end of pemetrexed infusion she had chest pain, shortness of breath, cough, swallowing difficulty, erythema on face and body, nausea and vomiting. she was diagnosed as anaphylaxis and adrenaline was administered besides antihistamine and methylprednisolone. symptoms and findings of the patient were improved within 15 minutes. oncologists decelerated no suitable alternative therapy for the patient. although skin tests (prick test with 1/1 concentration, intradermal test with 1/10 000-1/10 concentration) were negative with pemetrexed, taking into account the severity of the reaction, pemetrexed desensitization was applied with the consent of the patient. no reaction was observed during the procedure result: desensitization is a successful and safe method of reusing the culprit drug. successful desensitization of pemetrexed with immediate type hypersensitivity reaction is described. the 28 years old man was admitted emergency department with fever, rash (maculo-papular) and pain in joints. it was the 9th day of taking of amoxicillin. the hematological abnormalities were revealed -eosinophilia, increased erythrocytes sedimentation rate. the level of serum ecp was 183 μg/l. the liver functional tests were increased too. hepatomegaly and cervical lymphadenopathy were observed. the patient was treated as a dress syndrome (infusion therapy, systemic steroids) and discharged after 2 weeks with improvement. all hematologic parameters were in normal limits. lymphadenopathies were resolved. the level of ecp was retaken -84 μg/l. patient was prescribed oral steroids till normalization of limits of ecp. it lasted 2 weeks after discharging. the serum level of ecp can play key role in the management of dress syndrome and in the making of diagnostic processes. until now, allergic or anaphylactic reactions to peg have been rarely reported. although patient with hypersensitivity to peg should avoid peg-containing drugs or products, patient who needs colonoscopy has few alternative bowel cleansing methods. no successful desensitization to peg has been reported to date. we report a case of successful desensitization and subsequent safe colonoscopic examination in patient with allergic reaction to peg. method: a 50-year-old woman developed generalized urticaria, pruritus, throat swelling, and shortness of breath immediately after taking a bowel preparation solution for colonoscopy. she had the first symptoms 3 years ago, and has had 2 more experiences so far. the symptoms appeared within 20-30 minutes of taking cleansing solution, and the endoscopy was no longer possible. seven years ago, she underwent endoscopy with no specific symptom. when the last symptom occurred a year ago, she was treated at emergency room because of severe dyspnea and dizziness. the patient came to our clinic for the proper diagnosis of allergy reaction and possible colonoscopic evaluation. objectives: to describe a successful desensitization to vedolizumab in one patient diagnosed with ulcerative colitis, refractory to infliximab and intolerant to azathioprine and sulfasalazine. methods: our patient was a 38 year old woman receiving treatment with intravenous vedolizumab (300 mg/cycle). cycles 1 and 2 were well tolerated, but in cycles 3, 4 and 6 she experienced hypotension and dyspnea, in spite of premedication with oral dexamethasone and metoclopramide. during cycle 6, she also showed facial angioedema, systemic urticarial reaction and oropharyngeal pruritus treated with methylprednisolone and ebastine. the results of prick (vedolizumab concentration 60 mg/ml) and intradermal skin tests (1:10 and 1:100) with vedolizumab were negative in our patient and in ten healthy controls. total ige level was 26.4 ui/ml and specific ige against dermatophagoides were positive, being negative for hamster epithelium and latex. since vedolizumab was the only therapeutic alternative, the patient was planned to undergo vedolizumab desensitization according to an 8-step protocol. patient informed consent was obtained previously. premedication consisting of ebastine, acetylsalicylic acid, montelukast and methylprednisolone one hour before desensitization was administered. desensitization protocol was performed with a total duration of 4 hours and 35 minutes and a total dose of 293 745 mg. dose steps were 0.015, 0.03, 0.3, 0.6, 1.2, 9, 18 and 264.6 mg. conclusions: our 8-step protocol desensitization to vedolizumab resulted safe and effective in our patient and it has allowed the continuation of treatment with vedolizumab for her ulcerative colitis. montelukast, anti h1 and h2 blockers were used for the pretreatment of desensitization. all procedures (skin and blood tests, desensitization) were carried out with the informed consent of the patient. we present an exceptional, non-immediate case of fever after cisplatin and etoposide infusion with positive skin test. case report: a 63-year-old man, recently diagnostic of lung cancer stadium iv, in first line of treatment with cisplatin and etoposide, started 2 hours after finishing the 2nd infusion: facial erythema that becomes generalized after 4-5 hours from infusion. twelve hours later, developed warmth sensation, shivering and fever (39°c) that persisted despite the use of several oral antipyretics treatment. infectious disease was discarded, so he was referred to our department in order to assess further administration of cisplatin and etoposide. methodology: skin testing was performed 30 days after the last reaction to minimize false-negative results, as follows (a) cisplatin prick test (1 mg/ml) and intradermal tests (0.1 mg/ml); (b) etoposide prick test (20 mg/ml) and intradermal tests (2 mg/ml); with histamine as the positive control and nacl-diluent as the negative control. the results of skin test were negative for immediate reading. but two hours later, intradermal test for cisplatin turned into red and itchy and 12 hours later, still associated a wheal. the patient was classified as high-risk (lung diseases, forced expiratory volume in 1 second <1 l) and underwent programmed inpatient desensitization according to the standardized birmingham women's hospital protocol. desensitization was performed in the medical intensive care unit. the patient received only standard oncology premedication. he tolerated the final dose of cisplatin with no breakthrough reactions followed by etoposide standard infusion. two additional desensitization procedures were performed, with no breakthrough reactions. therapy ended when the disease worsened. the importance of this case, lies in the fact that fever has not been described as a clinical hypersensitivity reaction for cisplatin but for oxaliplatin. although a non-immediate reaction at the 2nd infusion of cisplatin could scarcely suggest a hypersensitivity reaction, the positive skin test and successful desensitization with this drug, could suggest it. introduction: propylthiouracil is commonly used as the first treatment option in patients with hyperthyroidism. although it is generally a well-tolerated drug, it may lead to some side effects including liver damage, leucopenia and skin rash. among skin rash findings, urticaria is considerably common. nevertheless, in cases that developed urticaria, a rapid desensitization protocol specific to propylthiouracil has not been encountered. we represented a case in which we applied successful oral desensitization via a scheme in accordance with general desensitization principles in a case that developed propylthiouracil-induced urticaria. case report: propylthiouracil at a dose of 50 mg/day was initiated for a 36 year-old female patient with diagnosis of hyperthyroidism in internal diseases clinic. the patient developed widespread itching and swelling in the body 5-6 hours after she took the first dose of the drug. she had experienced a similar reaction with use of propylthiouracil in 2012. the patient who was breastfeeding a baby and did not have any treatment option other than propylthiouracil was referred to us with pre-diagnosis of drug allergy. the patient was thought to have propylthiouracil-induced hypersensitivity reaction and desensitization was planned. we prepared a desensitization scheme in accordance with general desensitization principles (table 1 ). in accordance with this prepared scheme, we successfully applied the desensitization protocol with propylthiouracil for the patient. the patient gave informed consent before testing and desensitization. results: spt was negative, but idt reaction was positive at 1:1000 method: we present a desensitization protocol to intravenous etoposide used in a 35-year-old male for non-hodgkin's lymphoma who was referred to the department of allergy at sotiria general hospital of athens. within 5 minutes after receiving the first dose of the drug, the patient complained for flushing, retrosternal pain, difficulty in breathing and weakness. the infusion was ceased immediately and the patient received proper treatment with gradual recovery of the symptoms. the next day, skin prick test (spt) and intradermal test (id) were performed with etoposide at dilution 1:10 (2 mg/ml). both of the tests, spt and id, were negative. histamine and nacl 0.9% were also used as positive and negative controls, respectively. a desensitization protocol of three-day cycle with intravenous etoposide was conducted. premedication for 3 days was administered including methylprednisolone, cetirizine, ranitidine, paracetamol and montelukast. results: the desensitization protocol of the first day consisted of 11 steps of rapid pulses administered at increasing infusion rates every 15 minutes, and 1 step of drip infusion at a final rate of 60 ml/hour (372 mg/232.5 ml) until completion of the infusion. the following 2 days, the patient received a modified rapid protocol consisting of the administration of the calculated dose of 400 mg in only one step of infusion rate of 60 ml/hour completing in only 4 hours and 15 minutes. the same protocol was applied in another three-day cycle with no adverse reactions. conclusions: hsrs to etoposide are rarely described in the literature. we propose a three-day modified rapid desensitization protocol to intravenous etoposide that could be particularly useful compared to other time-consuming desensitization protocols. case report: imatinib, a tyrosine kinase inhibitor, sometimes causes cutaneous reactions that can be of various severity. we present a case of a patient who was started on imatinib 400 mg daily and after 3 months developed diffuse mildly pruritic rash with some desquamation of palms of the hands. the dose of imatinib was reduced to 300 mg daily and therapy with prednisone 30 mg was started. after resolution of rash, the dose of prednisone was tapered to 10 mg daily, but the rash reappeared, although milder in intensity. the dose of prednisone was increased and levocetirizine added and rash resolved. prednisone was slowly discontinued and rash did not appear. in the case of reactions to imatinib the dose of drug can be reduced and short course of oral corticosteroid given. milder reactions can be treated with antihistamine or topical corticosteroid. therefore, when adverse skin reaction to imatinib occurs, induction of tolerance to this important drug should be attempted. method: the exosomes were collected from in vitro primary human sinonasal epithelia cell, which derived from three different groups (normal control, chronic rhinosinusitis and chronic rhinosinusitis with asthma). generation of exosomes in epithelia was confirmed by nanosight, tem and western blot. the proteins of exosomes were identified by proteomics analysis. the cellular proliferation and ciliogenesis were analyzed by cck8 and qpcr.the ciliary beat frequency was detected by sava system. we found that epithelial cellular exosomes from chronic rhinosinusitis and chronic rhinosinusitis with asthma could reduce the multiplication rate of normal epithelial cell at a certain concentration (≥10 μg/ml).we found that exosomes from chronic rhinosinusitis with or without asthma could interrupt the cellular ciliogenesis and ciliary beat frequency. using mass spectrometric analysis we demonstrated that the epithelial exosomes contained different proteins in different disease states. conclusion: our findings first identified that exosomes could be secreted by nasal epithelial cells. we also demonstrated exosomes from chronic rhinosinusitis with or without asthma could be a pathogenic factor in the remodeling of sinonasal mucosa. it could be considered as a significant biomarker for detecting the progress of chronic rhinosinusitis and a alternative therapy target. background: mucociliary transport (mct) is a major respiratory tract host defense mechanism and chronic exposure to allergen can deteriorate the these defense mechanism. the aim of this study was to investigate the effects common allergen (dp/df) on human nasal mucociliary transport in allergic rhinitis patients, and to determine the pathophysiology of ciliary beat frequency (cbf) during allergeninduced change method: allergic nasal mucosa cells of allergic rhinitis patients were exposed to common allergen (dp/df), and cbf was analyzed using an optical flow technique with the peak detection method results: the allergen(dp/df) exposed group showed a decreased cbf when compared to the control group. in the cytotoxicity assay, difference in survival rates was not found between the two groups. in the allergen(df/df)-exposed group, protein kinase c (pkc) activity was increased during a pkc activity assay. the broad pkc inhibitor, calphostin c abolished the allergen(dp/df)-induced decrease of cbf. the allergen-induced decrease of cbf was abolished by gf 109203x, a novel pkc (npkc) isoform inhibitor, whereas the decrease was not attenuated by g€o-6976, a specific inhibitor of conventional pkc (cpkc) isoform. conclusion: allergen may inhibit cbf via an npkc-dependent mechanism. therefore, we have confirmed that chronic exposure to allergen could decrease cbf by increasing pkc activity. method: ova-alum allergic rhinitis mouse model (ar model) and poly(i:c) induced il-17 dominant mouse model (neutrophil dominant model) were used. both mouse models were exposed to tio2 particles for 2 hours twice daily for 7 days, while the controls (n = 5) were not. sirius red staining for eosinophil infiltration, immunohistochemistry for neutrophil and il-17a, serum immunoglobulin (ig) g and e were assayed by using enzyme-linked immunosorbent assay. in addition, the expression of interleukin (il)-4, il-17, and interferon (ifn)-γ in the nasal mucosa and cervical lymph nodes was measured by immunohistochemistry, and real-time reverse transcription-polymerase chain reaction (rt-pcr), il-17 monoclonal antibody (secukinumab) was administered in vivo to evaluate il-17a dependency. results: tio2 exposure did not influence eosinophil infiltration in both ar and neutrophil dominant model. however, tio2 exposure increased neutrophil infiltration in both models and neutrophil infiltration was correlated with il-17 expression in the nasal mucosa. serum igg and ige levels were changed significantly in the tio2exposed group. th2 cytokines (il-4, il-5) and th1 cytokine, ifn-γ were not changed significantly in both models after tio2 exposure, however, il-17 were increased in tio2 exposure group. and these increased type 17 pathway and neutrophil infiltration were reversed after il-17 monoclonal antibody administration. conclusion: exposure to airborne tio2 induced neutrophil infiltration in the nasal mucosa. the type 17 response seems to play a dominant role in the nasal immune response following airborne tio2 exposure. 1501 | toll-like receptor 9 ligands increase type i interferon induced b-cell activating factor expression in chronic rhinosinusitis with nasal polyposis results: first: paf-r mrna expression was very low in fibroblasts from nm and np (data not shown). paf-r mrna expression was detected in whole sinonasal tissue, submerged and ali epithelial cell cultures from both controls nm and np. paf-r mrna was also detected in peripheral blood eosinophils. although no differences were found between nm and np tissues and cultures, paf-r mrna expression was significantly higher (p < 0.001) in eosinophils than in upper airway tissues and cells. second: protein paf-r was found expressed in whole tissue (predominantly in the epithelium and submucosal glands), submerged and ali epithelial cell cultures from both nm and np. peripheral blood eosinophils also showed paf-r protein expression. conclusion: both paf-r mrna and protein expression was found in sinonasal nm and np tissues (epithelium and submucosal glands) and in peripheral blood eosinophils. these findings suggest the paf/ paf-r system could play a pathophysiological role in crswnp through the modulation of structural and inflammatory cell functions. "this study was funded with a research grant from uriach group". background: allergic rhinitis (ar) is an increasingly more common nasal inflammatory disease in which an antigen such as pollen or dust mites triggers symptoms such as itching, sneezing, and rhinorrhea, which can lead to nasal obstruction. ar is mediated by thelper type 2 cells together with mast cells, eosinophils, and several inflammatory cytokines and chemokines. for example, recent abstracts | 757 research indicates that hypoxia-inducible factor 1α (hif-1α) is involved in the mechanism of ar development. the anti-heart failure drug digoxin has a specific inhibitory effect on hif-1α, and thus, the aim of the present research was to explore the anti-hypertensive effect and mechanism of digoxin in ar. method: an animal model of ovalbumin-induced ar was established in guinea pigs. the experimental group was treated with digoxin through the tail vein. for the comparison of symptoms between the experimental and control groups, the incidence of sneezing was recorded, and the eosinophilic interleukin il-4 and il-5 levels in nasal secretions were measured by enzyme-linked immunosorbent assays. western blotting and reverse transcription polymerase chain reaction analyses were conducted to evaluated hif-1α expression in guinea pig nasal mucosa. results: the ar symptoms of guinea pigs in the experimental group were significantly improved after administration of digoxin. specifically, the experimental group exhibited a significantly lower numbers of sneezing times(average 36.0 ± 1.10 vs 7.4 ± 0.78, p < 0.05) and lower il-4 and il-5 secretion levels (p < 0.01) compared with the control group. moreover, guinea pigs of the experimental group showed less severe nasal mucosa edema, lower hif-1α production, and reduced eosinophil infiltration in nasal mucosa compared with the control group. conclusion: the anti-heart failure drug digoxin may ameliorate the symptoms of ar by inhibiting hif-1α production. campo p 1 ; eguiluz i 1 ; bogas g 1 ; gomez f 1 ; ariza a 2 ; espino t 1 ; torres mj 1 ; rondon c 1 1 allergy unit-regional hospital of malaga-ibima, malaga, spain; 2 allergy laboratory_regional hospital of malaga-ibima, malaga, spain background: similarly to what has been described in allergic rhinitis, there is an important association of local allergic rhinitis (lar) with lower airway symptoms suggestive of asthma, being selfreported in 24.4% of lar patients after five years of follow-up, and increasing to 30.7% after 10 years. however, clinical suspicion alone it is not enough for asthma diagnosis and could overstate its real prevalence. the aim was to evaluate the real prevalence of asthma in lar patients based on validated objective methods. method: seventy-five patients (29 with lar, 20 with non-allergic rhinitis (nar), 18 with allergic rhinitis (ar)), and 8 healthy controls (hc) were included. all patients had perennial history of rhinitis and bronchial symptoms suggestive of mild-moderate asthma for at least two years. non-specific airways hyperresponsiveness (methacholine challenge test, using tidal breath method following ats guidelines) was performed in all subjects. results: subjects were mostly young females, non-smokers. median μg/day of inhaled corticosteroids (budesonide/equivalent dose) was similar in all groups. median fev1% in ar group (75.5%) was significantly lower compared to lar (90%, p = 0.002), nar (85%, p = 0.007) and hc (88%, p = 0.005). in the lar group, 15/29 (51.7%) had a positive methacholine, 12/20 (60%) in the nar, 15/18 (83.3%) in ar group and 0/8 (0%) in hc. patients with lar had a significant lower percentage of confirmed asthma than ar (p = 0.031) and similar to nar (p = 0.771). no differences were detected between ar vs nar (p = 0.155). conclusion: presence of objectively demonstrated asthma was lower in lar compared to ar, and with better lung function. conclusion: ambient air pollution influenced the hospital visit of patients with rhinitis, even, the level of pollutants, below the national standard. so2, o3, no2, and pm10 could increase an incidence of rhinitis and/or induce an aggravation of rhinitis symptoms. health care provider might expect upraising patients with rhinitis in the clinic with increase of air pollutants, even under the standard levels. results: during relapse of erosive oral lichen planus mononuclear cells obtained from peripheral blood of patients showed increased number of nk-cells cd3 + cd56 + in acute (15.5 ± 4.5%) and chronic (14.9 ± 6.3%) disease periods, and cd16 + grb cells in acute (18.1 ± 1.5%) and chronic (14.5 ± 2.5%) disease periods, p < 0.05. in patients with the non-erosive forms of olp there were cd3 + cd56 + and cd16 + grb cells in acute (8.9 ± 2.5%) and (7.3 ± 1.3%) and chronic disease (9.5 ± 2.2%) and (8.2 ± 3.1%), p < 0.05. the number of cd3 + cd56 + and cd16 + grb cells in the controls were (9.8 ± 2.1%) and (6.2 ± 5.4%), p < 0.05. conclusion: acute relapse of erosive oral lichen planus, unlike nonerosive forms, is characterized by increases in the number of cd3 + cd56 + and cd16 + grb cells. chronic disease in patients with erosive oral lichen planus showed a steady increase in the number of cd3 + cd56 + killer cells and cd16grb lymphocytes. bite", were observed in 6 patients (85%). typical hyper-and hypopigmentation were observed in six patients mainly on the fingers and the cheekbones. fibrosis of the skin of the fingers often leads to flexion contractions, which we observed in 6 patients. we were watching two-sided swelling of the fingers, but it was very pronounced in 5 patients (71%). 86% of our patients have impaired motility of the esophagus. accelerated esr and c-reactive protein were found in 5 patients as follows-2 intensively accelerated and 3 moderate. in our patients with positive ana, we observed 4 patients -at low titer 1:40 at 2 and titration 1:80 in 2 patients. the spectrum of ana found by us in raynaud's syndrome patients is closer to scleroderma than to lupus. we underline the importance of ana (57%) and anti-cc antibodies (27%) for the early diagnosis of raynaud's syndrome and scleroderma, which is also seen in our patients. anti-scl-70 antibodies were observed in 3 patients coinciding with other publications describing about 40% of the patients. low levels of complement were observed in 2 patients. low hemoglobin levels were observed in 1 patient, with no iron deficiency. conclusion: 1. we observed a typical fibrinoid necrosis and polymorphonuclear infiltration, and collagen accumulation in the walls of small and medium-sized blood vessels. results: statistically significant increase of il4 level (3.23 pg/ml [2.18; 5.02]; 3.42 pg/ml [2.8; 4.18] respectively) was determined in patients with uc both in acute stage and remission compared to controls (1.87 pg/ml [1.4; 3.2] , (p = 0.002; 0.009 respectively). statistically significant increase of il17a level (15 pg/ml [12.11; 23.38] ); 14.68 pg/ml [11.29; 17.19 ] respectively) was also observed in patients both in acute stage and remission compared to controls (7.36 pg/ml [5.18; 8 .06], p = 0.00007, p = 0.00029 respectively). besides statistically significant increase of ifnγ both in acute stage (176.15 pg/ml [65.15; 359.84] ) and remission (42. 6 pg/ml [29.4; 64.45 ]) compared to controls (16.5 pg/ml [12.3; 23 .2], p = 0.00107; 0.0118 respectively) was revealed. background: the presence of antinuclear antibodies (ana) is commonly associated with a broad spectrum of connective tissue diseases. low titres might be detected rarely also in healthy individuals, especially in higher age. an indirect immunofluorescence (iif) detection of ana antibodies on hep-2 cells is the most frequently used laboratory method in this respect. the method is quite reliable regarding sensitivity, however the specificity of this test is lower. we would appreciate a biomarker for clinical discrimination of anaother autoantibodies were tested in relation to basic diagnosis. results: a cohort of patients was divided into 6 groups according to main diagnosis: immunodeficiency, connective tissue diseases, bronchial asthma and allergic rhinitis, recurrent infectious diseases, gastrointestinal diseases, endocrinopathy and others and the last group was generated from healthy subjects. the presence of anti dfs70 antibodies was highest in the group of recurrent infections, mostly in females. in these subjects homogenous pattern of ana antibodies by iif was also detected quite often, probably induced by non-specific activation of immune system. on the other hand, in a group of connective tissue diseases, we have not found any anti dfs70 positive patient. the clinical impact of anti-dfs70 antibodies is not yet finally confirmed, but their low frequency in connective tissue diseases and presence in 5%-10% of healthy subject suggests their potential role as a new biomarker to be used as a negative predictive factor in non aard. confirmation of presence or absence of anti-dfs70 antibodies seems to be helpful to exclude potential diagnostic errors in iif ana positive patients. background: multiple sclerosis is a debilitating autoimmune and degenerative condition of the central nervous system, that predominantly affects young adults. both genetic and environmental factors are associated with increased risk for this disease. we propose that the effect of environmental factors, particularly latitude of childhood, is mediated through epigenetic mechanisms. specifically, we propose that unfavourable gene methylation predisposes individuals to multiple sclerosis, that this is set in childhood and adolescence, and transmitted from haematopoietic stem cells to progeny. method: cd34 + , cd14 + and cd56 + cell subsets were isolated from peripheral blood of healthy controls. libraries enriched for cpg islands and promoter regions were generated using modified reduced representation bisulfite sequencing and subjected to next generation sequencing. site specific methylation profiling of genome wide cpg islands, including ms susceptibility genes was conducted using methpipe software. results: genomic coverage was consistent with other published methylomes using modified reduced representation bisulfite sequencing. the methylation signature of peripheral blood derived subsets showed greater differences in methylation compared to buccal cells than with each other. individuals displayed differences in cd34 + methylomes, and these were recapitulated in the progeny cd56 + and cd14 + cells for those individuals. methylation of specific genes regions (e.g. prf1), were consistent with the known biological function of these genes and their potential contribution to ms risk. the vast majority of cpg islands interrogated show recapitulation of their methylation signature from cd34 + to progeny. however, individual differences and cell subset differences identified, likely reflect the known biological function of these genes in progeny cells. our preliminary results are consistent with the hypothesis that the epigenetic signature (that predisposes to ms risk) is set in childhood and adolescence. the physiological basis underlying the setting of this epigenetic signature is still to be elucidated, but may involve uv light and/or vitamin d, and may provide novel therapeutic targets, especially at a personalised level, for treatment of ms. background: auto-inflammatory diseases are rare disorders characterized by recurrent episodes of fever/inflammation affecting serosal surfaces, joints, eyes and skin without autoantibody production or an underlying infection. innate immunity is implicated in their pathogenesis and the underlying genetic defect has been identified in a fraction of the syndromes. during last years, the increased knowledge about auto-inflammatory diseases and the difficulty in their characterization aroused great interest to better understand these pathologies. the acidic soluble fraction of salivary proteome of patients and controls (hc) were analyzed by rp-hplc-esi-ms. 60 known salivary proteins (salivary acidic proline-rich phosphoproteins (aprps), histatins (hst), salivary cystatins s, sn and sa, statherin, p-b peptide, α-defensins 1-4, cystatins b, c, thymosin β-4, s100a7, s100a8, s100a9, and s100a12 proteins) and several derivatives (acetylated, glutathionylated, phosphorylated, and oxidized forms) were searched in the chromatographic profiles by xic (extracted ion current) procedure. 21 adult patients (mean age ± sd: 34.4 ± 10.1; 15 f, 6m) were enrolled and compared with 27 sex/age matched healthy controls (mean age ± sd: 33.4 ± 9.6; 18 f, 9m). patients are classified on the base of clinical manifestations as follows: 6 patients with fmf (mean age ± sd: 33 ± 7.9; 5 f, 1m), and 15 with unclassified fever syndrome (uc) (mean age ± sd: 34.9 ± 11.1; 10 f, 5m). results: fmf patients showed low levels of α-defensins 2, 3 and 4, this last was absent, with respect hc, and high levels of the glutathionylated proteoforms of cystatin b, and s100a9, and of antileukoproteinase (slpi). similar results were obtained on saliva of unclassified patients, which showed also levels of cystatin c higher than controls. interestingly, proteins and peptides typically secreted by salivary glands (cystatin c, histatins, statherin, aprps) were found more abundant in uc patients than in controls, and in some cases also than fmf patients (see table) . an evaluation of relative abundance of phosphorylation of phosphorylated proteins/peptides highlighted a significant hypophosphorylation of hst-1, prp-1 and prp-3 in uc patients with respect to controls, probably due to a less active fam20c kinase responsible for their phosphorylation conclusion: we show by a top-down proteomics approach a wide salivary modification, highlighting dysregulation in neutrophil-derived proteins and significant differences between fmm and uc patients. the control group consisted of 10 healthy donors aged 40-50 years. immunological methods of investigation included determination of membrane antigens b cells: cd3 − cd19 + cd45 + , cd19 + cd5 + cd45 + , cd19 + cd23 + cd45, cd19 + cd25 + cd45 + , cd19 + cd40 + cd45 + , cd19 + cd86 + cd45 + , cd3 + cd4 + cd40l + cd45 + , cd19 + cd45ra + cd27 + cd45 + , by flow cytometry. results: in the study subpopulation composition of lymphocytes in seropositive variant form of ra visceral a statistically significant increase in relative amount as b1-cells with immunophenotype cd19 + cd5 + cd45 + (0.6 ± 0.01% 0.12 ± 0.03%) and b2 lymphocytes with the phenotype cd19 + cd5 − cd3 − cd45 + (16.4 ± 1.2% and 7.9 ± 0.5%). in the analysis of the processes of maturation and differentiation of b2 cells detected statistically reliable increase of the relative number of mature cd19 + cd3 − cd45 + naïve b2 cells cd19 + cd45ra + cd27 number of mature cd19 + cd3 − cd45 + naïve b2 cells cd19 + cd45ra + cd27 − cd45 + (11.8 ± 0.9% and 5.7 ± 0.5%) compared to the control group. in the study of surface markers b2 lymphocytes revealed an increase of expression of costimulatory cd19 + cd40 + (19 ± 1.3% and 7.0 ± 0.42%) molecules and increasing the relative amount of cd40l 0.9 ± 0.2% (0.3 ± 0.05%) ligand on cd3 + cd4 + cd45 + subpopulation of t-lymphocytes. analysis of surface antigenic receptor b2 cells in the visceral form of ra showed an increased expression of early markers of cd19 + cd23 + cd45 + (2.9 ± 0.08% and 0.91 ± 0.1%), cd19 + cd25 + cd45 + (1.6 ± 0.4% 0.05 ± 0.01%) activation in comparison with the control group. case: a 44 year-old male patient who works as a dental technician with a history of lung silicosis and recurrent sinusitis applied to an orthopedics clinic for left hip pain and difficulty in walking. he has a history of keeping a dog during childhood. hip mri revealed a 5 × 3 cm sized mass on left iliac wing extended to gluteus muscle and subcutaneous tissue. incisional biopsy was reported as chronic granulomatous osteomyelitis. the lesion was considered as tuberculous abscess. despite anti-tuberculous (fourdrug regimen) treatment for one year, the lesion showed no regression. excisional biopsy was carried out by the same orthopedics clinic. chronic inflammatory reaction and fibrosis was considered to be due to cyst hydatid in the detailed evaluation. antiechinococcus igg and igm was performed with elisa and found positive. no other lesion was detected in lungs and liver. albendazole 400 mg twice a day was initiated and substantial regression observed after three months. atypical and sustained infections made us think of primary immunodeficiency disorders. immunoglobulin subgroups were as follows: iga: <1 mg/dl (70case description: 31 year-old male was firstly admitted to gastroenterologist due to intermittent diarrhea, abdominal pain and reactive lymphadenopathy. celiac disease was suspected as genetic test showed hla dq8 (hla-dqa1*03 and hla-dqb1*0302), histological evaluation of duodenum biopsy provided picture of lymphoid hyperplasia and marsh iiia variant. however, laboratory testing for celiac disease showed very low amount of antibodies against transglutaminase. gluten free diet for almost one year was ineffective as patient had a continuous problem of gaining weight due to chronic diarrhea. additional questioning revealed recurrent respiratory tract infections with a need of antibiotics more than two times/year during last decade. lymphocyte phenotyping by flow cytometry showed that cd3, cd4, cd8, cd19 are in normal ranges, but amounts of all immunoglobulins are low: igm <0.22 g/l, igg 2.53 g/l and iga 0.09 g/l. based on clinical symptoms and immunological evaluation diagnosis of cvid was confirmed, and replacement therapy with subcutaneous immunoglobulin (400 mg/kg/month) was initiated. after six months of treatment patient affirmed reduction of gastrointestinal symptoms; he gained 12 kg of weight, has no more infections and stable sufficient level of igg (7.9 g/l). conclusions: this clinical case shows the importance of immune testing for primary immunodeficiency in all subjects (despite age) with unusual symptoms of autoimmune and/or infectious disorders. cvid may have manifestation of various symptoms, which can lead to misdiagnosis, as well as inadequate treatment. results: in our sample, all patients who progressed to hypogammaglobulinemia were receiving lymphomas. there is no immunoglobulin dosage record prior to treatment. of the 9 cases, mean age was 52 years (4 men and 5 women), 2 lost follow-up, and 1 of them also presented neutropenia. seventeen patients who continued in followup required ivig replacement, due to infectious exacerbations, mainly pneumonia and sinusitis. the mean serum igg dosage at the time of onset of ivig replacement was 491 g/dl. the mean time between the first dose of rtm and the need for ivig replacement ranged from 2 to 8 years, with an average of 5 years. the iga dosage was used as a parameter for the recovery of hypogammaglobulinemia, and it was observed that only 1 of the 7 patients presented recovery of the condition up to the moment. conclusion: given the data, we considered the immunoglobulin dosage to be important before initiating rtm treatment and periodically, in order to indicate the replacement of ivig or igsc in a timely manner avoiding complications such as potentially serious infections. background: steinert's disease, also known as type 1 myotonic dystrophy (md1), is the most common dystrophy of the adult. it is inherited with an autosomal dominant mechanism. it causes myotonia, progressive muscles atrophy, muscular weakness, and problems at the heart's conduction tissue and at the respiratory muscles. in patients with myotonic dystrophy, hypogammaglobulinemia is frequently described. the associations and the pathogenesis between those affections are not totally clear, but it is recognized an increased catabolism of the immunoglobulin in these patients. in most of the cases, hypogammaglobulinemia affects only the igg class and does not become clinically manifest. however, replacement treatment is not always successful in these patients. we report the case of a patient with myotonic dystrophy and hypogammaglobulinemia. case report: a 44-years-old man with md 1 came to our attention for a history of recurrent infections of the upper respiratory tract and persistent infection by helicobacter pylori. at the laboratory tests, we documented low serum igg levels (449 mg/dl), normal igm and iga levels and protective antibodies against tetanus consisting with the diagnosis of hypogammaglobulinemia. due to the recurrent infections, he started replacement therapy with ivig (0.4 g/kg/ months), switched one year ago to facilitated subcutaneous ig (fscig) with achievement of protective serum igg levels (>600 mg/dl) and significantly reduction of infectious episodes. conclusion: hypogammaglobulinemia is frequently reported in patients with md1. in literature most of the cases described does not become clinically manifest, but in our case, the patient was symptomatic with recurrent infections. the replacement therapy with fscig showed both clinical effectiveness and safety. 1532 | real-world experience of a novel, highly purified 10% liquid iv human immunoglobulin for the treatment of antibody deficiencies guidelines for immunoglobulin use (july 2011). a highly purified 10% liquid iv human immunoglobulin (ig), with low levels of iga, anti-a and anti-b haemagglutinins, factors xia, xiia, kallikrein and aggregates (i10e) was recently approved for use in the uk. here i report our centre's experience in using this novel 10% i10e in three patients with antibody deficiencies. case presentations: a patient who presented in clinic with a first diagnosis of pid, was initiated on 10% i10e at 30 g infused every four weeks. after starting i10e, they experienced a decrease in the rate and frequency of infections, in line with expectations for igrt. a young patient on home therapy with a 20% subcutaneous ig for pid presented in clinic with low trough igg levels. non-compliance was identified as the cause of these low trough levels and therapy was switched to 10% i10e at 40 g infused every four weeks in a clinical setting. both the rate and severity of infections reduced and trough igg levels normalised. an older patient on igrt for sad was reviewed in clinic due to discontinuation of their current igrt product. they were switched to 10% i10e at 20 g infused every four weeks. the efficacy and tolerability of i10e was comparable to their previous therapy. a detailed analysis of patient, clinical and safety parameters associated with the initiation of 10% i10e will be presented, including infection rates, white cell counts, c-reactive protein levels, tolerability and infusion-related adverse events. conclusion: these cases highlight the real-world use of 10% i10e in two patients with pid and one patient with sad. they show that i10e was well-tolerated and efficacious in one treatment-naïve, and two previously-treated patients. method: prospective study of families with one or more members with c1-inh-hae followed in 7 hospitals in the northern area of spain. a cohort of 105 patients from 28 families with c1-inh-hae was evaluated for familiar diagnosis of c1-inh-hae one or several patients from the same family were chosen and were given a questionnaire to identify the total family members from the family branch affected by c1-inh-hae that had been already studied (members with diagnosis of c1-inh-hae and healthy members) and those that had not been previously studied. we also register the difficulties for obtaining these data. family members not previously studied and that consent to be contacted were asked for study of c1-inh-hae. for c1-inh-hae screening we use c4 blood levels results: we have studied 28 families with c1-inh-hae, 24 (87%) type 1 and 2 (7%) type ii; 13 families had all their known members already studied for c1-inh-hae (50%): 12 families have all their members studied (42.8%), 18 families have 90% or their known members studied (64.2%) and 10 families had less than 50% of their total known members studied. we have identified 85 members from 11 unrelated families that had not been previously studied for hae, 10 healthy, 4 had low c4 levels and had presented symptoms of hae; 1 had not presented symptoms of angioedema, had normal c4 levels, and low antigenic and functional c1-inh levels. difficulties for a complete family testing study have been: family dispersion, scarce or no family relationship, do not wish to know their possible pathology conclusion: it is crucial to insist on the study of the relatives of patients with hae. we propose to include a questionnaire to identify all patient's relatives at medical reviews of hae patients. case: a-4 year old boy was admitted to our clinic with the history of recurrent respiratory tract infections. his all immunoglobulins were low (igg <154 mg/dl, iga <25.4 mg/dl, igm <17.8 mg/dl) associated with the absence of b cells. his aunt cousin also had xlaa missense point mutation, c562c>t in exon 17 of the btk gene was identified in both affected cousins. the patient was commenced on regular ivig treatment every 3 weeks. at the age of 8, he suffered from intermittent fever attacks, abdominal pain and weight loss. tests for giardia lamblia, clostridium difficile and cryptosporidium, noro virus or parasites were negative. mr-enterography revealed intra-abdominal fluid and thickened walls of his jejunum and cecum. histopathological examination of the biopsy material obtained from terminal ileum, colon and cecum showed crohn disease. initially, he was treated with prednisolone and infliximab. because of the lack of response, infliximab treatment was switched to adalimumab. terminal ileum was resected to relieve obstruction complication. although he had been treated with adalimumab for 1 year, a significant improvement was not observed. vedolizumab (entyvio ™ ), is a humanized monoclonal antibody α4β7 integrin-receptor antagonist, was commenced. induction dosing was 300 mg infusions at 0, 2, and 6 weeks followed by a maintenance phase at 8week intervals. at the 6 month of the treatment, fever and abdominal pain attacks reduced, while his weight and oral intake increased. no side effects were observed. discussion: vedolizumab is effective for inducing and maintaining remission in adults with inflammatory bowel disease (ibd); however, there is limited pediatric data. this is the first immunocompromised child treated with vedolizumab. the symptoms of the patient receded and no side effect observed during 6 months of the treatment. results: louis-bar syndrome is a multisystem progressive disease with polymorphic manifestations which varies by age. the locomotor disability of these children is determined by neurological disorders, the exitus being caused by respiratory infectious and malignancies. the children involved in the study, had frequent episodes of respiratory infectious (bronchitis, pneumonia, atelectasis, empyema, lung abscess), ent infections (otitis, mastoiditis, sinusitis), chronic pulmonary disease (pulmonary fibrosis, bronchiectasis). index of death in this group is high (66.7%). in one of the boy, the pulmonary ct showed lymphadenopathy, later was confirmed non-hodgkin lymphoma, with subsequent death. another child died from pulmonary and systemic infectious complications. results: in this paper we present the clinical and morphological analysis of children with nezelof syndrome diagnosed post-mortem. clinically were predominantly the generalized intrauterine infections or their development in the postnatal period. at macroscopic examination all patients had thymic hypoplasia. later on the microscopic study of the thymus specimens determined dysplastic changes, defined by the presence of concentrically arranged epithelial cells. in all patients, was determined the total lack of hassall corpuscles and its predecessors. besides the above-mentioned modifications in all specimens, there was no cortico-medullary segregation. thymic parenchyma outside pseudorrhagia was made up of a reticular stroma with total lymphocyte depletion. conclusion: nezelof syndrome is a severe primary immunodeficiency associated with thymic dysplasia and alymphocytosis, which is manifested early with generalized infections and major risk of death in neonatal and infant. background: the study was aimed to evaluate the cytokine profile in nasal secretion and blood serum in patients with seasonal (sar) and perennial allergic rhinitis (par) with a potential for additional sensitization with microbial allergens. method: the inclusion criteria for ar were as follows: a diagnosis of ar for more than 2 years, the absence of nonallergic disorders of the nasopharynx, age of patients from 4 years to 60 years.control group: healthy volunteers at the age of 3-43 years without any allergic disorders at examination.in order to evaluate the innate and adaptive immunity, the cytokine profile of blood serum (il-4, il-10, and tgf-β) and nasal secretion (tslp, il-1β, tnf-α, and gm-csf) was determined. to determine tslp, tgf-β, il-10, and gm-csf concentrations, enzyme-linked immunosorbent assay kits were used (ebioscience, bender medsystems, r&d systems, mn, usa). we have noticed a significant correlation (r = 0 46, p = 0 014) between the tslp concentration in nasal secretion and as-ige level to staphilococcus aureus enterotoxin (allergen component m80) in patients with par. there was a significant correlation conclusion: staphylococcal superantigens might be one of the stimuli of local tslp hyperproduction by the epithelium. there was a significant correlation between gm-csf concentrations in nasal secretion and the intensity of sensitization to a staphylococcal enterotoxin (seb) in the patients with ar. seb is one of the polyclonal t cells activators, which may account for increased concentrations of cytokines such as gm-csf locally within the system of mucosal immunity. the patients with ar and additional high sensitization to ses demonstrated a higher tnf-α production profile due to macrophage and tcell activation by these toxins. 1547 | evaluation of circulating osteopontin level as potential biomarker of allergic asthma in patients with caucasian and south-east asian ethnicity background: osteopontin (opn) is a pleomorphic cytokine known to influence a wide range of immune cells; allergic asthma was previously associated with high circulating opn levels. in the present study, we aimed to verify if opn may qualify as biomarker of activated immune response in allergic patients belonging to two different ethnic groups: caucasians and south-east asians. method: serum opn levels were measured by elisa test (human osteopontin duoset, r&d systems) in a series of 121 italian adult patients affected by extrinsic asthma, allergic rhinitis, hymenoptera venom allergy, food allergy, allergic contact dermatitis and ige mediated hypersensitivity to beta lactams. 116 healthy subjects served as controls. 576 ethnic chinese subjects were recruited at the national university of singapore (nus) as cross-sectional cohort of an ongoing epidemiological study on the national prevalence of allergic diseases, and opn levels were detected by luminex (milliplex map, merck) and elisa assays (r&d systems). results: in the italian cohort, opn levels were significantly higher in cases compared to controls (p = 0.0010 by the mann-whitney test). statistically higher opn levels were found in asthma (p = 0.0269) and food allergy (p = 0.046) groups in comparison to controls. no significant differences were found (p = 0.597) between singaporeans with lifetime asthma and healthy controls, only the highest opn levels were heterogeneously found to correlate with asthma. however, a strong gender effect was shown, in both cases (p < 0.0001) and controls (p < 0.0001), with males presenting higher opn levels in comparison to females. consequently, we checked the mrna expression levels of opn gene (spp1) with illumina chips in whole blood of males and females, and no difference was found (p < 0.05). several experiments with western blots and different gel types were performed to verify if possible post-transcriptional/posttranslational modifications of opn could explain these findings. conclusion: opn seems to be a promising biomarker for current, active allergic asthma in caucasians even though technical difficulties, due to opn intrinsically disordered structure, the complex enzymatic metabolism, and the low circulating levels, significantly affect the experiments. further studies are needed to confirm these data. 1548 | mortality, intubation, and healthcare cost in patients with allergic bronchopulmonary aspergillosis in a hospital setting: a nationwide study fan x; luo y; yue b background: abpa is a complex hypersensitivity reaction to aspergillus fumigatus that colonize in airways, it is almost exclusively seen in patients with asthma or cystic fibrosis(cf). this study is to estimate hospitalization outcomes and healthcare cost of hospitalized patients with abpa. method: we conducted the study using data from national inpatient sample(nis) from 2010 to 2014. diagnosis were identified using icd-9-cm codes. hospitalization with a primary diagnosis of abpa and hospitalization with a primary diagnosis of acute respiratory failure/acute and chronic respiratory failure/respiratory distress/ asthma/cf and a secondary diagnosis of abpa were included. the study population was divided into groups including abpa with asthma, and abpa with cf. mortality and intubation rate were the primary outcomes; length of stay and total hospitalization cost(adjusted to cost in 2014 based on medical care cpi) were secondary outcomes. student t-test and chi-square were used for univariable analysis, linear and logistic regression were used for multivariable analysis. results: a total of 6308 hospitalizations with abpa were included, with 2896 hospitalizations with abpa and asthma, and 2793 hospitalizations with abpa and cf. the overall mortality rate was 0.82% (95% ci: 0.44%-1.50%), the mortality for abpa with asthma was 0.69% (95% ci: 0.26%-1.83%) and for abpa with cf was 0.56% (95% ci: 0.19%-1.63%). the overall intubation rate was 4.83% (95% ci: 3.77%-6.18%); the intubation rate for abpa with asthma was 5.51% (95% ci: 3.91%-7.72%) and 84.0% were early intubation (<3 days); the intubation rate for abpa with cf was 1.95% (95% ci: 1.13%-3.35%) and 36.6% were early intubation. the overall mean length of stay(los) was 8.7 (95% ci: 8.0-9.3) days, while the los for abpa with asthma was 5.6(95% ci: 5.2-6.1) days and the los for abpa with cf was 12.1 (95% ci: 11.1-13.0) days. the overall total cost was 147 million usd, the total cost for abpa with asthma was 33.4 million usd with a mean of 12 069, while the total cost for abpa with cf was 101 million usd with a mean of 38 005. conclusion: mortality among hospitalized patients with abpa is low<1%. intubation rate is relatively low, intubation, especially early intubation (<3 days), is more common in patients with asthma. although abpa is not a common disease in inpatient population, it does have a high health care cost and despite lower intubation rate, patients with abpa and cf generally have a longer hospital stay with a higher hospitalization cost. 1549 | frequent exacerbations of bronchitis with wheezing in adults: is it possible to predict and prevent asthma? case report: frequent episodes of bronchitis, accompanied by wheezing and dry with a prolonged duration in adults, the clinical course may be similar to bronchial asthma. the aim is to assess the risk of asthma in adult patients with 2 or more episodes of acute bronchitis per year, had a prolonged duration and accompanied by a dry wheezing. for 5 years in two regional clinical pulmonology centers were observed in 46 patients (19 men and 27 women) with average age 34 ± 6.8 years. each had at least 2 episodes of acute bronchitis per year, which was accompanied by prolonged cough and presence of wheezes. average number of acute episodes per year was 3.2 ± 0.8. in the course of the observation the patients were divided into 2 equal groups. the first group consisted of 23 persons treated in acute episodes of the disease symptomatic therapy, including inhaled β2-agonists short-acting short course. in the second group to the corresponding treatment added montelukast 10 mg per day lasting for 1 month. in all cases of exacerbation had a viral nature. held in the period of remission of allergic sensitization, the survey revealed. starting from the first year of follow-up all patients were vaccinated against influenza annually. by the end of the fifth year of observation in the first group in 5 cases was diagnosed of bronchial asthma-4 cases easy persistent asthma and 1 case moderate. the diagnosis was exhibited in accordance with the gina criteria. in the second group, the diagnosis of bronchial asthma were exposed to 1 patient (hazard ratio of 0.18). prospective observation suggests that the use of anti-inflammatory potential antileukotriene medicines in complex therapy of recurrent acute episodes of bronchitis accompanied by a dry wheezing in adults may be a factor preventing the development of asthma. for more conclusive results require more extensive research. background: chemokine receptors play an important role in regulating the migration of t lymphocytes, monocytes and neutrophils from the peripheral blood into inflamed tissue, such as lung. however, little is known about their expression on natural killer (nk) and natural killer t (nkt) cells in patients with chronic obstructive pulmonary disease (copd). therefore the aim of the study was to determine the chemokine receptor profile of peripheral blood nk and nkt cells of copd patients. method: for analysis of lymphocytes subtypes the flow cytometry method was used. the study population consisted of 57 smokers with copd, 12 healthy smokers and 12 healthy non-smokers. results: we observed an increase in blood nk cells expressing cxcr3 receptors in smokers with copd compared to healthy smokers (p = 0.003) and healthy non-smokers (p < 0.001). the percentage of nkt cells containing cxcr3 receptors was also significantly higher in blood of smokers with copd compared to healthy smokers (p = 0.021) and healthy non-smokers (p < 0.001). copd smokers had significantly higher proportion of ccr5 + nk cells than smokers without copd (p = 0.002) and healthy non-smokers (p < 0.001). increased proportion of blood nkt cells expressing ccr5 on their surface was observed in smoking copd patients compared to healthy smokers (p = 0.002) and healthy non-smokers (p < 0.001). there were no significant changes in the percentage of cxcr3 + and ccr5 + nk and nkt cells between healthy smokers and non-smokers. in addition, no differences were seen in the proportion of nk and nkt cells expressing cxcr4, cxcr6, ccr6 and ccr7 among all studied groups. method: 58 patients with copd in stable condition (gold stage 2) aged 40-70 years old, smoking history of ≥10 pack-years, were studied. bmi of patients were divided into 2 groups: obese (n = 31) (bmi-30.0-39.9 kg/m 2 ) and non-obese (n = 17) (bmi-18.5-24.9 kg/ m 2 ). ten subjects with normal lung function and bmi were the control group. the level of il-26 assessed in induced sputum (pg/ml) was measured using an elisa (raybiotech ® ). serum levels of crp were measured using the "vector-best" (russia federation). spirometry was performed according to american thoracic society and the european respiratory society (ats/ers) guidelines. results: obese copd patients had significantly increased concentrations of il-26 compared with healthy subjects and non-obese copd patients by 2.6 fold (139.0 ± 85.4 pg/ml vs 53.15 ± 18.5 pg/ ml) (p < 0.008) and 1.15 fold, (139.0 ± 85.4 pg/ml vs 120.6 ± 60.15 pg/ml)(p < 0.04), respectively. non-obese copd patients had higher levels of il-26 by 2.3 fold compared with healthy subjects (120.6 ± 60.15 pg/ml vs 53.15 ± 18.5 pg/ml) (p < 0.008). results: among these three groups, the level of cer in lung cancer patients (0.35 ± 0.10 g/l) was significantly higher than that in ild patients (0.31 ± 0.25 g/l) and healthy individuals (0.25 ± 0.04 g/l) (p < 0.05). meanwhile, the levels of c3 and c4 in healthy individuals, which are 1.70 ± 0.29 g/l and 0.27 ± 0.34 g/l respectively, were both significantly higher than that in lung cancer patients (c3: 1.04 ± 0.26 g/l, c4: 0.24 ± 0.09 g/l) and ild patients (c3: 0.97 ± 0.25 g/l, c4: 0.21 ± 0.09 g/l), (c3: p < 0.05, c4: p < 0.05). results from optimal scaling demonstrated that lung cancer was closely associated with immune factors including crp, cer, c3 and c4 (cronbach's alpha = 84.7%). conclusion: for ild patients, when the level of crp and cer is increased and the level of c3 and c4 is decreased simultaneously, the risk of the development of lung cancer should be considered for these patients. results: among pbmc subpopulations, endurance exercises impacted the number of nkt and activated t cells with nkt cell numbers greater in male bobsledders vs bullet shooting and biathlon (42.4% and 44.3%, respectively). the number of activated t cells (cd25 + ) was greater in bullet shooting and bobsleigh athletes vs the biathlon group (34.9% and 22.7%, respectively). in female athletes the number of cd25 + cells in the shooting and bobsled groups was greater by 46.1% and 25.5%, respectively vs the biathlon group (p < 0.05). increased il-10 occurred in bobsleds in comparison to bullet shooting and biathlon: 32% and 80% in male and 70.5% and 83% in female, respectively (p < 0.05). the concentration of il-18 in male bobsledders and biathlon was 30% and 34% greater, respectively, compared with bullet shooting (p < 0.05). serum concentrations of ifnγ in male as well as female athletes showed an increase of 41.6% and 39.5%, respectively vs biathletes (p < 0.05). increased il-4 occurred in the male biathlon group by 39.7% and 13%, respectively, vs the bullet shooting and bobsleigh athletes (p < 0.05). il-6 was increased in the male biathlon group, compared to bullet shooting and bobsledders by 76.7% and 70.3%, respectively (p < 0.05). conclusion: prolonged endurance exercises impacts secretion of pro-and anti-inflammatory cytokines in athletes of different sport specializations. concentrations of studied cytokines did not exceed reference values perhaps due to specialized sport nutrition, which may restore immune function during endurance exercises. background: oral immunotherapy (oit) is a promising therapeutic approach to treat food allergic patients. recently, we have shown that the use of a mixture of short-chain-and long-chain fructo-oligosaccharides (scfos/lcfos) improves the efficacy of oit in cow's milk and peanut allergic mice. however, concerns with regard to safety and long-term efficacy of oit remain and there is a need to identify novel biomarkers (panels) that predict, monitor and/or evaluate the effects of oit. here we present a method for the selection of candidate biomarkers by using the computational approaches bayesian networks (bn) and topological data analysis (tda). method: data were used from scfos/lcfos diet-supported oit studies performed in 2 independent cow's milk allergy (cma) and 2 independent peanut allergy (pna) experiments in mice. first, a subset of the data was used for learning the data structure and their interactions in terms of a bn. this bn was used to compare the key parameters in both experimental food allergy models. finally, the relations within the dataset in combination with the bn were explored to identify and rank candidate biomarkers for the effect of oit by applying tda. the bn was able to predict the efficacy of oit in the cma and in the pna model with 82% and 80% accuracy respectively, thereby identifying a set of 5 parameters (allergen-specific ige and igg1, body temperature, mmcp-1, earswelling) being key in the mechanisms involved in both scfos/lcfos-aided oit food allergy models. the tda zoomed in on the full set of 67 previously analyzed parameters and identified clusters of biomarkers closely linked to biologically relevant clinical symptoms but also unrelated and redundant parameters within the network. taken together, this enables the prioritization of candidate biomarkers. moreover, the tda indicated differences between pna and cma models in how the data are related to each other. here we provide promising bioinformatics methods to compare mechanistic features between two different food allergies and to determine the biological relevance of biomarker (panels) of oit for food allergy. we have shown that the key drivers that influence pna and cma are similar, but that these phenotypically similar diseases show mechanistic differences in their subnetworks. these new insights provide excellent starting points to generate new hypotheses to explain why cma has a different disease pattern than pna and to select biomarkers that are useful in future clinical studies. 1562 | functional and immunoreactive levels of igg4 correlate with clinical responses during the maintenance phase of house dust mite immunotherapy basophils were identified as ssc low cd193 high , and cd63 was used as an activation marker. reactivity was confirmed by anti-ige as a positive control. results: in 4 patients, basophil reactivity and sensitivity was comparable for grass pollen extract and recombinant phl p5, while phl p1 only caused a lower basophil activation. in one patient, recombinant phl p5 did not cause any basophil activation, while phl p1 elicited an even higher sensitivity and reactivity than grass pollen extract. conclusion: in 4 patients, basophil reactivity was comparable for grass pollen extract and recombinant phl p5, while phl p1 only caused a minor basophil activation. in one patient, recombinant phl p5 did not cause any basophil activation, while phl p1 elicited an even higher sensitivity and reactivity than grass pollen extract. reactivity of extract and the main sensitizing components correlated, while sensitivity did not. 1564 | in vitro assessment of hypersensitivity to allergen before and after allergen immunotherapy with whole blood basophil histamine release assay wbbhr assay in these patients was performed 7-10 days before and 7-10 days after ait. heparinized whole blood samples (8 ml) of each patient after substitution of plasma with pipes buffer were incubated one hour at 37°c with different concentrations of birch pollen extract (t3) in u-shape 96-well micro-titer plates. after incubation plates were centrifuged and supernatants from each well of the plate were directly analyzed for histamine content by reversedphase high performance liquid chromatography with electro-spray ionization mass-spectrometry (rp-hplc-esi-ms). results were expressed as ng/ml released histamine. sensitivity (limit of quantification) was 5-7 ng/ml. to compare results of histamine release in patients before and after ait data were calculated as area under the curve (auc) values. results: in contrast to pre-immunotherapy activity of blood basophils there were significant decreases in hr induced by t3 extract after ait. according to auc values all patients demonstrated decrease in hr after ait in compare to hr before ait in a range of 25%-65% demonstrating a decrease of hypersensitivity to birch allergens. analysis of basophil hr in patients received s.c. or s.l. the asthma and rhinoconjunctivitis symptom scores during and after pollination season decreased significantly and showed correlation with histamine release by t3. 1565 | immunotherapy with the recombinant b cell epitope-based grass pollen allergy vaccine bm32 induces a biphasic allergen-specific igg1 and igg4 response background: immunotherapy with the recombinant b cell epitopebased grass pollen allergy vaccine has been shown to reduce symptoms of grass pollen allergy in a multicenter, double-blind, placebocontrolled study. aim of this study was to investigate the levels and kinetics allergen-specific igg responses in a double-blind, placebocontrolled phase iib combined field and exposure chamber trial studying the effects of three, four and five pre-seasonal injections of bm32 as compared to placebo. method: a quantitative elisa assay based on purified human monoclonal allergen-specific igg 1 as well as igg 4 antibodies as standards was developed to measure allergen-specific igg 1 and igg 4 concentrations induced by ait with bm32. results: we found rises in levels of both tested allergen-specific igg subclasses in the actively but not placebo-treated patients. phl p 1-and phl p 5-specific igg 1 levels up to 83 μg/ml and 784 μg/ml, respectively and phl p 1-and phl p 5-specific igg 4 levels of up to 468 μg/ml and 1423 μg/ml, respectively were measured in bm32treated patients. five pre-seasonal injections induced the highest allergen-specific igg levels. interestingly, allergen-specific igg 1 and igg 4 antibodies showed a biphasic response with early rises of allergen-specific igg1 which declined quickly after the pollen season and a delayed but very sustained allergen-specific igg4 response. conclusion: treatment with bm32 induces a biphasic allergen-specific igg response consisting of an early igg1 and a sustained allergen-specific igg4 response which may be responsible for early and sustained protection against allergic symptoms. 1566 | t reg cd4 + cd25 high in peripheral blood in patient with grass pollen allergy during sublingual specific immunotherapy slit the aim of this study was to evaluate t reg cd4 + cd25 high in peripheral blood in patients with grass pollen allergy during sublingual immunotherapy slit. method: we examined 27 adult patients, aged 20-41, 13 female and 14 male. patients were qualified to slit after confirmation of allergy-by skin prick tests, specific ige and nasal provocation tests. we determined t reg cd4 + cd25 high from blood sampling of those patients (by flow cytometry method), before the slit, after reaching the maintenance dose, before the grass pollen season, during the grass pollen season, and after one year of slit. results: during slit the percentage of t reg cd4 + cd25 high increase after reaching the maintenance dose, then it decreased before and during the grass pollen season, and again increase after one year os slit. we observed, that in the group with significant improvement of symptoms, t regcd4 + cd25 high decreased during grass pollen season, comparing to group without clinical improvement. conclusion: slit as a method of immunotherapy influence on levels of t reg cd4 + cd25 high cells. the observed decreased levels of these cells during the grass pollen season might be consider as a prognosing marker of clinical improvement. 1567 | t reg cd4 + cd25 high from peripheral blood during subcutaneous specific immunotherapy (scit) for grass pollen hofman a; hofman j; hofman t centrum alergologii, poznan, poland background: specific immunotherapy is the only causal method for grass pollen allergic rhinitis. however, we don't observe in every patients satisfying clinical effects. because the treatment of allergic rhinitis takes 3-5 years, and is quite expensive, everyone is constantly looking for a perfect parameter, which may prognose the effectiveness of specific immunotherapy (sit). the aim of this study was to evaluate t reg cd4 + cd25 high lymphocytes from peripheral blood in patients during subcutaneous specific immunotherapy (scit) for grass pollen . method: we examined 99 adult patients (36 female, 63 male), age 18-60, who undergo scit for grass pollen allergy. we have done skin prick tests and specific ige in those patients. additionally, we confirmed the allergy by nasal provocation tests. we have determined lymphocytes t reg cd4 + cd25 high from blood sampling from those patients, with flow cytometry method: before immunotherapy, after reaching the maintenance dose of scit, before and during the grass pollen season, and after one year of scit. our control group was represented by 12 adult healthy volunteers. after one year of scit we divided patients into two groups-with and without clinical improvement. results: in allergic patients we have observed decreased levels of t reg cd4 + cd25 high compared to control group before the start for scit. during immunotherapy, the percentage of t reg cd4 + cd25 high increased after reaching the maintenance dose, however it did not reached the level of healthy volunteers. again, levels of t reg cd4 + cd25 high decreased before and during the grass pollen season, and increased after one year of scit. we compared also patient with significant improvement of clinical symptoms, and without. and we observed that the level of t regs cd4 + cd25 high decreased during pollen season in improved group, and increased in the group without clinical improvement. conclusion: in patients with grass pollen allergy, during the grass pollen season, decrease of t reg cd4 + cd25 high cells might be conresults: in the group of patients treated with sit gene expression analysis revealed significant change in ifng expression (p = 0.03) (comparison between sample a and b). comparison between samples a and c showed significantly different expression in genes: afap1l1 (p = 0.006), commd8 (p = 0.001), pik3cd (p = 0.027), and twist2 (p = 0.0003). duncan's multiple range test confirmed difference between sample a and c for commd8 (p = 0.004) and also revealed new significant difference in tbx21 in samples a and b (p = 0.035; in wilcoxon's test p = 0.08). k nearest neighbors algorithm was built based on ifng, pik3cd, commd8 expression. the results of the study indicate, that there is a significant change in the expression of a few genes during the build-up phase of sit. it may be suspected, that this change contribute to the mechanisms involved in the building tolerance to allergen. k nearest neighbors algorithm may be useful for sit efficacy prediction. 1569 | regulation of cytokine thymic stromal lymphopoietin (tslp) in modulating tgf-ß1induced interstitial inflammation and cellular fibrosis background: thymic stromal lymphopoietin (tslp) has previously been linked to allergic inflammatory diseases, tissue fibrosis and organ dysfunction. it remains unclear, however, whether tslp plays any role in the occurrence of renal fibrosis, so this study investigated that underlying mechanism. method: an in vitro fibrosis model was established by treating normal rat kidney fibroblast (nrk-49f) cells with transforming growth factor-β1 (tgf-β1), after which the levels of various fibrogenic markers (e.g., fibronectin) and downstream fibrogenic signal proteins (e.g., smad 7) were investigated. also, tslp shrna was used to silence the effects of tslp, while an elisa was conducted to evaluate the fibronectin secretions. results: the level of fibronectin in the nrk-49f cells was doseand time-dependently increased by the administration of exogenous tslp (p < 0.05). tslp also significantly increased the level of fibrosis signaling, in addition to inducing a marked decrease in the down-regulation of smad7. interestingly, the application of tslp shrna caused a dramatic reversal of the tgf-β1-induced cellular fibrosis while simultaneously leading to the suppression of fibronectin and fibrogenic signal proteins. conclusion: taken together, these observations provide insights into how extracellular matrices develop and could lead to potential therapeutic interventions for the suppression of renal inflammation and fibrosis. abstracts | 779 1571 | effects of two years treatment with the recombinant b cell epitope-based grass pollen allergy vaccine bm32 on allergen-specific b and t cell responses background: bm32 contains recombinant fusion proteins of nonallergenic peptides from ige-binding sites of the four major timothy grass pollen allergens phl p 1, 2, 5 and 6 and pres protein from the hepatitis b virus as a carrier. in a multicentre, double-blind, placebocontrolled trial, 181 grass pollen allergic subjects were treated for two years either with bm32 or placebo. here we investigated in detail the effect of immunization with bm32 on allergen-specific t and b cell responses. during the study from 35 subjects treated in the vienna centre (bm32: n = 25, placebo: n = 10) were investigated regarding proliferation using 3 h thymidine incorporation and cytokine production in response to various recombinant allergens at 9 different time points. grass pollen allergen-specific ige, igg 1 and igg 4 levels were determined by immunocap and elisa. results: a significant increase of allergen-specific igg 1 and igg 4 levels was found in the bm32-but not in the placebo group in both years (year1 > year2) after treatment. there was no difference regarding t cell proliferation in response to phl p 1 and phl p 5 after first grass pollen season between actively and placebo-treated patients whereas proliferation in particular of phl p 1-specific responses seemed to be blunted in the active group in the second year. no significant differences regarding allergen-specific th1, th2 and tolerogenic (i.e., il-10) cytokines were observed between bm32and placebo-treated patients. the findings indicate that the bm32 induces high levels of allergen-specific blocking antibodies which may reduce allergen-specific t cell proliferation but does not induce significant increases of regulatory cytokines in t cells. this study was supported by grants f4605, f4613 and dk 1248-b13 of the austrian science fund (fwf). 1 hospital universitario ramón y cajal, madrid, spain; 2 department of immunology iis-fundación jiménez díaz, uam, madrid, spain background: shiitake mushroom (sm) (lentula edodes) is an edible fungi native to east asia. it is traditionally cultivated and used in many asian countries and its consumption is increasing worldwide. direct skin exposure to sm can cause cutaneous reactions, including allergic contact dermatitis and urticaria, while its oral intake may prompt "shiitake flagellate dermatitis" (sfd), which is a distinctive itching linear erythematous eruption. sfd is usually considered a toxic reaction to lentinan, a thermolabile polysaccharide that increases interleukin-1. we report 3 cases (p1, p2, p3) of shiitake flagellate dermatitis studied in our centre. method: skin prick tests (spt) to environmental allergens-including moulds -, prick-by-prick and patch test with raw and cooked sm were carried out. total ige and specific ige to mushroom, white mushroom and environmental moulds were also determined. a raw and cooked shittake mushroom extracts were prepared. both extracts were analyzed in all the patients by sodium dodecyl sulfate polyacrylamide gel electrophoresis (sds-page). results: skin prick tests, prick-by-prick, patch tests and specific ige were all negative except for p1, who had positive prick-by-prick to raw shiitake mushroom. sds-page ige immunoblotting assays with the patient's sera revealed ige-reactivity with proteins ranging from 16 kda to 32 kda for p1, p2 and p3. we report 3 cases of shiitake flagellate dermatitis with demonstrated ige-sensitization. physicians should take into account that some cutaneous reactions considered as toxic might be allergic reactions. vorozhko i 1 ; sokolnikov a 1 ; sentsova t 2 ; donnikov a 3 ; ilyenko l 2 ; denisova s 2 background: allergic diseases such as asthma, rhinitis and food allergy have increased in recent decades in tropical countries. the tropics has climatic, environmental and ecological peculiarities that allow us to emit several hypotheses that could explain this phenomenon. in one of them, it is postulated that the increase of the sensitization to food, is due to the presence of lower serum levels of vitamin d, product of the adoption of a western lifestyle, with lower sun exposure, which in its turn diminishes the immunomodulatory action of this vitamin at intestinal level, favoring the sensitization against food antigens. we evaluate differences between the titers of serum antibodies against food antigens between two populations with african ancestry but different environment (rural vs urban) and investigate the influence of vitamin d levels. method: an observational, cross-sectional and descriptive study was carried out on 200 afro-descendant children living in san basilio de palenque (rural) or in the city of cartagena, bolivar (urban). the sensitization was determined by a positive skin prick test to allergen extracts, including foods, and, specific ige, iga and igg4 to egg, milk and peanut extract, as well vitamin d, were measured by elisa. antibody and vitamin d titers were correlated by spearman's test and comparisons between groups were done using the wilcoxon rank sum test. a p < 0.05 was considered significant. results: atopy was more prevalent in the urban population (24% vs 7%, p < 0.001). however, none participant tested was positive for food allergens. regarding vitamin d levels, these were found to be higher in the rural population compared to the urban group (p < 0.001). among the antibodies analyzed, only ige against peanut showed differences, which were higher in rural population (p < 0.001) as well as those of iga to peanut, which were higher in the urban population (p < 0.001). we observed only a significant correlation between peanut specific ige (rho 0.2127259, p < 0.005) and iga (rho -0.342434, p < 0.001) response and vitamin d. conclusion: in our study, we found differences between the peanut specific ige and iga response in urban and rural populations. the correlation between the levels of specific ige and iga to peanut and vitamin d, suggest that this vitamin may influence peanut sensitization in this population, besides other components like diet and genetic and environmental factors. 1580 | evaluation of inhaled allergen sensitivity in patients with food allergies younger than two years of age kulhas celik i 1 ; aldemir es 2 ; buyuktiryaki b 1 ; ginis t 1 ; toyran m 1 ; dibek misirlioglu e 1 ; kocabas cn 3 ; civelek e 1 carbohydrates and pyruvate was observed in the severe group compared to the rest of allergic groups. in addition, an increment in lactate was noticed. these metabolites were closely associated with the energy metabolism. other metabolic changes included increased levels of fatty acids such as myristate, palmitate and laureate. these fatty acids might be precursors of arachidonic acid, a key molecule in inflammation. finally, alterations in some amino acids and adenosine were found method: to evaluate these critical processes, 22 five-week old germ-free c3h/hen mice were split into two groups; 12 were intraperitoneally sensitized to the peanut allergen ara h 2 and 10 remained ns. upon reaching 8 weeks of age, mice were intragastrically challenged with purified ara h 2. mice were harvested in two groups: 30-minutes and 60-minutes post-gavage. upon harvest, the left lobe of the liver was collected and sera were removed. sera and livers were evaluated for drp-ara h 2 using an in-house quantitative sandwich enzyme-linked immunosorbent assay (elisa). a sample of the proximal small intestine was monitored for drp-ara h 2 using immunohistochemistry (ihc) and for mast cell degranulation using toluidine blue stain. results: sensitization does not have a large effect on the concentration of allergen present in the sera or liver. however, s mice allowed to digest ara h 2 for 60-minutes were more likely to display tissues positive for detection of drp-ara h 2 than ns mice at the same time point. conclusion: there is drastic biological variation among mice in their capacity to absorb and transport allergens. the elisa used in these analyses proved effective in the quantitative detection of drp-ara h 2 in both liver and sera samples, while ihc provided inconsistent results for the detection of drp-ara h 2 in tissues. however, in positive ihc samples, staining was indicative of paracellular transport across the epithelial barrier. 1583 | eczema induces a high ovalbuminspecific ige/igg1 ratio and affinity maturation during the lactation period irahara m; kido h; shinahara w inst. for enz. res., tokushima university, tokyo, japan background: recent articles have revealed that ingestion of foods induces oral tolerance and cutaneous sensitization induces food allergy. relationships with levels of immunoglobulin subclasses, affinity of allergen-specific ige, and development of food allergy have also been indicated. however, relationships with levels and affinity of specific immunoglobulins and eczema during early infancy remain poorly understood. therefore, the present study aimed to elucidate these relationships. method: this study enrolled women who visited naruto hospital (tokushima prefecture, japan) in late pregnancy and their children. blood samples and information on skin condition were taken every 2 months from neonate to 6 months old. egg white and milk allergen-specific immunoglobulin subclasses and affinity of ovalbumin (ova)-specific ige levels were measured using the densely carboxylated protein (dcp) microarray with 20 μl of serum. results: this study included 84 infants whose parents agreed to join this study. of these, 42 infants (50%) were diagnosed with eczema by 6 months old. egg white (ew) and milk-specific igg4 were detected in a few subjects at 6 months old. however, these specific ige and igg1 were detected in some subjects at that time ew-and ova-specific ige levels and ige/igg1 ratios were significantly higher in participants with eczema than in those without eczema at 6 months old. moreover, subjects with high ova-specific ige/igg1 ratios showed higher affinity ova-specific ige antibodies than subjects with low ova-specific ige/igg1 ratios. these results were not reflected in milk-specific ige levels. the milk-specific ige level differed between breast feeding and formula-fed infants, with no difference in the ige/igg1 ratio. conclusion: eczema contributed to high ew-and ova-specific ige levels and ige/igg1 ratios. high ova-specific ige/igg1 ratios involved high affinity ova-specific ige antibodies. however, the milk source during early infancy had no effect on the specific ige/igg1 ratio with eczema. these results suggest different sensitization routes provoke different results in levels and affinity of immunoglobulins. 1584 | purification and characterization of naturally occurring post-translationally cleaved ara h 6, an allergen that contributes substantially to the peanut allergome background: the 2s albumin ara h 6 is one of the most important peanut allergens. a post-translationally cleaved ara h 6 isoform has been described in the past but had not been characterized in detail, nor had its relevance for peanut allergy been investigated. method: post-translationally cleaved ara h 6 (para h 6) and intact ara h 6 (intact ara h 6) were purified from virginia type peanuts and the cleavage site was mapped using high-resolution mass spectrometry. biochemical characteristics were determined by sds-page, uv absorbance spectroscopy, far uv cd spectroscopy, and immunochemical reactivity of both forms of ara h 6 was compared by igg immunoblotting and ige-elisa using sera from individuals sensitized to peanut. reversed-phase liquid chromatography was applied to study the occurrence and abundance of para h 6 in various peanut types. results: compared to intact ara h 6, para h 6 lacks a 5-amino acid stretch, resembling amino acids 43-47 (uniprot accession number q647g9) in the non-structured loop. consequently, para h 6 consists of 2 chains; a n-terminal chain of approximately 5 kda, and a c-terminal chain of approximately 9 kda, held together by disulfide bonds. intermediate post-translationally cleaved products, in which this stretch is cleaved but not removed, are also present. the secondary structure and ige-binding of para h 6 resembles that of intact ara h 6, indicating that the loss of the non-structured loop is not critical for maintaining conformational ige-epitopes. both forms of ara h 6 were reactive with several commercially available igg antibodies. the peanut cultivars runner, virginia, valencia, and spanish contained para h 6 at equivalent levels, suggesting para h 6 is a consistent and important constituent of the peanut proteome. conclusion: a post-translationally cleaved form of ara h 6 is abundant in the main peanut market types, and has ige-binding comparable to intact ara h 6. this should be taken into account when ara h 6 is investigated in peanut-containing products. 1585 | release of major peanut allergens from their matrix at various ph and at saliva conditions; ara h 2 and ara h 6 are quickly bioaccessible background: the oral mucosa is the first immune organ that encounters allergens upon ingestion of food. peanut is often consumed in solid form, and it is not known if peanut allergens are released from the food already in the mouth. we set out to investigate the solubility of individual peanut allergens at conditions that mimic the first exposure site, i.e. the mouth. method: light roast peanut flour was suspended in buffers of various ph mimicking saliva. protein concentration was measured in supernatant, and release of major allergens ara h 1, ara h 2, ara h 3, and ara h 6 was assessed by sds-page. also, the allergen profile of un-dissolved material was assessed. results: peanut protein solubility is poor in the ph range 3-6, while at low ph (1.5) and at moderately high ph (>8), the solubility is higher. at all conditions tested, there was a substantial amount of un-dissolved protein. this indicates that the ph range of saliva, between 6.5 and 8.5 in healthy individuals, may be critical for the release of peanut protein from its matrix. in this ph range from 6.5 to 8.5, ara h 2 and ara h 6 are readily released, while ara h 1 and ara h 3 are poorly released. increasing the ph from 6.5 to 8.5 slightly increased the release of ara h 1 and ara h 3, but still the recovery was low (approximately 20% for both ara h 1 and ara h 3) compared to that of ara h 2 and ara h 6 (approximately 100% and 65%, respectively). this remarkable difference in extraction kinetics suggests that ara h 2 and ara h 6 are the first allergens an individual is exposed to upon ingestion of peanut-containing food. conclusion: based on our observations, we conclude that the peanut allergens ara h 2 and ara h 6 are quickly bio-accessible in the mouth upon ingestion of peanut. this new insight may contribute to the understanding of the extraordinary allergenicity of ara h 2 and ara h 6 compared to other peanut allergens. background: in proven cases of non-ige mediated cow's milk allergy clinical response can be partial even when treated with amino acid formulae e.g pain in infants. residual intestinal symptoms can be related to ongoing nerve hypersensitivity, changes in microbiome or motility disturbance. mast cells are thought to play crucial role in non-ige mediated food allergy. ketotifen is a first generation h1 antihistamine which has mast cell stabilising properties with pain blocking and anti tnf-a effect. hence ketotifen could have important role in symptom resolution where diet elimination has not been successful. we aim to find out effectiveness of ketotifen to unresponsive/partially responsive symptoms such as pain in non-ige mediated cow's milk allergy infants. method: children who presented to single specialist centre over 11 years had their case notes reviewed retrospectively. inclusion criteria were those children with confirmed non-ige mediated cow's milk allergy by elimination of cow's milk with improvement of symptoms and worsening of symptoms on reintroduction of dairy. where symptoms partially responded e.g pain, ketotifen was used at 0.5-1 mg once at night for 4 weeks and symptoms were reassessed. statistical analysis was performed using r v3.3.3 with significance was set at p = 0.05. results: 1031 patients were identified with 675 patients excluded due to unconfirmed non-ige mediated allergy. of the 358 case (206 males, age 3-50 months), atopic co-morbidities were found in 62% children. common symptoms were abdominal pain (51%), vomiting (47%), back arching (37%), constipation (35%), bloating (33%), food aversion (29%) and diarrhoea (26%). we compared the children who had symptom improvement on ketotifen and cow's milk elimination against children who improved on cow's milk elimination alone. significant difference of symptom improvement was found with abdominal pain; 69% using ketotifen compared to 53% who did not use results: a total of 3548 analysis for ttgiga have been performed for a total of 2965 patients during the study period (2010, 2012, 2014, 2016) . 128 patients showed at least once a positive ttgiga. among these, 11 had a negative result at first testing, and were positive at the second (n = 10) or third testing (n = 1). despite an increasing number of ttgiga requests, the number of positive results decreased. wige were rarely requested but were positive in about 45% of tested sera (table 1a and 1b). the amount of laboratory requests for ttgiga has increased, while those for wige remains stable and is rare. wheat allergy seems to be rarely investigated in our center and may deserve more attention. case report: eosinophil-associated gastrointestinal disorders (egids), including eosinophilic gastroenteritis (eog), are a inflammatory diseases, characterized by gastrointestinal symptoms and eosinophilic infiltration. patients with eoe have an increased incidence of allergy, with increased ige mediated food and inhalant sensitivities. use of either a targeted food allergen avoidance approach (based on allergy testing) or untargeted approach (based on food allergen avoidance) results in the resolution of eosinophilia in the gastrointestinal tract of 50%-70% of adult. we describe a case of a 27-year-old patient diagnosed with eosinophilic enteritis, associated to protein-losing enteropathy. the patient experienced severe diarrhea, nausea, vomiting and weight loss, that caused a severe dysproteinaemia and electrolytes abnormalities. an upper and lower endoscopy was performed, showing an ulcerative ileitis. the histological pattern was characterized by eosinophilic infiltration of ileum and duodenum>40 hpf. she presented also high levels of total ige (800 k/ui), high serum tryptase (20 μg/l, n.v. ≤9.0) and sensitization to the lipid transfer protein (ltp) of peach. the patient was prescribed to a six-food elimination diet (sfed) and underwent high doses of oral and intravenously corticosteroids, but a satisfactory therapeutic response was not achieved. we hypothesized that ige has a role in the mechanism of aeg and that blocking ige would have improved disease symptoms and reduced allergic inflammation, as measured by a decrease in intestinal tissue eosinophilia. we started off-label administration of omalizumab 300 mg/month subcutaneously, the same dosage schedule used in allergic asthma and, by other authors, in eosinophilic gastrointestinal disease after achieving informed consent by patient. except for an exacerbation of symptoms occurred 9 months after starting the therapy, when a further endoscopy, showing a gastrointestinal eosinophilic infiltration>50 hpf, was performed, a significant improvement of both gastrointestinal and cutaneous symptoms was observed during therapy, together with a normalization of laboratory parameters. after 30 months a clinical remission of disease was obtained and administration was stopped. although a histological remission during the first few months of treatment was not obtained, in a subset of aeg patients, ige plays a role in the pathophysiology of the disease and that anti-ige therapy with omalizumab may result in disease remission. 1590 | fullerene c60 reduces the allergic inflammation in food allergy mouse model background: a food allergy (fa) is an abnormal immune response to food. the signs and symptoms may range from mild to severe. they may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. food allergy is becoming increasingly common. fullerene c60 has the unique electronic properties making it an attractive candidate for allergic diseases therapy. the main purpose of our research was to assess therapeutic effect of fullerene c60 in a mouse model of fa. method: new efficient method for producing a water-soluble fullerene c60 has been developed. fa experimental model was induced in balb/c mice by the intragastrical (ig) ova administration after subcutaneous (sc) sensitization. fullerene c60 was administrated ig once a week, or twice a week, or daily. ova-specific antibodies were assessed by elisa. splenocytes cytokine production upon ova in vitro stimulation was detected by elisa. samples of jejunum of the small intestine were removed for histological examination immediately after the last ig allergen administration. results: it was shown that ova-specific ige and il-5 level were significant decreased in groups treated with water-soluble fullerene c60. the greatest effect was observed in mice receiving fullerene c60 daily. the ifn-gamma level was significantly higher in ig c60treated groups. the histologic analysis of jejunum of the small intestine samples showed that c60-therapy improved the histologic picture. the greatest effect was observed in mice receiving fullerene c60 daily too. conclusion: taken together, these results demonstrate that the water-soluble fullerene c60 exhibits a significant anti-inflammatory effect in a mouse model of fa, and possesses a high therapeutic potential. background: a 47-year-old male reported eight episodes of anaphylaxis after exercise. all the ingested food eight hours before each episode was analyzed. before each episode, he had always eaten chicken or turkey meat, and he tolerated these foods without exercising. in one of the episodes the patient had taken a tablet of dexketoprofen a few hours before. since several years, he referred chest tightness after eating some fish (emperor, salmon and whiff), however he tolerated others. the patient denied having eaten fish before any of the episodes of anaphylaxis. method: commercial skin prick tests (spts) and prick by prick tests (pp) with all food ingested and fishes were performed. tryptase, total serum ige (ige) and specific ige (sige) (immunocap. thermo-fisher scientific, uppsala, sweden) to the foods involved were determined. a controlled oral provocation test (opt) with dexketoprofen was performed. results: spt was positive to tuna extract (3 mm) and negative (0 mm) for the rest of fish extracts. it was also negative for chicken meat extract and other foods tested. pps were positive for raw and cooked turkey meat (3 mm), raw and cooked tuna (6 and 8 mm), raw emperor (11 mm), raw and cooked whiff (9 and 8 mm) and raw hake (18 mm). pps were negative to raw and cooked chicken meat. ige was 700ui/ml and tryptase 2.95 ng/l. sige was slightly positive to hake, cod and chicken meat. dexketoprofen opt was negative. at that moment, we recommended the patient to avoid chicken and turkey, as well as the fishes which he had symptoms with. since then, he has not suffered any new episode of anaphylaxis despite exercising daily. protein extracts from turkey meat, tuna, emperor, salmon, hake and whiff were prepared and analyzed by sds-page. conclusion: recently, triosephosphate-isomerase (28 kda) has been identified as a new chicken meat allergen. this allergen could be responsible for the cross-reactivity between bird and fish meat and the episodes of anaphylaxis after exercise in our patient. the triosephosphate-isomerase has not been implicated previously as a cross-reactive allergen involved in the fish-chicken syndrome. results: twenty-three patients were included, 61% male, median age 30 years (iqr 12.5), 48% atopic, 30% asthmatic. non-specific lipid transfer proteins (nsltp) were implicated in 70% (n = 16) and ω-5-gliadin in 30% (n = 7). eighteen (78%) patients referred anaphylaxis in the reaction with co-factor, 7(22%) urticaria/angioedema, 2 had both depending on the co-factor. all patients in which ω-5-gliadin was the allergen involved had anaphylaxis in the presence of co-factor, with tolerance to wheat without it. in patients in which nsltp was the allergen involved, 12 (75%) had anaphylaxis in the presence of co-factor. reaction with co-factor was more severe than without in 13 (81%) patients; 4 patients had no previous history of reaction and subsequently tolerated the culprit food. only 1 patient had anaphylaxis in the absence of co-factor; the remaining presented oral allergy syndrome and/or urticaria. exercise was the main co-factor, present in 22 patients. nonsteroidal anti-inflammatory drugs (nsaids) were the only co-factor in 6 patients; all of them had anaphylaxis, 4 with allergy to ω-5-gliadin, 2 to nsltps. all subsequently tolerated the nsaids involved. conclusion: nsltps and ω-5-gliadin were the most frequently involved allergens in cefa, with exercise being the most frequent co-factor. nsaids were relevant co-factors, even when ω-5-gliadin was the allergen involved. several patients subsequently tolerated culprit foods and nsaids, difficulting the diagnosis and further emphasizing the importance of a correct cofactor evaluation. molecular allergens had an important role in the diagnosis, avoiding unnecessary ofc. information about co-factors must be included in all patients with allergy to nsltps and ω5-gliadin. 1594 | allergy to wheat-dependent exerciseinduced anaphylaxis (wdeia) proteins, without? 5-gliadins as responsible ferreira a 1 ; castillo m 2 ; martins s 1 ; pineda f 2 1 unidade de imunoalergologia hospital das forças armadas., lisbon, portugal; 2 departamento de aplicaciones. diater laboratorios, madrid, spain background: the second well-characterized form of allergy to wheat proteins is wheat-dependent exercise-induced anaphylaxis (wdeia), with the ω5-gliadins (part of the gluten protein fraction) being the major group of proteins which are responsible, but other forms of food allergy have also been reported, with the proteins responsible including gluten proteins, cm proteins and non-specific lipid transfer proteins. the patient was a 38-year-old man who visited the hospital with acute urticaria just eat bread before run (30 minutes). according the components of bread. it was formed by a mixture of wheat, rye and barley. with a history (for several years) of episodes of severe urticaria after intake a mixture of cereals and/or different kinds of beer. results: prick test and specific ige with wheat, rye and barley were negative and the proteins from allergenic extract from these cereals, and also the gliadins and glutenins fractions were transferred onto a pvdf membrane to carried out a western blot technique with the patient's serum. the patient's serum recognized several proteins from wheat and millet gliadins not compatible in molecular mass with a ω5-gliadins. the association of w5 gliadin as responsible for the symptoms produced after the intake of products containing wheat and exercise is well referenced but in the case of this patient could have other proteins involved as triggers of their symptoms. suksawat y phramongkutklao hospital, bangkok, thailand background: food-dependent, exercise induced anaphylaxis (fdeia) is an anaphylactic condition that develops in patients who ingest specific food followed by exercise. a variety of foods have been described to be the cause including shellfish, wheat and vegetables. the mechanisms of fdeia is believed that exercise increases allergen absorption or decreases threshold of mast cell. the investigations such as skin prick test or specific ige for food are useful because food sensitization is demonstrated. however, a challenge test including ingestion of suspected food followed by exercise is the only method to diagnose this disease. we report a case of fdeia in a 17-year-old adolescent male. result: he presented with generalized urticaria and hypotension after eating a barbecue buffet which was one hour followed by playing taekwondo. after treatment with intramuscular adrenaline, antihistamine and systemic steroid, his condition was improved. the barbecue buffet consists of many kinds of food including shrimp, squid, salmon and pork meat which were previously tolerated. he had no past history of anaphylaxis or drug allergy. he was referred to our allergy unit for investigation. we performed skin prick test with food allergens and many kinds of fresh foods that he ate on that day and the result was positive to shrimp (6 mm. in diameter). three-day challenge protocol was set up a month after recovery and we used aspirin as a cofactor. on the first day, open challenge for 500 gram of shrimp was administered and the result was negative. on the second day, exercise challenge test based on the american thoracic society guideline was also negative. however, on the last day, he developed generalized urticaria five minutes after the same exercise challenge test which was 1 hour preceded by aspirin intake and 500 gram of shrimp ingestion. but his vital signs appeared to be stable. the patient was administered intramuscular adrenaline and antihistamine with full recovery. he was strongly advised to avoid shrimp for 4-6 hours before exercise and carry an adrenaline autoinjector. the-three day challenge protocol is a definite tool to confirm the diagnosis of fdeia. a correct diagnosis is important to avoid unnecessary restricted diet. 1596 | food dependent exercise induced anaphylaxis in peach allergic patient-case report consumption of different types of food (pancakes with cream cheese and fruit, peach, chinese dish, sandwiches-all eaten on other occasions without symptoms) and co-occurring physical exercise (dancing, shopping, walking). during diagnosis we performed spt with inhaled and food allergens (allergopharma), prick by prick tests with peach, banana, apple, pear and bread. we established the concentration of allergen specific ige (peach, wheat flour, peanuts, hazelnuts) and the level of ige specific to allergen components (immunocap isac). we performed exercise provocation test and open food challenge with peach. results: spt were negative with all tested food and inhaled allergens (inc.egg; milk; cocoa; tomato; carp; apple; banana; strawberry; rye flour; wheat flour; peanuts; hazelnut; citrus, d. farinae; d. pteronyssinus; grass; weeds; clad. herbarium; alt. tenuis; dog; cat; poplar; hazel; alder; birch; mugwort). prick by prick tests were positive with fresh peach. concentration of peach specific ige was 0.55 ku/l. in immunocap isac we found elevated levels of ige specific to ltps from different allergen sources (jug r 3 -1.3; pru p 3 -0.8; pla a 3 -0.6; tri a 14 -0.5 [isu-e]). open food challenge with a medium size peach was negative. exercise provocation test without allergen exposition was negative. exercise provocation test after eating a medium size peach concluded with severe lip and eyelids edema, followed by whizzing, dyspnea and urticarial. patient received adrenaline 0.5 mg im, steroids and antihistamines with good clinical effect. conclusion: patient was diagnosed with food dependent exercise induced anaphylaxis (fdeia) due to ltp allergy. she was advised to eat peeled fruit and vegetables, avoid cofactors of allergic diseases and carry rescue set (adrenaline, steroids and antihistamines). cases reports: we report 1case of fdeia and 3 cases of wdeia. case 1:24-year-old woman with intermittent severe allergic rhinitis and food allergies since childhood. in the last 7 years she registered weekly episodes of fdeia (urticaria, angioedema, wheeze, drop of bp) especially when during effort and after alcohol intake. prick tests were positive for grass pollen, mugworth, ragweed, dust mites, celery, soy, sesame, pistachio, mango, honey and shellfish. she followed 3 years of subcutaneous immunotherapy for grasses pollen. the fdeia episodes frequency and severity diminished during it. provocation test for celery and mango were positive, for alcohol, soy, sesame, pistachio, honey and shellfish were negative. case 2:23-year old man with a 7-year history of acute gluten induced urticaria, recently developed 2 episodes of wdeia (flushing, severe urticaria and angioedema, wheeze) when he went for gym. skin test was highly positive for wheat flour and dust mites, in vitro tests for 5 omega gliadin and wheat-specific ige were positive. food challenge for wheat was positive. he followed oral immunotherapy for wheat. the wdeia episodes were rare and mild. case 3:30-years old female with mild allergic rhinitis and controlled asthma, with wdeia (urticaria, angioedema, wheeze, drop of bp) in the last 3 years. skin tests showed positive results for wheat flour, dust mites and dog hair. omega-5 gliadin and wheat specific ige were high, but the provocation test for wheat was negative meanwhile combined wheat and effort provocation test was positive. 25-year-old female athlete, otherwise healthy, experienced three episodes of fdeia following running sessions. two reactions were preceded by intake of salad containing lettuce, tomato and sunflower seeds and the third one occurred after eating celery salad. the patient denied occurrence of any symptoms with physical exertion or food ingestion alone. physical examination and blood testing did not reveal any abnormalities. the differential diagnosis was performed. in skin prick test and specific serum ige antibodies sensitization to house dust mite, grass and mugwort were found. the spt and specific ige assay to culprit and most common food allergens were negative. the molecular diagnostic has been applied (faber, caam, rome, italy). the test scored positive for art v, blo t, der f, der p, eur m, lol p, phl p. no positive results for available food molecules including celery, tomato, sunflower seeds and lettuce were found. the detection of culprit food in fdeia is of crucial meaning as the syndrome can be life-threatening. the molecular diagnostic has been applied already in diagnosis of wheat-dependent exercise-induced anaphylaxis (wdeia) proving ω-5-gliadin sensitization in the majority of the cases. as the presented case did not reveal sensitization to culprit food in traditional allergy tests the molecular diagnostic was performed. this test did not show sensitization to culprit food either. however, not all of the molecules are available in molecular assays yet. cross-reactivity reaction to mugwort and grass has to be considered. the pathophysiological components of physical exertion has to be taken into consideration as well. this could contribute to the assessment of reasonability of molecular approach in diagnostic work-up for fdeia and to the establishment of standardized protocols for diagnosis and management of that syndrome. case report: food allergy to wheat is rare in adults, often reported in exercise-induced anaphylaxis. food-dependent exercise-induced anaphylaxis (fdeia) is a form of food allergy induced by exercise. fdeia symptoms can include urticaria/angioedema, respiratory and gastrointestinal manifestations and hypotension/shock. a 61-year-old male patient presented to the emergency department, was admitted after an episode of hives, hypotension and loss of consciousness. his consciousness was restored after treatment with epinephrine, glucocorticoids as well as fluids, and thereafter, the patient reported that the anaphylactic episode occurred when he started rapidly walking 1 hour after eating a slice of pizza. he mentioned that the offended food was tolerated always when it was not followed by a physical exercise. review of his past medical history and family one were non-contributory with respect to this episode. the allergy skin prick testing for common foods revealed a positive response only to wheat, while and other laboratory test values were within normal ranges. the patient is discharged after instructions on the use of epinephrine auto-injector. he was also advised to avoid wheat containing products up to 6 hours prior to physical exercise. our case demonstrated that fdeia can be characterized by the onset of anaphylaxis soon after physical exercise, when preceded by the ingestion of the responsible food. avoidance of the combination of the exposure to respective allergen and exercise is the most efficient precautive measure toward subsequent fdeia episodes. 1600 | residual exercise-induced allergic reactions after successful rush oral immunotherapies for milk and wheat method: we conducted roit for 55 children (median 8.7 years old) with milk allergy and 46 children (median 6.8 years old) with wheat allergy during 2010-2015. after 5-12 days of the rush phase in the hospital and a slow-increasing phase at home, patients consumed the maintenance dose (6.5 g milk protein or 5 g wheat protein). after at least three months of the maintenance phase without allergic symptoms, we conducted an exercise provocation test (ept) after eating the target food. if the ept was positive, we repeated it after a couple of years to check for remission. the presence or absence of eiars was based primarily on the results of epts but also on the clinical history in some cases. results: as of december 2017, 44 milk-and 41 wheat-allergic patients were able to continue ingesting the maintenance dose (desensitization). in these patients, 38 milk-and 38 wheat-allergic patients underwent the first ept at a median of 635 (228-2538) days after roit, and the result was positive in 19 (50.0%) and 19 (50.0%) patients, respectively. among these ept-positive patients, 10 milk-and 9 wheat-allergic patients conducted a second ept at a median of 504 (119-1120) days after the first ept. the result of the second ept was positive in 7 milk-and 7 wheat-allergic patients. in addition, clinical histories of eiars were subsequently observed in 4 milk-and 4 wheat-allergic patients after negative results on an ept. altogether, 19 (43.2%) milk-and 21 (51.2%) wheat-allergic patients still had eiars even after getting desensitization as of december conclusion: patients with persistent milk and wheat allergy often have residual eairs even after three to five years of desensitization due to the administration of successful roit. abstracts | 791 1601 | anaphylaxis caused by omega-5-gliadin initially diagnosed as idiopathic anaphylaxis: a case report tziotou m 1 ; syrigos k 2 ; syrigou e 1 ; sinaniotis a 1 1 department of allergy,, athens, greece; 2 gpp,, athens, greece case report: we report the case of a 59-year-old man who experienced two episodes of wheat dependent exercise induced anaphylaxis, initially diagnosed as idiopathic anaphylaxis. first episode: the patient woke up in the morning and drove to his resort. while driving, he ate a piece of cheese and ham pie. when he arrived, he walked some meters to the garden and started feeling pruritus and dizziness. he lost consciousness and recovered by himself. he was carried to hospital where his vital signs were normal. the patient has a history of atrial fibrillation and has been on flecainide bid and aspirin at noon for the last four years. a month after the first episode he visited an allergist. skin prick tests to aeroallergens and prick to prick tests to the ingredients of the pie were negative. tryptase levels were within normal limits and skin biopsy was negative for mastocytosis. an endocrinology workup was also negative. the patient was prescribed an epinephrine autoinjector and was asymptomatic for eight months. second episode: that morning he had a cup of milk and two slices of toast for breakfast and started working in the garden. two hours later he experienced pruritus and urticaria and fell unconscious. his wife had to administer two epinephrine autoinjectors before he regained consciousness. after the second episode it was decided to start treatment with omalizumab. two months later he experienced an episode of urticaria while working in the garden. he could not recall what he had eaten before. based on history, we thought that a cofactor might contribute to the occurrence of anaphylaxis. we performed skin prick tests with peach (ltp) and gliadin, allergens associated with food dependent exercise induced anaphylaxis in our region. the test to gliadin was positive. specific ige in serum to omega-5-gliadin was also positive, while specific iges to all ltps tested were negative. the patient was advised to avoid wheat and has been asymptomatic ever since. cases diagnosed with idiopathic anaphylaxis may actually be cases in which the culprit allergen has not been identified. detailed history and extensive workup may contribute to the successful management of these patients. written informed consent has been obtained from the patient. 1602 | wheat-dependent exercise-induced anaphylaxis (wdeia) and nsaids: clinical history is crucial conclusions :we present a case clinically compatible with wdeia with nsaids intake as augmenting factor. this case emphasizes that a carefully and thoroughly taken medical history is of crucial importance, otherwise wdeia can easily be unrecognized. as a result, non-allergic hyperreactivity to nsaids could be excluded and the diagnose of selective allergy to arylpropionic acids was made. exercise challenge test could not be performed in our case. case report: kounis syndrome (ks) has been defined as an acute coronary syndrome that manifests as unstable vasospastic or non-vasospastic angina, and even as acute myocardial infarction. it is triggered by the release of inflammatory mediators following an allergic insult. a 77-year-old woman with type ii diabetes and hypertension, and unstable angina pectoris as cardiovascular risk factors, has consumed chamomile tea. thirty minutes later, she developed generalized itching, skin rash, swelling of the face and the throat, chest tightness, dyspnea and syncope. the patient was transferred immediately to the emergency department, and sodium chloride, 50 mg prednisolone, 8 mg dexamethasone, 80 mg methylprednisolone, 5000ui heparin, 75 mg voltaren were intravenously administered along the subsequent 60 minutes under simultaneous treatment with oxygen therapy. an ekg examination is performed based on the patient disease's history, showing a 2.5-3 mm st-depression on d1-d3 leads, 1 mm on v3, and 3.5 mm on the v4-v6 ones. in addition, 2.5 mm st-elevation on the avr and 1 mm on the v1 derivation was observed, associated by a negative t-wave on the v1, v2, and avr leads. blood tests revealed a normal troponin i level (of 0.07 ng/ml). five hours later in the ekg was noticed: isolined st-segments, and negative t waves on the d3, avr, and v1 leads. ultrasound examination revealed normal heart kinetics and function. following the heart changes, the patient was administered sol. heparin 5000ui twice i.v., nebivolol 5 mg, plavix 75 mg, atorvastatin 80 mg, abstracts | 793 monocinque 20 mg, ordinary insulin 10ui s.c., glargine insulin 20ui s.c., and sol. furosemide 20 mg i.v. the patient progressed favorably, and four days after the anaphylactic episode the ekg revealed a 0.5 mm st-depression on leads v4, and v5, negative t-wave on avl lead, and normalized one on the v3 one. this case emphasizes the role of serious allergic reactions as cause of acute coronary syndrome in patients with altered coronary arteries and food intake as cause of kounis syndrome. 1605 | recall urticaria in two young patients with alpha-gal-syndrome after tick bites case report: patient a (m, age 25) had suffered from 7-8 anaphylactic reactions (hives, nausea, dyspnea and dizziness) within the past 15 months. all episodes occurred 3-5 hours after ingestion of red meat, once with alcohol as a co-factor. all episodes started with a wheal measuring about 0.5 cm in exact the same spot where he had been bitten by a tick one year before. specific ige to galactose-alpha-1,3-galactose (alpha-gal) was positive (2.55 ku/l). skin prick testing using raw pork kidney suspension and intradermal testing with gelafundin ® 4% diluted 1:10 also showed positive reactions. we performed an oral challenge with cooked pork kidney under careful monitoring being able to reproduce the recall urticaria as described above with a cumulative dose of 8 g pork kidney. we stopped the challenge and treated the patient with antihistamines and corticosteroids. patient b (m, age 22) reported on several anaphylactic reactions within the past 4 years with symptoms including abdominal pain, diarrhea, as well as dyspnea and loss of consciousness in one of the episodes. all episodes occurred several hours after ingesting food. furthermore the patient remembered a tick bite about 2 years before the first anaphylactic reaction, which repeatedly became inflamed and only healed completely over months. every episode started with pruritus and a wheal in the area of the former tick bite (in loco). specific ige to galactose-alpha-1,3-galactose was positive (4.37 ku/l) as well as the skin prick testing with cooked pork kidney and intradermal testing with gelafundin ® 4% diluted 1:10. this patient refused performance of oral challenge tests. an elimination diet of red meat for 12 months resulted in the absence of the symptoms as described. the diagnosis of alpha-gal-syndrome with recall urticaria in loco was made in both cases. this symptom may also be useful in evaluating results of oral challenge tests as well as an important clinical sign in medical history. pali-schöll i 1 ; meinlschmidt p 2 ; purschke b 2 ; hofstetter g 1 ; einhorn l 3 ; mothes-luksch n 3 ; jensen-jarolim e 3 ; jäger h 2 background: insects have gained interest as alternative nutrient source for humans and animals. however, being a "novel food" in the industrialized part of the world, several safety aspects, like allergenicity, need to be thoroughly addressed. in the present work we evaluated the cross-recognition of ige from patients allergic to crustaceans, house dust mite or stable flies, using house cricket acheta domesticus (ad), desert locust schistocerca gregaria (sg) and mealworm tenebrio molitor (tm). we further investigated changes of immune-recognition in terms of ige-binding in differently processed insect extracts. method: migratory locust locusta migratoria (lm) was subjected to different extraction methods, enzymatic hydrolysis or thermal processing, whereas tm larvae (tml) were evaluated after different centrifugation modes and ph levels. results: we revealed that ige from patients with crustacean allergy shows cross-recognition of acheta domesticus, schistocerca gregaria and stable flies. ige from house dust mite allergic individuals binds to acheta domesticus and schistocerca gregaria. importantly, the cross-reactivity to lm can be deleted by enzymatic hydrolysis with different enzymes or heat treatment (cooking, autoclaving), but not by different extraction methods. changes of ph and varying centrifugation steps are not sufficient to reduce ige-binding to tml. our results show that patients allergic to crustaceans, house dust mite or stable flies-allergic patients cross-recognize desert locust and house cricket proteins, and crustacean-allergic patients also flies proteins. furthermore, we confirm that the appropriate food processing method of insect proteins can reduce the risk of cross-reactivity for crustaceans-and house dust mite-allergic patients. the study was supported by the austrian science fund fwf (grant sfb f4606-b28 to ejj). results: the mean age at diagnosis was 10 years in children and 34 years in adults, more frequent in males (3:1). in the pediatric group, three had first-degree relatives with eoe and three had celiac disease. two children had performed milk oral immunotherapy and five adults aeroallergens subcutaneous immunotherapy. most of them were atopics with sensitization to aeroallergens (77.5% of children and 82.5% of adults) and food allergens (75% of children and 82.5% of adults), without statistically significant differences. the most frequent foods were fruits and nuts in both groups. we found significant statistical differences in fruits (35% of children abstracts | 795 and 57.5% of adults; p = 0.007) and cereals sensitization (5% of children and 47.5% of adults; p < 0.001). in the clinical presentation we observed significant statistical differences in impaction (22.5% of children and 82.5% of adults; p < 0.001), dysphagia (42.5% of children and 77.5% of adults; p < 0.001) and abdominal pain (25% of children and 7.5% of adults; p = 0.034). in the endoscopic findings children had more frequently exudates (92.5%; p < 0.001) and adults had esophageal trachealization (50%; p < 0.001). significant statistical differences were found in the treatment with topical corticosteroids (30% of children and 77.5% of adults; p < 0.001) obtaining a variable positive response. 77.5% of patients in both groups received food elimination diet, 45% with four or more foods. conclusion: eoe presents differences in the sensitization profile, clinical manifestations and endoscopic findings according to the age of presentation. the response to pharmacological treatment is variable and a high percentage of patients receive food elimination diets. it is a pathology difficult to control, therefore new non-invasive techniques would be useful in order to facilitate its management. 1610 | modulation of gut microbiota in patients with nickel allergy and ibs after diet and probiotics supplementation mb 1 ; garcía-figueroa be 2 department of allergy1 department of allergy fang l 12 united states 1431 | bcx7353 improves health-related quality of life in hereditary angioedema with c1-inhibitor deficiency bygum a 4 fang l 16 former yugoslav republic of; 6 division of clinical immunology huissoon a 2 bygum a 3 ; panovska vg 4 united states callejas fdb 1 alobid i 1 ; muñoz-cano r 1 izquierdo i 2 icahn school of medicine at mount sinai method: the case report form was developed by experienced allergists, and the web-based registry was established in cooperation with a professional medical software team. twenty-two departments from 16 hospitals took part during the first year 8%), whereas in adults, drugs (54.5%) were more common than foods (31.4%). the most common food triggers were eggs (27.1%), milk (15.8%), and walnut (7.9%) in children, and shrimps (21.1%), wheat (15.8%), and crab (7.9%) in adults. among drug triggers in adults, antibiotics (50.0%) were the most common cause followed by nsaids (16.7%), and h2-blockers (13.6%). the onset time was≤10 minutes in 48.6%. in children, home was the place of occurrence in more than half of the cases, whereas adults experienced anaphylaxis in out-of-home settings more often than children. cofactors were present in 19%. among the 289 cases registered via the emergency department of participating hospitals, epinephrine was administered in 66.8% (62.5% in adults, 69.8% in children) and the route of administration was im in 90.8%, iv in 6.3%, both im and iv in 2.1%, and subcutaneous in 0.7%. the number of epinephrine administration was single in 83% conclusion: this multicenter prospective registry would provide a better understanding of anaphylaxis, and provide visionary modalities to improve the management and prevention of anaphylaxis in future a case of kounis syndrome after chamomile tea consumption characterized by symptoms related to esophageal dysfunction and esophageal mucosal infiltration by eosinophils objective: characterize patients (pts) with eoe diagnosis and analyze the differences between pts with diagnosis at pediatric (ch, <18 years old) and adult age epicutaneous tests(epict)], serum total ige and eos, findings in upper digestive endoscopy (ude) and biopsies. the correlation between food sensitization, clinical severity (visits to er services or hospitalization due to complications of eoe, sclin) or severe histology results: 74 pts (81% male, average age 27 ± 17 years) ad 31 and 34, respectively. 96% ch and 67% ad were atopics. the most frequent symptoms of eoe were dysphagia (73%) and gastroesophageal reflux(46%) in ch; impaction(85%) and dysphagia(46%) in ad. 92% ch and 71% ad had aeroallergens sensitization. 77% ch and 69% ad had food sensitization. the most frequent positive tests were for ch: spt to milk(25%) and shellfish(19%), epict to shellfish(50%) and meat(19%); for ad: spt to milk(21%), fresh fruits and nuts both 18%), epict to shellfish(35%) and meat(13%). ude showed: 65% striation and white plaques in 50% ch shist (46%) was associated with sclin (35%), p = 0.001 in ch; but this was not observed in ad group there was no correlation between food sensitization and sclin or shist in both groups(p > 0.01). the average values of serum total ige (kua/l) were 653 in ch and 458 in ad; eos were 679 and 413, respectively in ch and ad allergy unit-fondazione policlinico universitario a. gemelli, università cattolica del sacro cuore conclusion: ltp with a fixed dose (2000 iu in 4 ml) of ready-touse shp616 led to fewer severe attacks, a higher proportion of attack-free patients, and a clinically meaningful and statistically significant reduction in cumulative attack severity and daily severity in hae patients relative to placebo. background: c1-inh-hae is a rare, potentially life-threatening disease characterized by episodes of subcutaneous and/or submucosal swelling. apex-1 was a phase 2, double-blind, placebo-controlled study to evaluate the prevention of attacks with bcx7353, a once daily oral kallikrein inhibitor, in patients with c1-inh-hae.method: patients with c1-inh-hae with a history of at least 2 hae attacks per month were randomized to receive four different doses of bcx7353 (350 mg, 250 mg, 125 mg, 62.5 mg) or placebo for 28 days. blood samples for bcx7353 concentrations and kallikrein inhibition were obtained from patients before dosing and for 24 hours post-dose on day 14. pk analyses and pk-pd modeling were done in phoenix winnonlin v 8.0 and sas v 9.3. the pk population included 16, 14, 14, and 7 subjects in the 350 mg, 250 mg, 125 mg, and 62.5 mg groups respectively.after daily dosing achieved steady state, c max was reached at a median of 3-4 hours after dosing. there was a greater than dose proportional increase in exposure (auc tau and c max ) over the 62.5-mg to 350-mg dose range, with an approximate 14-fold increase in exposure with a 5.6-fold increase in dose. at doses ≥125 mg, which showed statistically significant and clinically meaningful reductions in hae attack rates, geometric mean plasma trough concentrations (c tau ) were maintained at or above the minimum target concentration (4-fold ec 50 ) estimated to be required for adequate plasma kallikrein inhibition. percentages of study subjects at steady-state with bcx7353 plasma concentrations>4-fold ec 50 were 0%, 57%, 100% and 100% in the 62.5, 125, 250, and 350 mg dose groups, respectively. a 125-mg dose provided a mean c tau of slightly above 4.0fold ec 50 , with a corresponding reduction in hae attack rate of 69% (p < 0.001) compared with placebo. consistent with the exposure data, a dose dependent inhibition of kallikrein was observed with bcx7353 treatment over the dose range. the drug effect on kallikrein inhibition was highly correlated with exposure (r = 0.867). in patients with c1-inh-hae, bcx7353 treatment at doses ≥125 mg resulted in clinically meaningful reductions in the mean weekly hae attack rate. concentrations of bcx7353 at doses ≥125 mg were maintained at or above a c tau of 4-fold the kallikrein inhibition ec 50 in most patients, and kallikrein inhibition was highly correlated with bcx7353 plasma concentrations.background: c1-inh-hae is a rare, life-threatening disease characterized by recurrent episodes of subcutaneous and/or submucosal swelling that lead to considerable morbidity and a poor quality of life (qol). apex-1 was a phase 2, double-blind, placebo-controlled study to evaluate the prevention of attacks with bcx7353, a once daily oral kallikrein inhibitor, in patients with c1-inh-hae.method: patients with c1-inh-hae with at least 2 hae attacks per month were randomized to four different bcx7353 doses (350 mg, 250 mg, 125 mg, 62.5 mg) or placebo. subject-reported qol assessments were conducted at the start and end of treatment using the disease specific angioedema quality of life (ae-qol) questionnaire that measures 4 domains (function, fatigue, nutrition, fear/ shame) and has minimal clinically important difference (mcid) of 6 points. the changes from baseline in total and domain scores was compared between the treatment and placebo groups. modified angioedema activity score (aas) values across 4 domains (daily activities, appearance, physical discomfort, overall severity) were calculated for each attack and a total score was derived for each subject by summing scores from each attack. total scores were compared to placebo using an ancova model with adjustment for qualifying attack rate. reduction of attacks was statistically significant for all 3 top doses and there was a dose related increase in adverse events.results: in the 125 mg dose group, qol assessed by ae-qol was significantly improved after 4 weeks of treatment compared to placebo for ae-qol total score (-26.0, p < 0.001) as well as across all 4 domains (function: -28.2, p = 0.002; fatigue: -12.7, p = 0.05; fears/shame: -36.5, p < 0.001; nutrition: -23.4, p = 0.012). all other treatment groups showed a trend towards improvement. qol improved the most in the125 mg group, and 92% of subjects in the 125 mg group showed ae-qol reduction of more than 6 points. disease activity as assessed by the aas was significantly reduced in the 350 mg, 250 mg and 125 mg dose groups as compared to placebo, whereas there was no significant reduction in the 62.5 mg dose group. results: there were no marked differences in the age, sex, total ige titer, comorbidity of bronchial asthma and atopic dermatitis or the starting dose of rush oit among the groups. all patients in the low-bmfi group achieved ≥100% of the target dose, whereas 28.6% of the middle-bmfi group and 50% of the high-bmfi group failed to achieve the target dose (p < 0.05). results: a total of 473 infants were diagnosed with food allergy (ige-mediated and mixed type) at our center during the study period, 305 of these patients underwent prick test for inhalant sensitivity, and 220 (64.9% male) of these were younger than 2 years of age. conclusion: sensitivity to inhaled allergen were found in 14 of 292 (4.9%) patients with food allergy. therefore, we believe that inhalant sensitivity should be evaluated in these patients. there is also a requirement for further studies to identify the influence of inhaled antigens on the disease activity of patients with allergic conditions. method: in this study, we aimed to perform the metabolic profiling of severe profilin mediated food allergic patients looking for biomarkers that might both, predict the prognosis of the disease and understand the molecular mechanisms of inflammation underneath. other allergic patients (mild and moderate) and non-allergic were recruited in the study as comparative groups. the allergic patients class was predicted using a mathematical algorithm from non-allergic vs severe model results: plasma samples from non-allergic subjects, mild, moderate and severe allergic patients were measured using gas chromatography coupled to mass spectrometry (gc-ms). the samples were from 4 different hospitals in spain covering the areas with the highest pollen exposure. the metabolic profile was composed of 95 metabolites for each sample. results after the statistical analysis showed differences between the groups. firstly, a clear reduction of several abstracts conclusion: we found, as expected, a predominance of males with eoe diagnosis. ch were more frequently atopic and had aeroallergen and food sensitization. impaction and esophageal stenosis were more frequent in ad than ch. shist was associated with sclin only in ch. method: three children with ee, boys aged 1.5-11 years, were assessed over 6 months to 3 years. results: 2 cases developed in infancy. one had dyspepsia and low weight gain in infancy soon after feeding began. another had symptoms in infancy but not diagnosed until age 6 with dysphagia and esophageal stricture.. the third case was diagnosed at 11 years old after 2 episodes of food impaction in the esophagus beginning at age 9. all cases had allergic comorbid diseases including atopic dermatitis in all 3 and allergic rhinitis in 2. skin prick tests were positive to several food allergens (cow's milk, egg protein) in 2, to dust mite in 2 and to pollens in 1. serum total ige levels ranged from 490 to 1039 iu/ml. eosinophils in peripheral blood were elevated in all 3, reaching 10%-13%. treatment included restricted diet and topical budesonide 1-2 mg daily depending with periodic endoscopic biopsy.in all cases clinical improvement occurred by one month of treatment, with endoscopic confirmation. morphological improvement folthe study aimed to evaluate the effects of probiotic supplementation, in addition to diet, in ibs and snas patients, in terms of modulation of faecal microbiota population, reduction of gi and cutaneous symptoms, increase of patient's quality of life and modification of gut dysbiosis.method: forty patients aged between 18 and 65 years, affected by ibs, ni sensitization and ltp sensitization were enrolled to evaluate gut dysbiosis. dna extraction method (next generation sequencing) with commercial kit (microbiopassport ® ) was performed on stool samples. ibs patients were divided in two groups, according a gluten free diet prescription or a low fodmaps diet prescription for three months. similarly, (suspected) snas patients (confirmed by 5% ni sulfate in petrolatum patch test) were prescribed a low ni diet (100 μg/kg nickel content during the first four weeks and then up to 200 μg/kg up to three months). two ltp (lipid transfer protein) sensitized patients underwent a ltp free diet.gut dysbiosis was re-assessed after a fixed probiotic supplementation. a sex-age matched group of individuals without history of ibs, snas or any gastrointestinal disease was considered as control.gastrointestinal symptoms were evaluated using the visual analogue scale before and after treatment. conclusion: our preliminary findings suggest that probiotic implementation could be useful in patients with snas on a low-ni diet to increase population diversity, which could contribute to restore the intestinal homoeostatic conditions. 