key: cord-278761-cqrggpmj authors: manus, jean-marie title: sars-cov-2 et kawasaki, rapprochement à risque date: 2020-07-01 journal: rev francoph lab doi: 10.1016/s1773-035x(20)30215-x sha: doc_id: 278761 cord_uid: cqrggpmj nan focus © zilvergolf/stock.adobe.com le lancet a publié une observation, d'une équipe de pédiatrie de l'hôpital pape-jean-xxiii de bergame [1] , évoquant ce kawasaki-like sévère avec l'épidémie de covid-19. la province de bergame, très affectée par l'épidémie, est un observatoire naturel de ses manifestations en population. les médecins ont évalué les caractéristiques cliniques d e s p a t i e n t s k a w a s a k i -l i k e lors de l'épidémie, ilsont repris les obser vations de maladie de kawasaki des cinq dernières années au service de pédiatrie, selon un groupe 1 (avant le covid-19) et un groupe 2 (après le début du covid-19). la présentation de kawasaki-like a été comparée à la maladie de kawasaki selon les critères de l'american heart des cliniciens français ont récemment établi un rapprochement entre le covid-19 et la maladie de kawasaki chez l'enfant très symptomatique porteur du sars-cov-2, à type de kawasaki-like. on a appris, à la mi-mai, le décès, à marseille, d'un garçon de 9 ans, première victime française de ce syndrome, par atteinte neurologique liée à un arrêt cardiaque, assimilant les complications circulatoires du covid-19 à celles de cette maladie rare, essentiellement pédiatrique. sars-cov-2 et kawasaki, rapprochement à risque . an outbreak of severe kawasaki-like disease at the italian epicentre of les auteurs rappellent brièvement dans leur article les principales caractéristiques cliniques de la maladie de kawasaki key: cord-304533-qwbbsg14 authors: jones, imogen; bell, lucy c k; manson, jessica j; last, anna title: an adult presentation consistent with pims-ts date: 2020-07-10 journal: lancet rheumatol doi: 10.1016/s2665-9913(20)30234-4 sha: doc_id: 304533 cord_uid: qwbbsg14 nan the patient had no previous his tory of covid19 symptoms or con tact with known covid19 cases. nasopharyngeal and stool samples were negative for sarscov2 by pcr. other infective and inflammatory conditions were excluded (appendix p 2). adult and paediatric specialists conferred and concluded that the most likely diagnosis was kawasaki like disease on the pimsts spectrum. the patient was treated with intra venous immunoglobulin and methyl prednisolone, which resulted in rapid resolution of symptoms and normalisation of blood parameters (appendix p 3); he was discharged on lowdose aspirin 8 days after admission to hospital. sarscov2 serology 3 (checked before treatment with intravenous immuno globulin) was strongly posi tive, suggesting recent exposure to sarscov2 (appendix p 2). kawasaki dis ease has been described in adults in association with viral infection. 4, 5 to the best of our knowledge, this is the first reported case of adult kawasaki like disease related to sarscov2 infection. there is an urgent need to recognise and fully characterise pims ts in young adults to improve our understanding of pathogenesis, guide treatment decisions, and prevent sequelae in these patients. hyperinflammatory shock in children during covid19 pandemic an outbreak of severe kawasakilike disease at the italian epicentre of sarscov2 epidemic: an observational cohort study preexisting and de novo humoral immunity to sarscov2 in humans a case of complete adultonset kawasaki disease: a review of pathogenesis and classification kawasakilike syndromes in hivinfected adults key: cord-283349-9x2d1qip authors: paolino, jonathan; williams, david a. title: peripheral blood smears of children with multisystem inflammatory syndrome demonstrate prominence of early myeloid forms with morphologic evidence of toxic change date: 2020-07-24 journal: pediatr blood cancer doi: 10.1002/pbc.28551 sha: doc_id: 283349 cord_uid: 9x2d1qip nan to the editor: there is a growing body of evidence that suggests that children have largely been spared of much of the morbidity associated with the ongoing sars-cov-2 pandemic 1,2 over the last several weeks, however, there has been an increasing awareness and understanding of a hyperinflammatory shock syndrome that appears to mimic some aspects of kawasaki disease in some pediatric patients. [3] [4] [5] it has been termed multisystem inflammatory syndrome in children (mis-c), and clinically this syndrome presents as a constellation that may include high-spiking fevers, abdominal pain, rash, conjunctivitis, peripheral edema, hypotension, and cardiac dysfunction. [3] [4] [5] the pathophysiology that underlays this syndrome has yet to be elucidated; however, the overlap in clinical presentation with kawasaki disease may suggest a commonality. work to further clarify this relationship is ongoing. what is well described is an association between this syndrome and recent infection with sars-cov-2. 3 given the clinical overlap of mis-c with kawasaki disease, there has been an effort to identify a common pathway that may be involved in the two entities. while the role that neutrophils play in the development of kawasaki disease continues to be clarified, it is described in the literature that higher neutrophil to lymphocyte ratios (nlrs) may portend an increased risk of resistance to treatment with intravenous immunoglobulin as well as development of coronary aneurysms 6, 7 indeed, there is also evidence that suggests that higher nlrs in patients with covid-19 are associated with increased levels of inflammation and clinical severity. 8 neutrophils in kawasaki disease have been observed to exhibit morphologic changes, including vacuolization and toxic granulation, a phenomenon observed in inflammatory states and sepsis. [9] [10] [11] here, we report our observations from peripheral blood smears for three children for whom the pediatric hematology service at our institution was consulted for assistance in management of covid-19related coagulopathy. during the course of their care, we reviewed the peripheral smears of these children and noted the changes described below. these children all met diagnostic criteria for mis-c as outlined by the centers for disease control and prevention. 12 all were less than 21 years of age and presented with fever and evidence of a severe inflammatory process, including elevation in crp, ferritin, and d-dimer (table 1 ). all required admission for severe illness with multisystem organ involvement and all were found to have evidence of current or recent infection with sars-cov-2. baseline characteristics, clinical features of illness, and hematologic parameters are depicted in table 1 . cell counts shown in table 1 represent peak counts prior to receipt of corticosteroids. nlrs were calculated using the ratio of absolute neutrophil count (anc) to absolute lymphocyte count (alc). peak inflammatory markers represent maximal values resulted during the course of admission. the images shown in figure 1 are from peripheral smears obtained prior to receipt of systemic corticosteroids. through review of hematologic parameters for these three patients with mis-c, we make two observations. the first is that these children exhibited high nlrs, a phenomenon previously described in adult patients with severe courses of covid-19 but also in children with kawasaki disease. 6, 7 this is notable, given considerable overlap between sars-cov-2-associated mis-c and atypical kawasaki disease. we additionally observed the consistent finding of a left-shifted blood smear with prominent bandemia and presence of other early myeloid forms, including metamyelocytes and myelocytes. prominent vacuolization and toxic granulation, along with the presence of dohle bodies, was observed in the myeloid lineage. these findings have been described in severe inflammatory processes, sepsis, and, notably, kawasaki disease. [9] [10] [11] morphologic changes in peripheral blood smears have been reported recently in patients with covid-19, 13, 14 however this has, to our knowledge, not been described in the pediatric population. these epidemiology of covid-19 among children in china characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units hyperinflammatory shock in children during covid-19 pandemic an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic high neutrophil: lymphocyte ratio is associated with refractory kawasaki disease value of neutrophil-lymphocyte ratio in predicting outcomes in kawasaki disease neutrophil-to-lymphocyte ratio and lymphocyteto-c-reactive protein ratio in patients with severe coronavirus disease 2019 (covid-19): a meta-analysis early reactive neutrophil changes in an infant with kawasaki syndrome value of degenerative change in neutrophils as a diagnostic test for kawasaki syndrome degenerative changes in neutrophils: an indicator of bacterial infection centers for disease control and prevention. multisystem inflammatory syndrome in children (mis-c) associated with coronavirus disease morphological anomalies of circulating blood cells in covid-19 abnormalities of peripheral blood system in patients with covid-19 in wenzhou, china key: cord-343387-7el80yby authors: gallizzi, romina; corsello, giovanni; pajno, giovanni battista title: kawasaki disease epidemic: pitfalls date: 2020-08-27 journal: ital j pediatr doi: 10.1186/s13052-020-00887-4 sha: doc_id: 343387 cord_uid: 7el80yby recent reports have described in the pediatric population a new type of hyperinflammatory response manifested following contact with sars-cov-2, with some of the clinical features attributable to kawasaki disease (kd). the purpose of this commentary is to remark on a possible recent association between sars-cov-2 and kd. although today little is known about the etiology of kd, the most accepted hypothesis is that of a probable viral etiology, therefore, even the sars-cov-2 virus could trigger, in genetically predisposed subjects, an exaggerated inflammatory response that is clinically evident like the one described in kd. kawasaki disease (kd) is a vasculitis of the small and medium caliber vessels with a preference for coronary arteries and it is the most common cause of heart disease acquired in children [1] . the diagnosis of kd remains clinical and there are no specific laboratory tests; the american heart association (aha) criteria and guidelines reviewed in 2017 are used [2] . the cause of kd remains unknown. a careful study connects the seasonality of kd to tropospheric wind patterns, that provides the transportation of an agent which, if inhaled by genetically sensitive children, it triggers the kd immunological cascade. another study suggests new rna virus infection that enters the upper respiratory tract [2] . activation of the innate immune system is an initial event, with evidence of the activation of the interleukin signal pathway (il-1, il-6 and tnf-alpha) [3] . the self-limited nature of the disease combined with a low rate of recurrence suggests the rotation of t and b memory cells which are protective against future encounters with the agent of kd [4] . kd has been reported from more than 60 countries across the world, around the equator to areas near the poles and is seen in both hot and cold areas. this confirms that several infectious agents may trigger the disease in different geographical areas and seasons [5] . indeed turnier et al. in 2015 described that 28% of the positive results were attributable to rhinovirus/enterovirus, 8.7% due to parainfluenza and the remaining pathogens: respiratory syncytial virus, influenza, adenovirus and human coronavirus (strains 229e, hku1, nl63, oc43) were each positive less than 5% of the time [6] . following the outbreak of sars-cov-2 infection, covid-19 pandemic is emerging as a global health issue. in this context the scientific community is wondering about a possible correlation between sars-cov-2 virus infection and the onset of kawasaki-like diseases. from studies reported so far, the pediatric population appears to be affected less than adults. in the last period with the increase in number of infections, there have been first reports of kd secondary to sars-cov-2 infection [7] , some typical forms, other atypical ones. shelley riphagen et al. during a 10-day period in mid-april, in the uk, reported a cluster of 8 children with hyperinflammatory shock syndrome. this cluster of cases formed the basis of a national alarm. they suggest that this clinical picture represents a new phenomenon that affects previously asymptomatic children with sars-cov-2 infection manifesting itself as a hyperinflammatory multi-organ involvement syndrome similar to a shock syndrome in kd [8] . kawasaki disease shock syndrome (kdss) is characterized by cardiovascular shock, associated with resistance to immunoglobulins, coronary anomalies and hyperinflammatory state with possible cardiovascular shock [9] . in studies of adult patients with covid-19, a subset of patients showed hyperinflammation and multi-organ failure due to excessive release of cytokines caused by an uncontrolled immune response. similarly, genetically susceptible pediatric patients, after contact with covid-19, could develop a disease complicated by hyperinflammatory shock. kd, as mentioned above, is known to recognize infectious triggers, most often viruses, and sars-cov 2, which is, at present, the most common infectious agent in the world, could probably induce the development of epidemic clusters outbreaks by kd. the recorded anomaly could be the significant percentage of severe kd cases: this could be explained by the fact that the typical covid-19 cytokine storm has a substantial overlap with that of kawasaki disease, with high levels of il-1, il-6 and tnf-alpha, and also the presence of circulating activated macrophages that characterize both the diseases [10] . it is therefore necessary, in order to avoid diagnostic and therapeutic pitfalls, in the presence of a child with symptoms compatible with kd, to exclude an infection with sars-cov-2 virus, even in the presence of an initial negativity of the search for sars-cov-2, through nasopharyngeal swab and serological research tests. of note, epidemiological studies are awaited in order to avert overestimated prevalence of kd correlated somehow with covid-19 infection. in the meantime several medical societies have issued strict statements with the aim of either accurate diagnosis and appropriate treatment. diagnosis, treatment, and long-term management of kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis, and kawasaki disease, council on cardiovascular disease in the young diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association immunological profile of peripheral blood lymphocytes and monocytes/macrophages in kawasaki disease memory t-cells and characterization of peripheral t-cell clones in acute kawasaki disease kawasaki disease: epidemiology and the lessons from it concurrent respiratory viruses and kawasaki disease an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study hyperinflammatory shock in children during covid-19 pandemic kawasaki disease shock syndrome: unique and severe subtype of kawasaki disease on the alert for cytokine storm: immunopathology in covid-19 publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. authors' contributions rg made literature search and wrote the manuscript. gc and gbp performed critical review of the work. the author(s) read and approved the final manuscript. not applicable.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors have no conflicts of interest to declare. key: cord-300216-3mvfiuwc authors: montenegro-villalobos, jiulliana; miranda-jiménez, brian; ávila-aguero, maría l; ulloa-gutierrez, rolando title: subconjunctival acute bilateral hemorrhages due to kawasaki disease in a costa rican girl: an unusual clinical manifestation of the disease date: 2020-09-02 journal: cureus doi: 10.7759/cureus.10212 sha: doc_id: 300216 cord_uid: 3mvfiuwc kawasaki disease is an acute systemic vasculitis and is the leading cause of acquired cardiac disease in children. among the ocular manifestations in these patients, bilateral non-suppurative conjunctival injection and uveitis are the most common. we describe a six-year-old costa rican girl with acute kawasaki disease who developed severe bilateral conjunctival injection with subsequent bilateral subconjunctival hemorrhages. for her ocular involvement, she was treated expectantly, and after six weeks there was complete resolution. to our knowledge, this is the first report from latin america and among the few in the literature of a child in whom severe bilateral subconjunctival hemorrhages occur as a manifestation of kawasaki disease. kawasaki disease (kd) is an acute systemic vasculitis and the leading cause of acquired cardiac disease in children, with approximately 80% of cases occurring in children in the first five years of age. among ocular manifestations in these patients, non-suppurative conjunctivitis and acute uveitis are the most common and both are usually self-limited [1] . this report describes the presence of bilateral subconjunctival hemorrhages as an unusual manifestation of kd in a girl who was transferred to the only national pediatric tertiary referral and academic hospital of costa rica, which belongs to the network of hospitals of the caja costarricense de seguro social (ccss). maternal written informed consent and institutional authorization were obtained for the publication of this report. a six-year-old girl presented to a regional peripheral hospital with a six-day history of persistent fever, bilateral non-suppurative bulbar conjunctivitis, cheilitis, a non-tender cervical right-side 1.5 cm diameter lymphadenopathy, and diffuse abdominal pain. she had been treated during the last three days with oral amoxicillin/clavulanic acid for an upper respiratory infection but had no improvement. acute kd was clinically suspected because of persistent fever despite antibiotic and antipyretic treatment, oral mucositis, and strawberry tongue, and the girl was referred to our center for specialized management and treatment. upon direct admission to our pediatric infectious disease ward, temperature was 38.8°c, heart rate 118/min, blood pressure 113/73 (mean arterial pressure [map] 86) mmhg, pulse oximetry 94% 02 saturation. non-suppurative bilateral conjunctivitis with limbar sparing (figure 1 ) was documented, strawberry tongue, and right-side non-tender cervical lymphadenopathy, and looked acutely ill. laboratory findings showed complete blood count hemoglobin 12.7 g/dl, hematocrit 34.8%, 6770 leukocytes/mm3 (neutrophils 2300, 2480 lymphocytes, 30 eosinophils), and 285,000 platelets/mm3. c-reactive protein (cpr) was 59 mg/dl (normal range <20 mg/dl), and biochemistry tests were normal. no sterile pyuria was documented. intravenous immunoglobulin (ivig) at 2 g/kg on single infusion, and oral acetylsalicylic acid (asa) at 80 mg/kg/d were initiated. the patient evolved satisfactorily with fever resolution over the next 24 hours. however, one day after ivig infusion was completed, she developed extensive bilateral subconjunctival hemorrhages of temporal predominance (figures 2, 3) , which increased in intensity during the following two days especially in the left eye. given this finding, an evaluation by pediatric ophthalmology was performed, a normal eye fundus was documented, anterior uveitis was ruled out, and conservative eye management was recommended. an echocardiogram during admission showed normal coronary arteries, with no abnormalities in function or structures of the heart. she was discharged on oral asa 5 mg/kg/ day. on followup appointments, a second echocardiogram was normal eight weeks after. she had resolution of the hemorrhages after approximately six weeks and no visual sequelae have been documented so far. no peeling in hands or feet was described subsequently, neither thrombocytosis was found on her follow up complete blood count test. the third echocardiogram has been postponed due to the coronavirus disease 2019 (covid-19) pandemic. kawasaki disease is a systemic vasculitis of small and medium sized vessels. kd etiology is presumed to be infectious, however, a specific agent has not been identified and the etiology is multifactorial. complete (typical) kd diagnosis is clinical, based on the presence of fever persisting for at least five days and accompanied by four of five findings: changes in the extremities including hand and/or foot erythema or swelling during the acute stage and fingertip scaling over convalescence; polymorphous skin exanthema; bilateral conjunctivitis with no purulent discharge and classically with perilimbal sparing; oral mucositis including strawberry tongue; and cervical unilateral lymphadenopathy with a 1.5 cm or larger diameter. in some cases, patients do not fulfill the classic criteria for kawasaki disease and are classified as having incomplete (atypical) disease, this is more common in younger infants and older children. ocular complications in kawasaki disease usually occur during the acute and subacute phases, are usually transient, and resolve during the following months. the most common ocular feature is bilateral conjunctival injection, which is present in up to 90% of patients [1] . ohno et al. in 1982 were among the first researchers to describe prospectively the ocular manifestations of kd patients, by using slit-lamp biomicroscopy, ophthalmoscopy, determination of visual acuity and tonometry whenever possible and follow them up frequently. in an analysis of 18 children, they found bilateral conjunctival injection in 16 (89%) patients, superficial punctate keratitis in 4/18 children (22%), vitreous opacities in 2/17 (12%), papilledema in 2/18 (11%), and subconjunctival hemorrhage in 1/18 (6%). except for subconjunctival hemorrhage, these symptoms were also bilateral. in a more recent publication of 115 kd cases from brazil, alves et al. described the presence of ocular complications in 13.2% of patients, being the most frequent complication anterior uveitis in 13, papilledema in one, and conjunctival hemorrhage in one, being this unilateral as well [2] . in 2007, al-abbadi et al. [3] performed cytopathological tests by means of pap smear of the conjunctiva of patients with kawasaki disease in the acute stage, and after treatment with ivig. they found that in the acute stage of the disease there is a predominantly neutrophilic inflammatory infiltrate, which rapidly changes to mononuclear and resolves in the convalescent stage, and that similar changes occur at the peripheral blood level, which correlates with the histological changes. the presence of anterior uveitis in kd can manifest in up to 25 to 50% of patients, is usually self-limited, and has even been proposed as an additional diagnostic tool for early disease recognition and its timely treatment [4, 5, 6] . retinal ischemia may occur as vasculitis progresses; some authors suggest prompt evaluation by an ophthalmologist if ocular complications are suspected [6] . gao et al. in 2018 reported a case of a girl with incomplete kd and reduced eye volume, cataracts, retinal detachment, choroid, and chorioretinal folds. besides ivig, she was treated with eye steroids and had total recovery within one month [7] . more recently, suganuma et al. described a seven-year-old boy who developed retinal vasculitis with impairment of visual acuity, and also refer to the only three reports in the literature with long-term visual impairment due to kd [8] . in our patient, despite the significant conjunctival affection, anterior uveitis was ruled out by ophthalmology, and this is consistent with previous reports in the literature that severe ocular complications can occur during kd in the absence of uveitis. expectant management was given, without the need to use any other treatment than ivig, and no topical steroids were used. in the vast majority of the literature, various complications of kd are described at the ocular level, both in the anterior and posterior segment, and unilateral subconjunctival hemorrhages have been described, but to the best of our knowledge, our patient represents the first case report in which bilateral subconjunctival hemorrhages manifest as a complication of kd, at least in latin america. kd has well-defined clinical criteria, but since it is a systemic disease, unusual manifestations can occur also. the real incidence of ocular complications and in particular subconjunctival hemorrhages among children with kd is unknown, as most descriptions in the literature are single case reports, small case series, or retrospective studies. prospective multicenter studies focusing on the ocular involvement and complications of children with kd are needed, particularly in latin america where there is a paucity of information on this disease. human subjects: consent was obtained by all participants in this study. 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. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. ocular manifestations of kawasaki's disease (mucocutaneous lymph node syndrome) prospective study of kawasaki disease complications: review of 115 cases conjunctival changes in children with kawasaki disease: cytopathologic characterization conjunctival biopsy in patients with kawasaki disease usefulness of anterior uveitis as an additional tool for diagnosing incomplete kawasaki disease uveitis as an important ocular sign to help early diagnosis in kawasaki disease rare ocular manifestations in an 11-year-old girl with incomplete kawasaki disease: a case report a case of kawasaki disease complicated with retinal vasculitis key: cord-315001-1ui27pkc authors: peterson, nicholas; sagdeo, kaustubh; tyungu, donna; harper, cristin; mihaylo, kyle; pollak-christian, elza title: discovering associations: kawasaki disease and covid-19 date: 2020-09-28 journal: case rep pediatr doi: 10.1155/2020/8880242 sha: doc_id: 315001 cord_uid: 1ui27pkc the covid-19 pandemic has resulted in over 3.6 million confirmed cases and over 254,000 deaths worldwide. it has been theorized that children who are asymptomatic or who do not display significant respiratory symptoms are potential vectors for community transmission of the sars-cov-2 virus. this is incompletely understood due to the current lack of widespread testing in the pediatric population. we describe a case of a 2-year-old female who presented with symptoms of prolonged fever, conjunctivitis, extremity edema, rash, dry/cracked lips, fussiness and fatigue, and a notable absence of respiratory symptoms. she was diagnosed with and treated for kawasaki disease. due to her prolonged fever, she was tested for covid-19 which was positive; however, she did not develop respiratory symptoms during her illness. at the time of manuscript submission, this is the second case report to our knowledge showing an association between kawasaki disease and sars-cov-2 virus, both of which are poorly understood diseases in the pediatric population. this case highlights the value of testing pediatric patients for covid-19 who present with fever in the absence of other symptoms to improve epidemiologic measures during the ongoing pandemic, and it also adds to a foundation of cases for future research on the presence of a link between kawasaki disease and covid-19. e coronavirus disease of 2019 (covid-19) pandemic has resulted in over 3.6 million confirmed cases and over 254,000 deaths [1] . studies have shown that pediatric patients represent a small percentage of confirmed cases [2] . at the time of the writing of this manuscript, it is theorized that the pediatric population may play a role in community transmission of the sars-cov-2 virus [3] . we present a case showing an association between kawasaki disease and the sars-cov-2 virus. is case highlights the value of testing patients for covid-19 during evaluation for kawasaki disease (kd). a previously healthy and fully immunized 2-year-old female presented to the emergency room for prolonged fever, conjunctival erythema, hand swelling, rash, dry/cracked lips, fussiness, and fatigue. at symptom onset, she developed a low-grade fever and fatigue. on days 4-5 of fever, she developed mild bilateral hand swelling, bilateral nonexudative conjunctivitis, dry/cracked lips, and a scant, maculopapular rash on her distal upper and lower extremities. on day nine, she developed the classic "strawberry tongue" papillitis. she neither developed any significant upper or lower respiratory symptoms nor any noticeable lymphadenopathy. roughout her illness, she had no known ill or febrile contacts, although she continued to attend daycare until three days before fever onset. e patient's father had just completed a two-week selfisolation period after returning home from south korea. he had not exhibited fever or any other symptoms of illness. e patient's mother had been working in a respiratory clinic during the covid-19 pandemic, where patients presented for covid-19 testing if they exhibited concerning symptoms; she reported wearing proper personal protective equipment (ppe) during all patient encounters at her workplace. her last shift occurred two days prior to the patient's admission. on day ten of fever, the patient presented to a local emergency department. her laboratory testing showed a normal white blood cell count (wbc), normocytic anemia (hemoglobin 9.4 mg/dl), thrombocytosis (498,000 cells/mm 3 ), elevated inflammatory markers (esr 58 mm/hr, crp 89.9 mg/l), hypoalbuminemia (2.9 g/dl), elevated alt (64 u/l), and mild pyuria on urinalysis (5-10 wbc/hpf). rapid group a streptococcal testing was negative, and a one-view chest radiograph showed no significant abnormalities. she was subsequently transferred to our tertiary children's hospital for direct admission for suspected kd. before the patient's arrival, the decision was made by the pediatric hospitalist and pediatric infectious disease attending to send covid-19 pcr testing on arrival. on admission, she was afebrile and with normal vital signs for age, and examination was notable for mild bilateral conjunctivitis, dry lips, mildly swollen hands and feet, and a healing scant papular rash on all extremities. kawasaki disease was diagnosed when the patient met four out of five clinical criteria (bilateral nonexudative conjunctivitis, erythematous oral mucosal changes, peripheral extremity swelling, and generalized rash noted on extremities) in the setting of her prolonged fever. an echocardiogram was normal without evidence of coronary artery dilatation or decreased cardiac function. she was given a single dose of 2 g/kg intravenous immunoglobulin (ivig) and started on medium-dose acetylsalicylic acid (asa, 44 mg/kg/day) per current recommendations [4] . covid-19 pcr test result was positive within ten hours of the patient's admission. infection prevention and control and the transfer hospital were immediately notified of the result. e patient's mother was instructed to notify all of the patient's known contacts over the past two weeks so that they could self-isolate and monitor for symptoms. e patient did not develop any respiratory symptoms during admission and was discharged after a 24-hour resolution of fever. she was transitioned to low-dose asa (∼5.5 mg/kg daily, for ease of dosing) with plans to follow-up with pediatric cardiology for repeat echocardiogram two weeks after discharge. her family was instructed to quarantine at home for fourteen days from her positive test date. written informed consent to publish the patient's case was obtained from her parents prior to discharge. human coronaviruses (hcovs) are ubiquitous and are thought to cause the "common cold" in children with mild symptoms of the upper respiratory tract [5] . hcovs are also capable of acute severe respiratory illness outbreaks predominantly affecting the adult population, such as the severe acute respiratory syndrome coronavirus (sars-cov), the middle east respiratory syndrome coronavirus (mers-cov), and the current covid-19 pandemic caused by the sars-cov-2 virus. similar to the prior sars and mers outbreaks, sars-cov-2 virus causes fewer and less severe symptoms in otherwise healthy children. pediatric cases are associated with a much lower mortality rate than adults [2, 3, 6] . children have the same likelihood as adults to become infected with covid-19, but the majority of pediatric cases are asymptomatic or show a relatively mild course with a good prognosis [2, 6] . ere is prior published evidence such as winter-spring prevalence in regions with nontemperate climates that suggest that kd may be triggered by respiratory viral infections [7] . prior large cohort studies have found that up to 42% of children with kd have a positive respiratory viral pcr [5, 7, 8] . ese studies also found that hcovs are associated with up to 7.1% of kd cases [5] . is is comparable to studies that also showed a 7% positive rate for hcovs in a random cohort of asymptomatic children [8] . hence, the evidence for hcov as a causative trigger for kd is inconclusive. e first published case of kd and covid-19 infection reported a 6-month-old child with five days of fever and typical clinical findings meeting criteria for classic kd [9] . due to fever, nasal congestion, and a chest radiograph finding of a faint opacity in the left lung, the patient was tested for covid-19. she was treated with ivig and asa and discharged home. her covid-19 test resulted positive after she was diagnosed and treated for kd. in our case, apart from having a prolonged fever, the patient did not display any other symptoms typical for covid-19. covid-19 testing resulted early in the course of admission but did not alter the management of the patient. her positive covid-19 status did allow for increased vigilance in infection control measures during her admission and contact tracing in order to reduce the spread of covid-19. is patient's presentation emphasizes the need for more widespread testing. it is notable that this patient would not have screened for covid-19 testing according to our hospital's initial testing guidelines, and may otherwise have never been tested for covid-19 given her lack of respiratory symptoms, and the need to test selectively. given that covid-19 remains a disease for which there is currently no vaccine or proven cure, widespread testing and aggressive contact tracing are likely to remain paramount in controlling future outbreaks. we report a case showing a link between kawasaki disease and the sars-cov-2 virus. is case highlights the value of testing patients for covid-19 during evaluation for possible kawasaki disease. at the time of this manuscript submission, it is unclear whether or not covid-19 triggers or alters kawasaki disease but we have shown that discovery can provide knowledge to improve infection control 2 case reports in pediatrics practices. as clinical practice becomes more targeted regarding whom to test, healthcare providers should be aware of this association. abbreviations mg: milligrams g: grams dl: geciliter mm: millimeter u: units l: liter hpf: high-power field esr: erythrocyte sedimentation rate crp: c-reactive protein alt: alanine aminotransferase. no data were used in the manuscript. all authors have no financial relationships relevant to this article to disclose. e authors have no conflicts of interest to disclose. world health organization covid-19 in children: initial characterization of the pediatric disease 2019 in children-united states kawasaki disease concurrent respiratory viruses and kawasaki disease coronavirus infections in children including covid-19 viral infections associated with kawasaki disease human coronavirus in young children hospitalized for acute respiratory illness and asymptomatic controls covid-19 and kawasaki disease: novel virus and novel case no funding was secured for this study. key: cord-309317-cgs0sui7 authors: galeotti, caroline; bayry, jagadeesh title: autoimmune and inflammatory diseases following covid-19 date: 2020-06-04 journal: nat rev rheumatol doi: 10.1038/s41584-020-0448-7 sha: doc_id: 309317 cord_uid: cgs0sui7 emerging reports show that severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection precedes the appearance of various autoimmune and autoinflammatory diseases, including paediatric inflammatory multisystemic syndrome (pims) or multisystem inflammatory syndrome in children (mis-c), thus adding to the growing mystery of this virus and raising questions about the nature of its link with autoimmune and autoinflammatory sequelae. several emerging reports show that coronavirus disease 2019 (covid-19), a pandemic respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), could lead to autoimmune and autoinflammatory diseases, such as paedi atric inflammatory multisystemic syndrome (pims; which includes kawasaki-like disease, kawasaki disease shock syndrome, toxic shock syndrome, myocarditis and macrophage activation syndrome) in children [1] [2] [3] [4] [5] [6] . in general, compared with adults, children are least affected by covid-19 and have mild clinical symptoms. however, as reported by verdoni et al. 1 and others 2-6 , a sudden spike in pims (or multisystem inflammatory syndrome in children (mis-c), as it is also known) has left clinicians and the scientific community with several questions about how and why it follows sars-cov-2 infection in certain children. infectious diseases have long been considered as one of the triggers for autoimmune and autoinflammatory diseases, mainly via molecular mimicry. a number of infectious agents have been implicated as the main trigger for the development of kawasaki disease 7 , an acute vasculitis of unknown pathogenesis that occurs mainly in children <5 years old, and sars-cov-2 is now added to the list. the european centre for disease prevention and control reported a total of 224 cases of pims across europe as of 12 may 2020 (ref. 5 ). a team from bergamo, italy, described study of 35 patients across twelve french and one swiss medical centre 4 , revealed that in addition to gastrointestinal symptoms, skin rashes, cervical lymphadenopathy, cheilitis and high levels of inflammatory markers, myocardial involvement was common 3, 4 . many patients presented with an incomplete form of kawasaki disease. in the usa, the new york city health department on 4 may 2020 reported that 15 children aged 2-15 years had presented with symptoms of mis-c, including persistent fever and increased levels of inflammatory markers, and many also had rash, abdominal pain, vomiting or diarrhea; ten of the 15 child ren were positive for sars-cov-2 infection 6 . by 12 may 2020, the number of cases of suspected mis-c had risen to 102 (ref. 6 ). all these reports indicate that the symptoms of covid-19-associated pims overlap with kawasaki disease, but affected patients also present with symptoms not commonly associated with kawasaki disease. therefore, it is critical to make the fine distinction between classical kawasaki disease and kawasaki disease associated with covid-19 (kd-covid-19). italian paediatricians noticed that, compared with classical kawasaki disease, patients with kd-covid-19 were older and had gastrointestinal and meningeal signs; they also had leukopenia with marked lymphopenia, thrombocytopenia, increased ferritin and markers of myocarditis 1 . other reports also recorded a high incidence of myocarditis and cardiac involvement in kd-covid-19 (refs 2-4 ). the increased incidence of myocarditis highlights that patients with kd-covid-19 are more severely ill and are often hospitalized in intensive care. future a 30-fold increase in the incidence of kawasaki disease and reported ten patients with kawasaki-like disease, eight of whom were positive for igg or igm against sars-cov-2 (ref. 1 ). in london, uk, eight children reportedly had hyperinflammatory shock with features simi lar to atypical kawasaki disease, kawasaki disease shock syndrome or toxic shock syndrome; all eight were positive for sars-cov-2 antibodies 2 . in a report issued on 14 may 2020, the french national public health agency documented 125 cases of atypical pims occurring between 1 march and 12 may 2020 (ref. investigations should aim to dissect the underlying molecular mechanisms that lead to pims following exposure to sars-cov-2 (box 1). the clinical history of patients with pims suggests that many had previously experienced mild symptoms of covid-19 or had contact with covid-19-positive family members. in the french study 3 , the median period between covid-19 symptoms and onset of pims signs was 42 days (range 18-79 days). accordingly, most of the patients with pims were positive for igm or igg antibodies to sars-cov-2 when the autoinflammatory symptoms appeared. the presence of igg, which typically appears ~2 weeks after primary infection, suggests a delayed onset of pims following primary infection. however, nasopharyngeal and oropharyngeal swabs from several patients with pims were positive for sars-cov-2 (refs 1-6 ), indicating that pims might even occur during the late phase of covid-19. in adults, the spectrum of complications following covid-19 is broader than in children and includes autoimmune diseases but their incidence is too rare. idiopathic thrombocytopenic purpura, guillain-barré syndrome and autoimmune haemolytic anaemia have been recorded in one, five and seven patients respectively, 4-13 days following onset of covid-19 symptoms [8] [9] [10] . thus, in contrast to pims, autoimmune symptoms in adult patients appeared during the early, active phase of covid-19. although a causal link between sars-cov-2 and the appearance of autoimmune and autoinflammatory diseases has not yet been firmly established, it is suggested by the temporal association with the current covid-19 pandemic and the history of exposure of affected patients to sars-cov-2. we can envi sage two possibilities. first, sars-cov-2 could act as a direct trigger of autoimmune and/or autoinflammatory conditions either by molecular mimicry or other, unknown mechanisms. a fine analysis of homology between various antigens of sars-cov-2 and self-antigens, by use of in silico approaches and validation in experimental models, should be considered in order to confirm this hypothesis. a second possibility is that inflammation and dysregulated immune responses following sars-cov-2 infection might prompt other environmental insults to cause the observed pathologies in predisposed individuals. as mentioned, several pathogens have been proposed as triggers for kawasaki disease and other autoimmune diseases in the past 7 . in fact, although the french 3 and italian 1 studies suggest that patients are negative for common viruses that trigger kawasaki disease, data from other european countries reveal appearance of pims, with clinical and biochemical features distinct from that of classical kawasaki disease and affecting children up to 17 years old. although only a small proportion of sars-cov-2-infected children subsequently develop symptoms of pims (or mis-c), most of them require intense clinical management because of the severity of the disease. as fundamental aspects of pims remain largely unknown, future investigations will require close interaction among various disciplines including paediatrics, internal medicine, rheumatology, immunology, genetics, infectiology, cardiology and epidemiology. the reports from the uk and france suggest that pims is more frequent in patients of afro-caribbean descent 2,3 , and cases of kd-covid-19 have not been reported in asian countries (where the incidence of kawasaki disease is typically the highest), which suggests genetic predisposition could be a factor in the development of kd-covid-19. various genetic factors have been identified that predispose children for kawasaki disease 7 . investigation of predisposing factors, for example, in genome-wide association studies, will provide mechanistic insights on the incidence of pims. another area that requires attention is whether the appearance of pims or autoimmune responses is associated with a particular variant of sars-cov-2 (box 1). as autoinflammatory signs are sequelae to sars-cov-2 infection and mostly appear several weeks post-infection, highly sensitive and specific serological tests are critical for establishing a causal link between covid-19 and pims. current reports indicate that the spectra of autoimmune and autoinflammatory conditions in sars-cov-2-infected populations are mostly responsive to intravenous immunoglobulin (ivig) therapy 7 . early diagnosis of covid-19-linked autoimmune and autoinflammatory diseases, and prompt initiation of therapy, is crucial for successful recovery and preventing end-organ damage and fatality. however, compared with classic kawasaki disease, resistance to ivig therapy was more common in kd-covid-19 (refs 1,3 ) and needed adjunct steroids. to resolve the severe inflammatory state associated with pims, three children in the french-swiss study 4 were successfully treated with anakinra, an il-1 receptor antagonist (d. bonnet, personal communication). patients with pims also have elevated il-6 concentrations compared with normal controls 1,3,4 , similar to what is seen in severely ill adults with covid-19. il-6 has been implicated in the pathogenesis of myocarditis. importantly, il-6-targeted immunotherapies produced favourable responses in adults severely ill with covid-19. therefore, inhibition of il-6 signalling in pims by blocking il-6 receptor by use of either tocilizumab (a humanized monoclonal antibody) or sarilumab (a fully human monoclonal antibody) could also be considered in patients with pims. the current covid-19 pandemic has given rise to many surprises, including the www.nature.com/nrrheum an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study hyperinflammatory shock in children during covid-19 pandemic outbreak of kawasaki disease in children during covid-19 pandemic: a prospective observational acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic european centre for disease prevention and control. paediatric inflammatory multisystem syndrome and sars-cov-2 infection in children the centers for disease control and prevention (cdc) health alert network. multisystem inflammatory syndrome in children (mis-c) associated with coronavirus disease predisposing factors, pathogenesis and therapeutic intervention of kawasaki disease immune thrombocytopenic purpura in a patient with covid-19 guillain-barré syndrome associated with sars-cov-2 autoimmune haemolytic anaemia associated with covid-19 infection j.b. acknowledges support from the covid emergency fund from université de paris. the authors declare no competing interests. key: cord-000627-gvzs9vxr authors: yang, ya-ling; chang, wei-pin; hsu, yu-wen; chen, wei-chiao; yu, hong-ren; liang, chi-di; tsai, yao-ting; huang, ying-hsien; yang, kuender d.; kuo, ho-chang; chang, wei-chiao title: lack of association between clec5a gene single-nucleotide polymorphisms and kawasaki disease in taiwanese children date: 2011-12-22 journal: j biomed biotechnol doi: 10.1155/2012/398628 sha: doc_id: 627 cord_uid: gvzs9vxr background. kawasaki disease is characterized by systemic vasculitis of unknown etiology. previous genetic studies have identified certain candidate genes associated with susceptibility to kd and coronary artery lesions. host innate immune response factors are involved in modulating the disease outcome. the aim of this study was to investigate clec5a (c-type lectin domain family 5) genetic polymorphisms with regards to the susceptibility and outcome of kd. methods. a total of 1045 subjects (381 kd patients and 664 controls) were enrolled to identify 4 tagging single-nucleotide polymorphisms (tsnps) of clec5a (rs1285968, rs11770855, rs1285935, rs1285933) by using the taqman allelic discrimination assay. the hardy-weinberg equilibrium was assessed in cases and controls, and genetic effects were evaluated by the chi-square test. results. no significant associations were noted between the genotypes and allele frequency of the 4 clec5a tsnps between controls and patients. in the patients, polymorphisms of clec5a showed no significant association with coronary artery lesion formation and intravenous immunoglobulin treatment response. conclusions. this study showed for the first time that polymorphisms of clec5a are not associated with susceptibility to kd, coronary artery lesion formation, and intravenous immunoglobulin treatment response in a taiwanese population. kawasaki disease (kd) is characterized by acute, febrile, and systemic vasculitis and was first described by kawasaki et al. in 1974 [1] . in developed countries, kd is the leading cause of acquired heart diseases in children [2, 3] . kd occurs worldwide and particularly in japan, korea, and taiwan and mainly affects children less than 5 years of age [4] [5] [6] . the most serious complication of kd is the occurrence of coronary artery lesions (cals) [7, 8] . the prevalence of kd in children younger than 5 years is the highest in japan, followed by korea and taiwan, and lowest in europe. previous studies have either failed to identify causative pathogens for kd or reported discrepant results [9] [10] [11] . therefore, it is possible that a genetic background plays an important role in the pathogenesis of kd. clec5a (c-type lectin domain family 5, member a; also known as myeloid dap12-associating lectin (mdl-1)) journal of biomedicine and biotechnology contains a c-type lectin-like fold similar to the naturalkiller t-cell c-type lectin domains and is associated with a 12-kda dnax-activating protein (dap12) on myeloid cells [12] [13] [14] . signaling via this complex constitutes a significant activation pathway in myeloid cells and plays an important role in immune defense. recently, it has been demonstrated that clec5a acts as a signaling receptor for proinflammatory cytokine release, and that blockade of clec5a-mediated signaling attenuates the production of proinflammatory cytokines by macrophages infected with dengue virus [14] . in contrast, it has been demonstrated that mdl-1 stimulation induces a significant amount of rantes and macrophage-derived chemokine (mdc) production in cooperation with signaling through tlr in mouse myeloid cells [15] . furthermore, there is ample evidence that activation of peripheral blood monocytes/macrophages [16] [17] [18] , proinflammatory cytokines [16] , and the rantes gene play a central role during acute kd [19, 20] . a persistent or increased expression of chemokine genes in the convalescent phase in patients is associated with coronary artery lesions [17, 19] . in addition, infiltration by the cells is notable in affected tissues in autopsy cases and in skin biopsy specimens from kd patients [21] . however, no clec5a genetic association with kd has previously been reported. to gain further understanding of the genetic role of clec5a in the pathogenesis of kd, the aim of our study was to determine if any clec5a snps are associated with susceptibility to kd, cal formation, or ivig treatment response in taiwanese children. all study cases were children enrolled from chang gung memorial hospital, kaohsiung medical center, between 2001 and 2009, who fulfilled the diagnostic criteria for kd. all patients were treated with ivig (2 g/kg) and aspirin as per our previous studies [7, 8, 18] . this study was approved by the institutional review board of chang gung memorial hospital. blood samples were collected after informed consent was obtained from parents or guardians. cal formation was defined as the internal diameter of the coronary artery measuring at least 3 mm (4 mm if the subject was over the age of 5 years) or the internal diameter of a segment at least 1.5 times that of an adjacent segment, as observed in echocardiography [8, 22] . ivig responsiveness was defined as defervescence within 48 h after the completion of ivig treatment and no recurrence of fever (temperature > 38 • c) for at least 7 days after ivig with marked improvement or normalization of inflammatory signs [7, 8] . blood cells were subjected to dna extraction by treating them first with 0.5% sds lysis buffer and then protease k (1 mg/ml) for digestion of nuclear protein for 4 h at 60 • c. total dna was harvested by using a gentra extraction kit followed by 70% alcohol precipitation as described in our previous report [23] . susceptibility of kd. a total of 381 kd patients and 664 controls were included in this study ( table 1 ). the distribution of clec5a genotypes was in accordance with the hardy-weinberg equilibrium for both cases and controls (table 2) . however, none of the tsnps was significantly associated with the genotype or allele frequency of the controls or kd patients under 3 genetic models (dominant, recessive, or allelic models) ( table 2) . in this study, 37 patients (9.9%) had cal formation and 49 patients (13.1%) had resistance to the initial ivig treatment (table 1) . however, no tsnps were significantly associated with genotype or allele frequency in the kd patients with or without cal formation (table 3) . additionally, the clec5a polymorphisms tested in this study failed to show any significant associations with genotype or allele frequency in the kd patients who showed a response to ivig treatment (table 4 ). table 1 ), cal formation (supplemental table 2 ) and ivig treatment response (supplemental table 3 ) in the kd patients. however, none was significantly associated with the phenotype. the c-type lectin-like super domain (ctld) family has diverse functions, and in particular, is important in innate immunity including nature killer (nk) function or pathogen recognition [25] . clec5a belongs to the group v "nk cell receptors" family, and mdl-1 expression is upregulated in activated myeloid cells [26] and acts as a signaling receptor for proinflammatory cytokine and chemokine release [14] . even though a number of reports have demonstrated that kd involves activation of a wide array of immunological elements such as t cells and macrophages [16] [17] [18] 27] , with the subsequent release of several cytokines [28] , only a few reports have addressed the role of lectin in the pathogenesis of kd. several genetic associations with susceptibility to kd and cal formation have been reported, but the results are inconsistent [29] [30] [31] [32] . previous genetic association studies have indicated that the intronic snp (rs28493229) of itpkc, 1,4,5-trisphosphate 3-kinase c, reduces gene expression by altering splicing efficiency, and the c allele contributes to immune hyperreactivity in kd patients [29] . recently, it has been demonstrated that rs28493229 is associated with susceptibility to kd and cal formation [24, 29] . itpkc is able to regulate the immune system via calcium-dependent nfat pathways [29] . similarly, previous studies have indicated that c-type lectin receptors (clrs) are critical in the activation of the syk-mediated nfat signaling pathway [33] . in addition, clec5a has been shown to play a key role in host defense and to be involved in dengue virusmediated disease [14] . this finding suggests clec5a may be a potential target protein that involves calcium-dependent immune regulation and contributes to the development of coronary artery lesions. however, we did not find evidence to support a genetic role of clec5a in the pathogenesis of kd. since we picked tagging snps from the hapmap database, only the tagging snps with a minor allele frequency of more than 10% were selected. although our tsnp could capture majority of the underlying genetic variances with maf > 10% across the clec5a gene, the rare causal genetic polymorphisms in clec5a may not have been detected in this study. therefore, we cannot rule out or exclude rare causal genetic polymorphisms in clec5a. in addition, there are, at least, seventeen groups of clrs in vertebrates. indeed, it has been reported that mannose-binding lectin gene polymorphisms are associated with susceptibility to kd [34] and cal formation [35] . thus, large-scale dna sequencing to clr family is needed to better understand kd. in conclusion, this study showed for the first time that tsnps of clec5a are not associated with susceptibility to kd, cal formation, and ivig treatment response in a taiwanese population. a new infantile acute febrile mucocutaneous lymph node syndrome (mlns) prevailing in japan kawasaki disease: infection, immunity and genetics kawasaki syndrome kawasaki disease in korea epidemiologic features of kawasaki disease in taiwan increasing incidence of kawasaki disease in japan: nationwide survey association of lower eosinophil-related t helper 2 (th2) cytokines with coronary artery lesions in kawasaki disease serum albumin level predicts initial intravenous immunoglobulin treatment failure in kawasaki disease association between a novel human coronavirus and kawasaki disease lack of association between infection with a novel human coronavirus (hcov), hcov-nh, and kawasaki disease in taiwan lack of association between new haven coronavirus and kawasaki disease myeloid dap12-associating lectin (mdl)-1 is a cell surface receptor involved in the activation of myeloid cells clec5a 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and gene-environment interactions on ige production in prenatal stage itpkc single nucleotide polymorphism associated with the kawasaki disease in a taiwanese population how c-type lectins detect pathogens the c-type lectin-like domain superfamily unique activation status of peripheral blood mononuclear cells at acute phase of kawasaki disease advances in kawasaki disease itpkc functional polymorphism associated with kawasaki disease susceptibility and formation of coronary artery aneurysms itpkc gene snp rs28493229 and kawasaki disease in taiwanese children clinical implication of the c allele of the itpkc gene snp rs28493229 in kawasaki disease: association with disease susceptibility and bcg scar reactivation transforming growth factor-β signaling pathway in patients with kawasaki disease the syk tyrosine kinase: a crucial player in diverse biological functions association of mannose-binding lectin gene polymorphisms with kawasaki disease in the japanese association of mannose-binding lectin genotype with cardiovascular abnormalities in kawasaki disease this study was partly supported by grants from the national science council, taiwan the authors declare that no competing interests exist. key: cord-007277-86lynlxn authors: kenneth, mcintosh title: coronaviruses in the limelight date: 2005-02-15 journal: j infect dis doi: 10.1086/428510 sha: doc_id: 7277 cord_uid: 86lynlxn nan for ∼35 years after their first description by tyrrell and byneo in 1965 [1] , the field of human coronaviruses (hcovs) was pretty dull. there were classic early descriptions of their respiratory pathogenicity in volunteer studies [2, 3] , and there were seroepidemiologic studies of the 2 most easily studied strains, hcov-229e and hcov-oc43 [4] [5] [6] . efforts to implicate hcovs in diseases of the gastrointestinal tract were largely unsuccessful, with the possible exception of a postulated role in necrotizing enterocolitis of newborns [7] . during this time, the fields of animal covs and of the molecular biology of covs were, in contrast, buzzing. covs were discovered in large numbers and were implicated in a rich variety of animal diseases in multiple species. diseases as widely varying as progressive peritonitis, nephritis, acute and chronic hepatitis, and subacute encephalitis were described, along with the more traditional respiratory and gastrointestinal syndromes, and pathogenesis was explained through broad mixtures of viral cytopathogenicity, immunologic damage, and genetic susceptibilities. the cov genome proved to be the largest of all of the rna viruses and to have a unique strategy of replication, with transcription and protein production occurring through a nested set of mrna molecules [8] . then, in 2003, the appearance of severe acute respiratory syndrome (sars) suddenly brought the field of hcovs back into the limelight. it seemed clear that this disease, unique in its clinical spectrum, resulted from the movement of an animal cov across species lines, and it seemed possible that the virus spread in the human population through a process of adaptation by deletion and mutation [9, 10] . the rapid recognition of the etiology of sars depended heavily on genomic sequence data assembled from the study of multiple animal covs, allowing the sars agent to be quickly identified and classified and leading to the development of detection methods that would guide the containment of the epidemic. it is in this context that the article and brief report by esper et al. that appear in this issue of the journal of infectious diseases should be read [11, 12] . in the first of these papers, esper et al. use the accumulated knowledge of the coronaviral genomic sequence to search for new hcovs in children with respiratory disease [11] . the authors' discovery of a previously undescribed hcov was accomplished through the design of a polymerase chain reaction assay that was based on the common region of the polymerase gene. this method was logical, intelligent, and highly original-and a new vi-rus, designated "new haven coronavirus" (hcov-nh), did appear. in fact, esper et al.'s finding was not surprising. the reason for this is not that a very similar hcov was being described by 2 independent groups of virologists in the netherlands [13, 14] at the same time (that virus was not known when esper et al. started their work), but rather that, in some of the earliest work on covs during the 1960s, viruses were reported that were then forgotten-viruses that came from adults with respiratory illness, that grew only in human embryonic tracheal organ culture, that caused illness in volunteers, and that were not, or were only distantly, antigenically related to the 2 hcov species that were subsequently the best studied, hcov-229e and hcov-oc43. one of these forgotten viruses, b814, was the first hcov to be described [1] . the others-hcov-oc16, hcov-oc37, and hcov-oc48-were 3 of the 6 strains recovered from organ culture in my laboratory [15] . all 4 of these strains produced colds in volunteers [2, 3] , but none grew in tissue culture, and none could be adapted to grow in animal models. thus, the subsequent neglect of these potentially important viruses stemmed from the fact that, essentially, no methods were available to study them at the time. esper et al.'s findings on the clinical impact of hcov-nh infection, although limited, are consistent both with those from europe on the novel hcov reported in the netherlands and with the available information on hcov-229e and hcov-oc43 infection in children hospitalized with acute respiratory disease [5, 13, 14] . however, the details from esper et al.'s study-the seasonal distribution, the percentage of positive samples, the associated respiratory syndromes, and the numbers of infected children at various ages, for example-were heavily influenced by both the particular population that was investigated and the clinical setting, so it is essentially impossible to draw conclusions on the epidemiology, pathogenicity, and relative importance of hcov-nh in relation to other respiratory viruses. on the other hand, it seems to be likely that this is not the last chapter in the story of respiratory hcovs and that additional studies will clarify the picture. moreover, it seems quite possible that other strains will be found, by use of similar methods. in contrast, the findings reported in esper et al.'s brief report were, to this reader, quite surprising [12] . esper et al. have shown a temporal association with quite strong statistical significance between infection with hcov-nh and kawasaki disease, establishing this association by means of a case-control study in hospitalized children. until there are corroborating studies, it would seem wise to retain a healthy level of skepticism with regard to the significance of this association. nevertheless, the findings are extremely interesting and set off in me a series of thoughts as to what might be going on. first, the skepticism. the linking of an agent to kawasaki disease follows a long trail of previously failed or still-struggling attempts to identify the etiologic agent of this important syndrome, ranging from an unidentified retrovirus [16] , to parvovirus b19 [17] , to epstein-barr virus [18] , to chlamydia pneumoniae [19] , and to toxinproducing staphylococcus aureus or streptococcus pyogenes [20] , with a scattering of others along the way. although the association shown by esper et al. was statistically compelling, previous initial find-ings were equally so (the first descriptions of both parvovirus b19 and the toxin-producing bacteria included similarly significant associations) and have been difficult to confirm. there are, however, some tantalizing facts about both covs and kawasaki disease that might allow for cautious optimism with regard to esper et al.'s reported association. first, there was early epidemiologic evidence [21] , subsequently confirmed [22] , that a respiratory syndrome preceded the onset of kawasaki disease. (incidentally, the interval between the onset of the respiratory syndrome and the onset of kawasaki disease appeared to be ∼2 weeks [21] , which seems a long time for the shedding of a respiratory hcov, although pertinent data on infants are lacking [23] [24] [25] .) second, kawasaki disease is frequently seasonal, with peaks during the winter and spring; its seasonality is roughly similar to that of infection with respiratory hcovs [5, 6] . third, and more recently, there has been evidence from molecular immunopathologic studies by rowley et al. indicating that, during kawasaki disease, some external agent triggers a powerful iga response in the respiratory tract as well as in other organs (including medium and large muscular arteries), suggesting that the target of the extensive immunologic reaction during kawasaki disease is a specific microbe (rather than an nonspecific stimulus, such as a superantigen) and that this microbe enters the body through the respiratory tract [26] [27] [28] . if this is, in fact, the case, then a respiratory hcov might be the inciting agent. fourth, the sars story reminds us of what veterinarian virologists have known for many years: that covs, with their huge genome, are capable of enormously varied pathogenicity, causing diseases that affect multiple organs through a variety of pathogenetic mechanisms. also, sars-cov crossed species lines and was genetically quite distant from the 3 known cov groups, whereas hcov-nh (along with its companion novel virus reported in the netherlands) appears to be a member of the group 1 covs and has other features that make it appear to be closer to hcov-229e and hcov-oc43 in its pathogenicity [13] . if hcov-nh is, in fact, the agent responsible for kawasaki disease and is acting alone, then we have to postulate that it has acquired a pathogenicity that is quite different from that of its close relatives and of other respiratory viruses. clearly, a lot more work needs to be done. because esper et al.'s study of kawasaki disease was epidemiologic, confirmation in broader epidemiologic terms (other places, other times, other detection methods, other populations) is required, as is nonepidemiologic confirmation through the demonstration of an immunologic response to hcov-nh and of its presence in biopsy specimens. if the association is confirmed, then the pathophysiologic mechanism will need to be further worked out. kawasaki disease has a complex pathogenesis and has been the subject of much study by microbiologists, immunologists, rheumatologists, cardiologists, and molecular biologists [29] . much is known about many of the mechanisms of kawasaki disease, and in some way these must be linked to the presumed microbial etiology. a broad question would be: is the pathogenesis of kawasaki disease the product of hcov-nh infection by itself? there are several animal cov diseases that are models of complex pathophysiologic mechanisms-the multiple sclerosis-like disease of mice caused by certain neurogenic strains of mouse hepatitis virus [30] and the complex, immunologically mediated, progressive feline peritonitis caused by the cov of that name [31] , for example. in these diseases, genetics, the immune system, and the complex cov genome all interact. alternatively, might there be another microbial pathogen involved in the pathogenesis of kawasaki disease, such that it is a 2-hit disease requiring both a virus and a toxin? we will watch this field with great interest. cultivation of a novel type of common-cold virus in organ cultures effects of a "new" human respiratory virus in volunteers coronative antibody titres in sera of healthy adults and experimentally infected volunteers virologic studies of acute respiratory disease in young adults. v. coronavirus 229e infections during six years of surveillance seroepidemiologic studies of coronavirus infection in adults and children the tecumseh study of respiratory illness. vi. frequency of and relationship between 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epstein-barr virus infection associated with kawasaki disease-like coronary artery aneurysms demonstration of chlamydia pneumoniae in cardiovascular tissues from children with kawasaki disease toxic shock syndrome toxin-secreting staphylococcus aureus in kawasaki syndrome kawasaki syndrome: description of two outbreaks in the united states investigation of kawasaki syndrome risk factors in colorado effect of specific humoral immunity and some non-specific factors on resistance of volunteers to respiratory coronavirus infection detection of human coronavirus 229e in nasal washings using rna:rna hybridisation the time course of the immune response to experimental coronavirus infection of man iga plasma cell infiltration of proximal respiratory tract, pancreas, kidney, and coronary artery in acute kawasaki disease oligoclonal iga response in the vascular wall in acute kawasaki disease detection of antigen in bronchial epithelium and macrophages in acute kawasaki disease by use of synthetic antibody kawasaki syndrome cutting edge: cd8 t cell-mediated demyelination is ifn-gamma dependent in mice infected with a neurotropic coronavirus natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease key: cord-270035-1e1wzdri authors: cazzaniga, marco; baselli, lucia augusta; cimaz, rolando; guez, sophie suzanne; pinzani, raffaella; dellepiane, rosa maria title: sars-cov-2 infection and kawasaki disease: case report of a hitherto unrecognized association date: 2020-07-03 journal: front pediatr doi: 10.3389/fped.2020.00398 sha: doc_id: 270035 cord_uid: 1e1wzdri coronavirus-associated disease (covid-19) was firstly reported at the end of 2019. generally, covid-19 seems to be a less severe disease in children than in adults. according to the current literature, children account approximately for 2% of diagnosed covid-19 cases. northern italy is one of the geographical areas mainly affected by the ongoing covid-19 pandemic. we describe a pediatric patient diagnosed and treated for atypical/incomplete kawasaki disease (kd) complicated with paralytic ileus, who also resulted positive for sars-cov-2. covid-19 infection is currently the most important health problem worldwide. according to the current literature, children account approximately for 2% of diagnosed covid-19 cases (1) (2) (3) . even if most of medical efforts are aimed to fight this disease, physicians still have to care for other acute and chronic disorders. kawasaki disease is not an exception, and there may be a risk that patients are not recognized early since patients may not seek medical care as usual for fear of getting infected (4) . the association of kawasaki disease and covid-19 infection has to our knowledge been reported only once (5), we report a second case from italy, currently the third most affected country in the world with regard to number of proven sars-cov-2 infections. we report the case of a 6-year-old, full term, previously healthy boy. in march 2020 he was seen by his pediatrician for fever lasting for 3 days, sore throat and asthenia, and antibiotic therapy with amoxicillin + clavulanic acid was prescribed. high fever persisted with vomiting and diarrhea appearing on day 4 and 5. on day 6 from onset of fever, erythematous rash in the back and hands, labial and conjunctival hyperemia appeared, and the child was admitted to a regional hospital. laboratory tests showed white blood cells count of 10.300/mm 3 (neutrophils 88.6%, lymphocytes 7.1%), hb 11.3 g/dl, platelets 1,49,000/mm 3 , elevated liver enzymes (ast 73 u/l, alt 189 u/l, ggt 128 u/l), c-reactive protein 13 mg/dl (nv < 5), fibrinogen (524 mg/dl, nv 165-350), ferritin (612 µg/l, nv 30-400), procalcitonin (5.05 µg/l, nv 0.02-0.06), hypoalbuminemia (2.7 g/dl), and hyponatremia (124 meq/l). the nasopharyngeal respiratory pathogen testing by reverse transcription polymerase chain reaction test (rt-pcr) was positive for rhinovirus and enterovirus, and a chest xray was normal. intravenous antibiotic therapy with cefotaxime and correction of hyponatremia was started. given the covid-19 pandemic period, the child was tested for sars-cov-2 with nasopharyngeal swab, negative in two determinations. as the patient experienced worsening abdominal tension and pain, abdominal ultrasound and ct scan were performed with evidence of fluid in pelvis and right iliac fossa, spleen size at the upper limits, and no air-fluid levels. plain abdominal xray showed gastrectasia and increased gas in the ileal loops. on day 7 of fever, an empirical intravenous antibiotic therapy with piperacillin/tazobactam and metronidazole was started. echocardiogram showed normal coronary arteries, minimal pericardial effusion, and mild mitral insufficiency. we were then contacted as reference center for kawasaki disease (kd) in our pediatric immunology unit: considering the clinical history (fever lasting more than 5 days, erythematous rash, labial, and conjunctival hyperemia) and the result of laboratory tests we confirmed the diagnostic suspicion of atypical/incomplete kd without coronary involvement, and started treatment with high dose intravenous immunoglobulins (ivig) 2 g/kg and high dose acetylsalicylic acid (asa 50 mg/kg/day). after 36 h from the end of the ivig infusion the child was apyretic, but abdominal tension with no bowel movements persisted, and mild respiratory distress with tachypnea and oxygen desaturation (91-92%) appeared. chest x-ray, lung ultrasound, and echocardiogram were performed, showing pulmonary infiltrates at the right base and minimal pericardial effusion. because of the worsening of respiratory and abdominal conditions, he was transferred to our hospital. when admitted, he was tested for sars-cov-2 and the nasopharyngeal aspirate resulted positive. repeated family history revealed that mother and grandmother had been symptomatic for fever, gastroenteritis, and cough in the previous weeks, and that later the father had experienced rhinitis, fever, cough, and ageusia. because of mild respiratory distress, the patient needed low-flow oxygen administration for 3 days. a repeated chest x-ray showed only accentuated bronchovascular markings in bilateral peri-hilar and paracardiac regions. considering the persistence of abdominal pain, no passage of stool or gas for more than 48 h from admission, a new abdominal x-ray without contrast was performed, highlighting ileocolic meteorism with multiple small diffuse air-fluid levels. abdominal pain with distension and lack of bowel movements were compatible with paralytic ileus associated with intestinal vasculopathy in kd. enema and polyethylene glycol (peg) oral therapy resolved the abdominal symptoms, asa 5 mg/kg/die therapy was started after 48 h of apyrexia, and laboratory blood tests showed progressive reduction in inflammation markers and rapid normalization of liver enzymes. in the setting of covid-19 there are several reports of using corticosteroids for acute respiratory disease syndrome (ards), but considering the not severe clinical course and presentation in our patient we did not start steroid therapy. at discharge echocardiogram showed normal coronary arteries, mild mitral insufficiency, and resolution of pericardial effusion. nasopharyngeal swab and aspirate for sars-cov-2 resulted positive, so the family was instructed to keep him in quarantine at home, until repetition of sars-cov-2 test visit and follow-up visit for kd, which are scheduled in the next future. kd is an acute, febrile, self-limited systemic vasculitis of small and medium sized vessels and represents the most common cause of acquired heart disease in children in developed countries (6) . typical or classic kd is characterized by the presence of ≥5 days of fever and ≥4 of the following clinical features: bilateral non-exudative conjunctivitis, erythema of lips and oral mucosa, changes in the extremities, skin rash, and cervical lymphadenopathy with or without coronary artery abnormalities (caa). incomplete kd occurs in patients presenting a typical fever without a sufficient number of main clinical criteria, with or without caa. atypical kd occurs in patients presenting typical fever and signs or symptoms different from the main clinical features of kd (e.g., meningeal inflammation, seizures, facial paralysis, acute abdomen, acute pancreatitis, cholestatic jaundice, arthritis, renal injury, pneumonia, etc.), with or without caa (6, 7) . the cause of kd is still unknown but may be related to the combined effects of infections, immune response, and genetic susceptibility. many studies have reported the role of viral infections in kd as a possible trigger, including enterovirus, rhinovirus, herpesviruses, adenoviruses, influenza, parainfluenza, and coronaviruses (8, 9) . in our case the child had a demonstrated infection by enterovirus, rhinovirus, and sars-cov-2 according to pcr tests. many viral infections may elicit systemic inflammation and consequently vasculitides such as kd, and it is also known that sars-cov-2 infection can activate uncontrolled inflammation which can lead to local and systemic tissue damage (10) . in our patient, more than one pathogen were detected, making it difficult to understand which of the three viral agents had been the trigger. our hospital protocol for kd, based on international guidelines (6, 7), recommends the troponin t and bnp dosage only in case of documented myocarditis and/or pericarditis and/or early aneurysms. since the patient was ivig responder, electrocardiograms did not reveal signs of ischemia and the echocardiograms performed did not show coronary artery abnormalities or depression of the ejection fraction, we did not measure troponin t or bnp. moreover, blood tests performed during admission to our hospital, showed a reduction in crp and normalization of liver enzymes so other investigations would not provide additional information. gastrointestinal involvement is not common in kd; the most common gastrointestinal manifestations include vomiting, diarrhea, abdominal pain, hepatomegaly, paralytic ileus, and hydrops of gallbladder (11, 12) . in many cases of kd with gastrointestinal involvement, the typical signs and symptoms of kd often occur after the intestinal ones (11) (12) (13) , and the delayed appearance of typical symptoms can be a cause of delayed therapy, which in turn can lead to a greater probability of cardiac involvement (13, 14) . in our case however suggestive symptoms for kd began simultaneously with intestinal symptoms. pediatric presentation of sars-cov-2 infection include completely asymptomatic subjects and patients presenting with mild symptoms like fever, cough, sore throat, vomiting, nausea, and diarrhea (15) . indeed, the clinical course and presentation of covid-19 in our patient were not severe, even if he transiently needed respiratory support with low-flow oxygen. considering the mild respiratory presentation, the absence of pathognomonic signs at chest x-ray and the good clinical evolution, we did not start a specific therapy for covid-19. to the best of our knowledge, up to now there is only one other published case of kd with concurrent covid-19, a 6-month-old baby with a complete form of kd (5) . however, cases are being informally reported among pediatricians, and recently patients with severe forms including myocarditis and cytokine storm syndromes have been seen in different countries e.g., italy, france, netherlands, and uk. an alert has been issued (https://mailchi.mp/05cc3497cda5/alert-possiblesars-cov-2-related-inflammatory-syndrome-in-children?e= 2e634f02aa) emphasizing the apparent rise in the number of children presenting with a multisystem inflammatory state requiring intensive care with overlapping features of toxic shock syndrome and atypical kawasaki. interestingly, abdominal pain and gastrointestinal symptoms have been a common feature in these patients, such as in our case. both covid-19 infection and kd are characterized by cytokine release, and both can be treated with anticytokines (anti-il-1 in particular) in severe cases. a cytokine storm syndrome, similar to macrophage activation syndrome, can in fact appear in both conditions (16, 17) . the connection between viral infections and kd, the analogies between the severe end of the two conditions, with myocarditis having been reported as well, opens new perspectives with regard to etiopathogenesis. a registry of kd cases associated with sars-cov-2 infection is currently ongoing in italy, and hopefully results will shed light on this unusual association. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. written informed consent was obtained from next of kin for the publication of any potentially identifiable images or data included in this article. sars-cov-2 infection in children coronavirus disease 2019(covid-19) in italy characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china missed or delayed diagnosis of kawasaki disease during the 2019 novel coronavirus disease (covid-19) pandemic covid-19 and kawasaki disease: novel virus and novel case diagnosis, treatment, and long-term management of kawasaki disease, a scientific statement for health professionals from the american heart kawasaki disease: guidelines of the italian society of pediatrics, part i -definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase viral infections associated with kawasaki disease concurrent respiratory viruses and kawasaki disease covid-19: immunopathology and its implications for therapy the surgical manifestations of the intestinal tract in kawasaki disease gallbladder hydrops associated with kawasaki disease: a case report and literature review intestinal involvement in kawasaki disease gastrointestinal presentation of kawasaki disease: a red flag for severe disease? epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china kawasaki disease complicated with macrophage activation syndrome: a systematic review on the alert for cytokine storm: immunopathology in covid-19 mc wrote the manuscript and designed the topic. rc and rd designed the topic and revised the manuscript. lb revised the manuscript. sg and rp contributed to clinical diagnosis. all authors read and approved the final manuscript and agree to be accountable for the content of the work. 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 cazzaniga, baselli, cimaz, guez, pinzani and dellepiane. 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-277908-d26xzean authors: kuo, ho-chang title: kawasaki-like disease among italian children in the covid-19 era date: 2020-08-18 journal: j pediatr doi: 10.1016/j.jpeds.2020.07.022 sha: doc_id: 277908 cord_uid: d26xzean nan question what thematic issues emerge from adolescent online-health-information searching behavior studies? design systematic review of qualitative studies. setting international. participants adolescents, 13-18 years old. intervention online health-information searching. outcomes theme development related to trusting online health information. main results there were 4 themes identified: information use despite distrust, heuristic reliance, websites more trustworthy compared with social media, action based on level of trust. conclusions adolescents are likely to benefit from healthliteracy-evaluation tools. commentary as one of the most active groups of internet users, adolescents frequently turn to online sources for health information and guidance to support their health and wellbeing. 1 health information technology offers many positives including empowerment, privacy, anonymity, a stigma-free environment, and removal of barriers to accessing health services. 1, 2 numerous studies have demonstrated that adolescents' skills are highly variable with regard to their ability to find, assess, and appraise relevant health information online. 3 normal adolescent development requires youth to develop independence and the ability to formulate abstract thought. consistent with this, it is important that young people develop the ability to discern the relevance and quality of the information they encounter. in their article, freeman et al explore one component of this process-trust, a complex construct, incorporating beliefs, intentions, motivations, emotions, and expectations. they use thematic synthesis methodology to extract and combine similar concepts among 22 quantitative and qualitative studies about adolescent internet use for health information to produce four key analytical themes. these themes include: adolescents generally distrust the internet but use it anyway, adolescents use heuristics to appraise the trustworthiness of online health information, adolescents trust websites more than social media, and adolescents' level of trust in online information guides their actions and responses. their review of the qualitative literature uses strong methodology, including a broad literature search, appraisal for transparency employing a commonly used framework (coreq), and using reporting methods recommended for synthesis of qualitative research (entreq). the findings are therefore likely credible, dependable, and confirmable. limitations of this study, as with other systematic reviews of qualitative research, include the potential minimization of cultural and contextual differences within individual studies, and potential barriers in incorporating diverse study designs. the authors' conclusions are potentially helpful in creating ehealth literacy interventions to assist adolescents in their evaluation of online health information. in addition to assisting adolescents with functional ehealth literacy (eg, using correct terms in searching) it is important to equip them with critical ehealth literacy (eg, differentiating accurate vs inaccurate information). understanding the role of trust may be helpful in achieving this goal. early-childhood prescribed antibiotics associated with type 1 diabetes main results 1,297 children (0.2%) developed dm1 (median age 4.0 years, range 0-8.3). antibiotics prescribed in the 1st year of life were associated with an increased risk of dm1, adjusted hazard ratio, 1.19 (95% ci, 1.05-1.36) with a higher risk among children born by cesarean delivery. conclusions early-life prescribed antibiotics for otitis media and respiratory infections, are associated with dm1 development, with a higher risk in cesarean delivery birth. commentary antibiotics are widely used in children worldwide based on the clinical premise of important benefit and minimal risk, but antibiotic overuse is well-documented. 1 wernroth et al examined whether use of antibiotics in pregnancy or infancy could increase risk of developing dm1. the authors conducted a large and well-executed cohort study with careful adjustment for measured confounders and a sibling-comparison design to reduce unmeasured genetic and environmental confounding. they showed a small but relatively consistent association between early antibiotic exposures and dm1 diagnosis before age 10, with larger effects in children delivered by cesarean section. one hypothesis is that this association was explained by residual confounding from the infections (often viral) that were treated with antibiotics; the authors did not directly adjust for infections. an alternative hypothesis is that earlyin-life antibiotic exposure, whether prenatally, perinatally, or during infancy, disrupts the development of infants' intestinal microbiome, disturbing immunologic development and ultimately promoting auto-immunity. 2 nonetheless, as assessments of causal relationships are rarely conclusive in observational studies, experimental models in predisposed animals are crucial for dissecting causation and mechanism. 3 clinicians should be aware of growing evidence suggesting that antibiotic-associated perturbation of early-life microbiota may be contributing to rising rates of dm1 across the globe. outcomes incidence. kawasaki disease shock syndrome was defined by presence of circulatory dysfunction, and macrophage activation syndrome (mas). the 19 pre-covid-19 era patients, mean age 3.0 (sd 2.5) years, january 1, 2015 -february 17, 2020, were compared with 10 covid-19 era patients (80% antibody positive), mean age 7.5 (sd 3.5) years, february 19 -april 20, 2020. those diagnosed in the covid-19 era demonstrated a higher incidence: 10 vs 0.3 per month, mean age: 7.5 vs 3.0 years, kawasaki disease shock syndrome: 50% vs 0%, mas: 50% vs 0%, and steroid requirement: 80% vs 15%, all p < .01. conclusions children with kawasaki disease in the covid-19 era, 80% of whom were antibody positive, were older and demonstrated more severe disease compared with those with kawasaki disease prior to the covid-19 era. commentary a thirty-fold increased incidence of so-called kawasaki-like disease was reported from italy during the sars-cov-2 epidemic in 2020. eight of the 10 patients with kawasaki disease tested positive for covid-19 with a high incidence (6/10) of cardiac involvement. news from new york, france, and england also showed an increased incidence and severity of kawasaki disease. prior to covid-19, coronavirus had been previously isolated in 7.1% of patients with kawasaki disease. 1 the incidence of kawasaki disease is not increasing in japan, taiwan, korea, hong-kong, or china, suggesting the importance of genetic issues in the relationship between kawasaki disease and covid-19. in this study, the kobayashi score, which identifies patients at high risk of ivig resistance, 2 revealed that of the 10 patients with kawasaki disease, none were younger than 12 months and all had platelet counts less than 300 â 10⁹/l. results from this study suggest that covid-19 may be one of the triggers of kawasaki disease. kawasaki disease in older patients with covid-19 is associated with an increased incidence of cardiac involvement, lower platelet counts, mas, and kawasaki disease shock syndrome. early adjunctive steroid treatment to prevent coronary artery lesions should be considered in these patients with covid-19 kawasaki disease. 3 chang gung university taoyuan, taiwan question what is the association of social/digital media viewing in the first 18 months of life and autism spectrum disorder (asd)? design cohort study based on data from the national children's study archive. setting us. participants 2152 children enrolled at birth, 2010-2012, analyzed at 26.6 (2.1), mean (sd), months of age. intervention modified checklist for autism in toddlers (m-chat) and parent-child play. primary outcomes m-chat and m-chat-r score associated with asd symptoms and risk. main results television and/or video viewing at 12 months were statistically associated with asd-like symptoms at 2 years of age, but not asd risk. parent-child play (daily vs not daily) was statistically associated with fewer asd-like symptoms at 2 years of age, but not asd risk. conclusions more early-age screen viewing and less parentchild play were associated with more asd-like symptoms at 2 years of age. commentary evidence is scarce linking early screen-media exposure and the emergence of asd. children with asd were reported to have been exposed to tv at a younger age and spent more time watching tv than their counterparts. 1 conversely, minimizing inappropriate screen-media exposure, in addition to behavioral and early intervention for young individuals with asd or asd-like behaviors, may improve developmental and behavioral outcomes, as often observed clinically. although tv viewing and caregiver-child play were obtained by self-report of single questions by heffler et al, their main findings are still intriguing for pediatric providers, as these experiential factors could be modifiable through high-quality parent-child interaction during early childhood development. these findings support another prospective study where children increasingly exposed to tv, including adult programs, from age 6 to 18 months, were more likely to have asd-like symptoms at age 18 months. 2 enriched parent-child interaction positively affects brain networks essential for cognitive, language, social, and emotional development during early childhood. children, especially those at risk for asd, should not be immersed in an environment with inappropriate and excessive screen media at a very young age. emphasizing, at health supervision visits, the american academy of pediatrics recommendations regarding appropriate media use with children, 3 parents should also be apprised of the association between earlier screen exposure and the risk of developing asd-like symptoms, although currently, a causal relationship cannot be inferred. question what are the maternal and neonatal outcomes in planned home birth compared with hospital birth? design consensus report. setting us. participants birthing women and neonates. intervention home birth vs hospital birth. outcomes rate of maternal medical intervention, intervention-associated maternal morbidity, and neonatal mortality risk. the maternal rate of medical intervention and intervention-associated morbidity is lower in non-hospital birth settings. neonatal mortality is 2-3-fold higher for non-hospital births. the neonatal mortality rate may be confounded by a lack of an integrated home-hospital system as exists in other countries, fetal/maternal risk stratification, birth-attendant-qualification regulation, and other factors. conclusions increased non-hospital-birth neonatal mortality rates may be elevated due to modifiable systems-related factors. commentary the recent nasem report is the most comprehensive examination to date of the state of us maternity care across birth settings (home, birth center, hospital). following an extensive review of the literature, it found that, compared with hospital birth, low-risk us women choosing home birth have lower rates of intervention, including cesarean birth, operative vaginal delivery, induction of labor, augmentation of labor, and episiotomy, as well as lower rates of interventionrelated maternal morbidity, such as infection, postpartum hemorrhage, and genital tract tearing. 1 us studies based on vital statistics data, found a higher risk of neonatal death in home compared with hospital births. 1 the committee included a review of the international data to better understand which systems-level factors influence maternal and neonatal outcomes. international studies suggest that home births may be as safe as hospital births for low-risk women and infants when: (1) they are part of an integrated, regulated system; (2) multiple provider options across the continuum of care are covered; (3) providers are well qualified and have the knowledge and training to manage first-line complications; (4) transfer is seamless across settings; and (5) appropriate risk assessment and risk selection occur across settings and throughout pregnancy. 1 however, the report found that such systems are currently rare in the united states, 1 which presents both a challenge and a road map for future improvement. instead of discouraging home birth, physicians and midwives could work together to make birth in all settings safer. for example, guidelines for transfers of care between home and hospital are available, 2 and physicians and midwives could work to build relationships for seamless transfer of care when warranted. although there are examples in the united states of such seamless transfers, 3 these are exceptions and not the norm. 4 greater opportunities for interprofessional education, collaboration, and research across all birth settings are also critical to improving understanding between providers, as well as for improving the quality of care. licensure and regulation for all us midwives that meet the international confederation of midwives (icm) standards for midwifery education and practice will help to bring all midwives in line with established protocols for selection of low-risk women for home birth. currently, midwives in a number of states educated to icm standards are not able to access licensure. ironically, expanding in-hospital access to services such as vaginal birth after cesarean, external cephalic version, vaginal breech birth (if version fails), and vaginal twin birth would in some cases prevent women from seeking these higher risk services elsewhere. university of maryland college park, maryland melissa cheyney, phd, ldm oregon state university corvallis, oregon health-related internet use by children and adolescents: systematic review health information-seeking behaviour in adolescence: the place of the internet adolescent health literacy and the internet bacterial prevalence and antimicrobial prescribing trends for acute respiratory tract infections antibiotics, pediatric dysbiosis, and disease antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice viral infections associated with kawasaki disease efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe kawasaki disease (raise study): a randomised, open-label, blinded-endpoints trial preventing coronary artery lesions in kawasaki disease comparison of television viewing between children with autism spectrum disorder and controls elevated background tv exposure over time increases behavioural scores of 18-month-old toddlers media and young minds best practice guidelines: transfer from planned home birth to hospital making home birth safer in the united states through strategic collaboration: the legacy health system experience home and birth center birth in the united states: time for greater collaboration across models of care portland, oregon key: cord-294729-c9f0iokr authors: orr, william b.; elward, alexis m.; lin, john c.; reich, patrick j.; scheel, janet n.; hayes, ericka v.; remy, kenneth e. title: delayed development of coronary artery dilitation in suspected severe acute respiratory syndrome coronavirus 2 multisystem inflammatory syndrome: more research needed date: 2020-10-01 journal: crit care explor doi: 10.1097/cce.0000000000000236 sha: doc_id: 294729 cord_uid: c9f0iokr although significant disease burden in the severe acute respiratory syndrome coronavirus 2 pandemic has been relatively uncommon in children, worldwide cases of a postinfectious multisystem inflammatory syndrome in children and possible atypical kawasaki-like disease attributing to severe acute respiratory syndrome coronavirus 2 infection have arisen. original thinking for coronavirus disease-19 disease was that an overwhelming proinflammatory response drove disease pathogenesis. emerging reports suggest that a robust immune suppression may be more relevant and predominant. recently reported data on children with multisystem inflammatory syndrome in children have demonstrated a heterogeneity of immune phenotypes among these patients, with concern for a strong initial proinflammatory state; however, data are lacking to support this. likewise, understanding development of certain clinical findings to changes in the immune system is lacking. case summary: we report a 12-year-old multiracial male with negative coronavirus disease-19 nasopharyngeal rna polymerase chain reaction testing but positive severe acute respiratory syndrome coronavirus 2 serology, subsequent development of vasodilatory shock with myocardial depression, and subsequent delayed development of coronary artery dilatation after resolution of myocardial depression. unlike previous reported cases of multisystem inflammatory syndrome in children, he exhibited profound lymphopenia without specific inflammatory cytokines elevations, whereas nonspecific markers (ferritin and c-reactive protein) were increased. he subsequently was discharged on day 12 of hospitalization with complete recovery. conclusion: our representative case of a patient with coronavirus disease-19-associated multisystem inflammatory syndrome in children without robust hyperinflammation and a delayed finding of coronary artery dilatation compared with reported case series highlights the need for further mechanistic understanding of coronavirus disease-19 disease and subsequent multisystem inflammatory syndrome in children or kawasaki disease development. this report offers a number of disease mechanisms and clinical evolution considerations for further elucidation to guide development of potential therapies. background: although significant disease burden in the severe acute respiratory syndrome coronavirus 2 pandemic has been relatively uncommon in children, worldwide cases of a postinfectious multisystem inflammatory syndrome in children and possible atypical kawasaki-like disease attributing to severe acute respiratory syndrome coronavirus 2 infection have arisen. original thinking for coronavirus disease-19 disease was that an overwhelming proinflammatory response drove disease pathogenesis. emerging reports suggest that a robust immune suppression may be more relevant and predominant. recently reported data on children with multisystem inflammatory syndrome in children have demonstrated a heterogeneity of immune phenotypes among these patients, with concern for a strong initial proinflammatory state; however, data are lacking to support this. likewise, understanding development of certain clinical findings to changes in the immune system is lacking. case summary: we report a 12-year-old multiracial male with negative coronavirus disease-19 nasopharyngeal rna polymerase chain reaction testing but positive severe acute respiratory syndrome coronavirus 2 serology, subsequent development of vasodilatory shock with myocardial depression, and subsequent delayed development of coronary artery dilatation after resolution of myocardial depression. unlike previous reported cases of multisystem inflammatory syndrome in children, he exhibited profound lymphopenia without specific inflammatory cytokines elevations, whereas nonspecific markers (ferritin and c-reactive protein) were increased. he subsequently was discharged on day 12 of hospitalization with complete recovery. conclusion: our representative case of a patient with coronavirus disease-19-associated multisystem inflammatory syndrome in children without robust hyperinflammation and a delayed finding of coronary artery dilatation compared with reported case series highlights the need for further mechanistic understanding of coronavirus disease-19 disease and subsequent multisystem inflammatory syndrome in children or kawasaki disease development. this report offers a number of disease mechanisms and clinical evolution considerations for further elucidation to guide development of potential therapies. key words: coronavirus disease-19; immune suppression; kawasaki disease; multisystem inflammatory syndrome in children; research s ignificant disease burden in the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) pandemic has been relatively uncommon in children with less than 5% of cases in the united states and globally under 18 years old (1) (2) (3) (4) (5) (6) . although severe disease is rare, many children become infected with the sars-cov-2 virus and some may serve as asymptomatic reservoirs for coronavirus disease-19 (covid-19) disease transmission (7) . however, although children appear to have a less severe acute disease course, worldwide cases of a postinfectious multisystem inflammatory syndrome in children (mis-c) and possible atypical kawasaki-like disease attributed to sars-cov-2 infection have arisen (8) (9) (10) . preliminary evidence and hypotheses suggested that covid-19 disease pathogenesis was driven by an overwhelming hyperinflammatory response. more recent emerging reports suggest that a robust immune suppression may be more relevant and predominant (11) (12) (13) . recently reported data on children with mis-c have demonstrated a heterogeneity of immune phenotypes among these patients, with concern for a strong initial hyperinflammatory state; however, data are lacking to support this. in these reported cases and in our own experiences with a case of mis-c with delayed development of an atypical kawasaki-like disease, a number of questions have been developed. a 12-year-old, previously healthy, fully immunized, multiracial male presented to our quaternary-care hospital after 1 week of fever and diarrhea. a nasopharyngeal covid-19 rna polymerase chain reaction was negative three times, and the serology of both parents was positive for sars-cov-2 immunoglobulin-g (igg) (abbott laboratories, chicago, il). at admission, he had vasodilatory septic shock with multiple laboratory and cardiac abnormalities including profound lymphopenia (absolute lymphocyte count [alc] 392), thrombocytopenia (nadir 57), hyponatremia, hypophosphatemia, and fever ( table 1) . during his 11 day icu course, he received empiric broad-spectrum antibiotics, hemodynamic support for catecholamine-resistant septic shock, stress dose hydrocortisone for critical illnessrelated corticosteroid insufficiency (two doses), and high-flow nasal cannula with subsequent noninvasive bilevel positive sirway pressure support without the need for intubation. cardiac specific evaluation showed initial electrocardiogram findings with prolonged corrected qt interval, transthoracic echocardiogram (tte) showed borderline left ventricle ejection fraction with dyskinetic septum, and probrain natriuretic peptide (bnp) and troponin-i were both significantly elevated (table 1) . by days 4-6, an sars-cov-2 igg test was positive, he became hypertensive requiring a nitroprusside infusion and subsequent transition to lisinopril, and his left ventricular ejection fraction increased to 50%. an initial cytokine panel demonstrated tumor necrosis factor (tnf)-α, interferon (ifn)-γ, and interleukin (il)-6 levels below the limit of detection and elevated il-2r and il-10 ( table 2) . all other cytokines were within normal limits. his nonspecific inflammatory markers all normalized including d-dimer, ferritin, c-reactive protein (crp), and fibrinogen, and he defervesced. at day 11, a predischarge tte revealed normal systolic function, but his left main coronary artery, left anterior descending artery, circumflex artery, and right coronary artery (rca) were all diffusely dilated with the rca demonstrating the greatest amount of dilation with a fusiform appearing aneurysm and proximal rca stenosis. he was discharged on low-dose aspirin and clopidogrel with a presumed diagnosis of covid-19 mis-c and atypical kawasaki-like disease. a 4-week postdischarge tte continued to have normal systolic function with unchanged coronary artery dilation and a slightly elevated troponin-i of 0.18 ng/ml. anticoagulation therapy was continued and antihypertensive medications stopped after normalization of blood pressure. recent u.s. and u.k. reports of over 500 mis-c patients have shown findings of lymphopenia, elevated crp, ferritin, bnp, d-dimer, il-6, and fibrinogen (8, 10, 14, 15) . however, unlike these case series, our patient had much higher nonspecific inflammatory markers (crp, ferritin, d-dimer, and fibrinogen) without elevation in il-6 or tnf-α cytokine levels. previous reports have demonstrated lymphopenia between 1,000 and 2,000 cells/mm 2 . in contrast, our patient had an alc less than 400, a finding similar to that seen in aids. our patient's divergent findings of elevation of some hyperinflammatory markers and depression of others highlight the presence of differing innate and adaptive immune phenotypes. in turn, this questions whether reported descriptive immune findings in adults can be accurately ascribed to children when children are presenting with different clinical manifestations over an altered time course. likewise, prior to uniform pediatric use of therapies that have been attempted in adults, we must gain better understanding of key mechanistic pathways of sars-cov-2 infection and extrapolate and apply known pathologic mechanisms in other similar and previously elucidated diseases (e.g., known kawasaki disease [kd] findings and other viruses). current covid-19-induced kawasaki-like disease may have overlapping mechanisms with canonical kd or may represent a completely different disease with overlapping clinical findings. comparing the clinical and laboratory characteristics of these two entities has very distinct properties. from a clinical standpoint, patients with mis-c have a broader age range with a median of 9 years, whereas kd patients have a narrower age range with a median of 2 years (8, 16) . patients with mis-c also have a lower prevalence of developing the classic kd findings of conjunctivitis, rash, mucositis, extremity swelling, and cervical lymphadenopathy (16) . interestingly, it has been reported that patients with mis-c compared with covid-19-associated kd have lower wbc counts, worsened thrombocytopenia and lymphopenia, and decreased erythrocyte sedimentation rates with less anemia (higher hemoglobin values) (16) . our patient demonstrated more severe lymphopenia than previously reported and yet had hematologic findings that bridged both previously reported findings in mis-c and kd (i.e., higher wbc counts with thrombocytopenia and anemia). additionally, our patient developed coronary artery dilatation 11 days after acute presentation and after recovery of myocardial function. this novel finding has not been reported in case series that have focused on cardiac manifestations of mis-c (17) . this further delineates mis-c and kd as heterogeneous syndromes with potentially differing subphenotypes. furthermore, canonical kd has previously demonstrated coronary vascular infiltration of neutrophils, cluster of differentiation 8 t lymphocytes, immunoglobulin-a-producing plasma cells, macrophages, and eosinophils (18) (19) (20) . numerous reports in adult covid-19 disease have demonstrated isolated proinflammatory marker elevations but likely predominant immune suppression with t cell exhaustion and significant peripheral lymphopenia (11) (12) (13) . based on preliminary concerns of a hyperinflammatory state driving disease progression, many patients with mis-c are treated with anti-inflammatory agents (corticosteroids, anakinra, and nonsteroidal anti-inflammatory drugs) (14, 15, 21, 22) . however, if children demonstrate similar findings as in adults with immune suppression, these agents may have negative effects including the potential for development of secondary infections and/or unmitigated viral tissue replication. it is unclear how this may affect development from acute disease to mis-c or kd. thus, a number of considerations remain regarding the broad definition of this syndrome, mechanisms involved, and the need for targeted rather than nonspecific therapies. this underscores a need for future studies in children to better characterize alterations in innate and adaptive immune functions not solely in acute infectious disease presentation but also in disease evolution to postinflammatory syndrome. our case describes a patient that meets centers for disease control and prevention criteria for mis-c with evolution of delayed kd findings of coronary artery dilations. a number of questions thus arise as follows: • what mechanistically could describe findings of mis-c at presentation and yet delayed findings of kd with coronary artery dilatation after four echocardiograms that have not been previously reported in large case series? • when and how often should echocardiogram surveillance occur with children that meet mis-c criteria at admission but may not have evidence of kd? • why in this illustrative case do we see a clinical presentation of vasodilatory shock with increased nonspecific inflammatory biomarkers and an absence of a "cytokine storm" of il-6, tnf-α, or related proinflammatory cytokines but with profound lymphopenia and reduction in ifn-γ demonstrating immune exhaustion? could changes in il-2r be more relevant than il-6 and provide further insight into jak1, jak3, or other tyrosine kinase/map kinase signaling pathways? • with oversampling of diagnostic testing including serial echocardiograms, are we unearthing a phenomenon restricted only to sars-cov-2 virus or would other common childhood viruses with the same testing reveal similar findings? • recent data suggest that children less than 10 years old have diminished nasal gene expression of angiotensin-converting enzyme 2 (ace-2) compared with greater than 10 year olds (23) . does this age-related increase in ace-2 expression play a role in the observation that kd-like disease in sars-cov-2 infection occurs more frequently in an older population compared with kd and what other potential signaling pathways may be involved? • would the well-established ability of other coronaviruses to block type 1 and type iii ifn responses provide further insights in additional therapies that may influence janus kinases-stat pathways? could further elucidation of these pathways demonstrate more refined targeted therapies with improved outcomes for this syndrome or previously described canonical kd? presently, our understanding of mis-c is limited to associations temporal to the covid-19 disease. better elucidation of relevant signaling pathways that define transition from acute disease to mis-c is not only important for covid-19 disease but may provide insights into understanding kd associated with other pathogens. further evaluation of these considerations and questions could present many avenues for further investigation. invariably, many children will present with sars-cov-2 positive antibody serology testing in the fall with signs and symptoms consistent with sepsis, hemophagocytic lymphohistiocytosis, or mis-c; differentiating between these entities diagnostically and with subsequent therapies will be important in patient management and potential outcomes. coronavirus disease (covid-19) and pediatric patients: a review of epidemiology, symptomatology, laboratory and imaging results to guide the development of a management algorithm clinical characteristics of novel coronavirus disease 2019 (covid-19) in newborns, infants and children covid-19 infection in children screening and severity of coronavirus disease 2019 (covid-19) in children in coronavirus disease 2019 in children -united states characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units lessons unfolding from pediatric cases of covid-19 disease caused by sars-cov-2 infection multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents in gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (mis-c) that is related to covid-19: a single center experience of 44 cases clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 immunotherapies for covid-19: lessons learned from sepsis targeted immunosuppression distinguishes covid-19 from influenza in moderate and severe disease severe immune suppression and not a "cytokine storm" characterize covid-19 infections multisystem inflammatory syndrome in children in new york state multisystem inflammatory syndrome in u.s. children and adolescents distinct clinical and immunological features of sars-cov-2-induced multisystem inflammatory syndrome in children characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (mis-c) associated with sars-cov-2 infection immunogenetics of kawasaki disease american heart association rheumatic fever, endocarditis, and kawasaki disease committee of the council on cardiovascular disease in the young; council on cardiovascular and stroke nursing; council on cardiovascular surgery and anesthesia; and council on epidemiology and prevention: diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association kawasaki disease: pathophysiology and insights from mouse models multisystem inflammatory syndrome in us children and adolescents safety and efficacy of early highdose iv anakinra in severe covid-19 lung disease nasal gene expression of angiotensinconverting enzyme 2 in children and adults we thank our patient and his family who provided consent for this report and to the washington university in st. louis institutional review board that who waived review with exempted approval.for information regarding this article, e-mail: kremy@wustl.edu key: cord-256642-payjduek authors: muthuvelu, sobana; lim, kev shiau-chong; huang, ling-yin; chin, shi-tying; mohan, anand title: measles infection causing bacillus calmette-guérin reactivation: a case report date: 2019-07-24 journal: bmc pediatr doi: 10.1186/s12887-019-1635-z sha: doc_id: 256642 cord_uid: payjduek background: reactivation of the bacillus calmette-guérin (bcg), manifesting as erythema, induration, ulceration or crust formation at a previous bcg inoculation site, is a common and highly specific feature of kawasaki disease (kd). we report the unusual finding of bcg reactivation in an infant with laboratory-confirmed measles. case presentation: a previously healthy 7-month old infant presented initially with fever, cough and coryza, and subsequently developed koplik’s spots followed by a typical morbilliform skin rash. there was significant contact history with a household relative who had recently been diagnosed with measles. on examination, a 2.5 cm area of erythema and induration was seen at the previous bcg inoculation site, in addition to the widespread maculopapular rash. no other clinical features of kd were present. measles virus was isolated from the throat swab and measles antibodies (igm) were present in the serum. the patient recovered completely with oral vitamin a and supportive therapy, and had normal echocardiography examination on follow up. conclusions: this case report highlights the rare finding of bcg reactivation in a child with confirmed measles infection, and suggests that this clinical manifestation may occasionally occur in children with infections or conditions other than kd. bacillus calmette-guérin (bcg) vaccine is used to prevent tuberculous meningitis, miliary tuberculosis and possibly other forms of tuberculosis, including pulmonary disease, in children [1, 2] . it is included as part of the expanded programme on immunization in over 150 countries worldwide, including malaysia [3] . in malaysia, as in most countries where it is used, bcg vaccination is recommended universally for all infants at birth or shortly after birth. following intradermal inoculation of the attenuated mycobacterium bovis bcg strain at the deltoid region of the left arm, a small papule usually appears after 2 weeks, gradually enlarges and typically ulcerates within 2-4 months, and slowly heals over the next few months to form the bcg scar [4] . reactivation of the bcg, manifesting as erythema, induration, ulceration or crust formation at the bcg site months or years after inoculation, has been described as an important feature of kawasaki disease (kd) [5, 6] . although not included in the diagnostic criteria of the disease, this clinical manifestation is reported in up to 50% of children with kd [7] . in addition, the clinical finding of bcg reactivation is regarded to be highly specific for kd, as it is very rarely described in other febrile illnesses or infections. for example, in a study of febrile japanese children aged < 2 years admitted over an 8month period with diagnoses other than kd, no bcg reactivations were observed [8] . in contrast, data from a japanese nationwide epidemiologic survey showed that > 70% of children in this age group who were diagnosed with kd developed bcg reactivation [8] . measles infection has not been reported to cause bcg reactivation. here, we present a case report of a 7-month old infant with laboratory-confirmed measles who presented with erythema and induration at the bcg inoculation site. a 7-month old boy was admitted to the paediatric ward of bintulu hospital in sarawak with a 4-day history of fever and 1 day of rash. his past medical history had been unremarkable and he had been thriving well. he had received bcg vaccination (bcg-japan, tokyo 172 strain) at birth, at the same hospital. according to his mother, a papule had developed at the inoculation site which had then healed completely to form a scar in the months prior to the admission. he had not received measles vaccination. his illness began abruptly with high fever, cough and coryza, for which he received symptomatic treatment as an outpatient at a private medical centre during the first 2 days after disease-onset. on the third day, his condition worsened as he fed poorly and was noted to have reduced activity, with persistence of the fever. a detailed history was then taken and revealed that the child's uncle, who lives with the family and had never received measles vaccination, had been admitted to the same medical centre 2 weeks earlier with a laboratory-confirmed diagnosis of measles. physical examination of the child revealed koplik's spots and he was then admitted to the medical centre. later that day, he developed a typical morbilliform rash which began behind the ears and neck, and spread to his face and trunk. the following day, he was referred to our hospital with a clinical diagnosis of measles. on admission, he looked unwell, was febrile (temperature 38.5°c) but had normal vital signs (pulse rate 125/min, respiratory rate 48/min). he had an erythematous maculopapular rash involving mainly the face, neck and trunk, with some areas of confluence (fig. 1a) . in addition, a welldefined erythematous, indurated area measuring 2.5 cm in diameter was seen at the site of the bcg scar (fig. 1b) . no conjunctivitis, cervical node enlargement, mucosal changes or extremity changes (swelling/erythema of the hands or feet) were found. laboratory investigations revealed a mild anaemia (haemoglobin 10.9 g/dl) with normal white blood cell (6.5 x 10 9 cells/l) and platelet counts (252 x 10 9 /l). both the c-reactive protein (< 6 mg/dl) and the erythrocyte sedimentary rate (10 mm/hour) were normal. other investigations including liver function tests (albumin 42 g/l; aspartate aminotransferase 41 u/l; alanine aminotransferase 17 u/l) and urine microscopy were also normal. blood for bacterial culture was negative. a throat swab and urine sample for measles virus isolation, as well as serum for measles antibodies were sent to the regional laboratory. he was treated with oral vitamin a and intra-venous fluids. his condition began to improve on day 6 of illness, with a resolution of the fever and improvement in feeding and activity. by the 7th day of illness, both the generalized rash as well as the bcg inoculation site erythema and induration appeared to be resolving, leaving some hyperpigmentation (fig. 1c, d) . he was then discharged home. follow-up revealed a healthy and thriving boy. no skin desquamation was noted. echocardiography at 2 and 10 weeks after discharge were normal. a review of the investigation results from the regional laboratory confirmed the diagnosis of measles, with measles virus isolated from the patient's throat swab and measles-specific antibodies (igm) present in the serum. isolation of measles virus from the throat swab was performed using vero/hslam cell lines. typical cytopathic effect was observed as formation of syncytia, which appeared as large multinucleated cells (giant cells). the cultures were then harvested and the presence of measles virus confirmed by an immunofluorescence assay (chemicon international, temecula, usa). measles-specific antibodies (igm) in the serum were detected by an indirect enzyme linked immuno-sorbent assay (elisa) using a commercially available test kit (siemens healthcare diagnostics products gmbh, marburg, germany). to the best of our knowledge, this is the first case report to describe bcg reactivation in a child with confirmed measles infection. a search of the pubmed/medline database using the key terms "bacillus calmette-guérin", "bacille calmette-guérin", "bcg" and "measles" revealed no reports of similar cases in the published literature. although the detection of bcg inoculation site erythema and induration did prompt a thorough investigation for kd in our patient, diagnostic criteria for the disease was not met. all clinical and laboratory findings were however consistent with the diagnosis of measles, and a complete and rapid recovery ensued with supportive therapy. the diagnosis of measles in the patient was confirmed by both measles virus isolation from the throat swab and also detection of measles-specific antibodies (igm) in the serum. having been exposed to an unvaccinated relative who had laboratory-confirmed measles, the patient, a 7-month old infant, then developed the classical manifestations and progressed through the typical natural history of measles infection, without developing any other complications. measles infection is caused by measles virus, a morbillivirus in the family paramyxoviridae [9] . the disease remains an important childhood affliction, causing 89 780 deaths globally in 2016, despite the availability of an effective vaccine [10] . in malaysia, measles vaccination is given to infants aged 9months. with a vaccination coverage of 94% in 2016, the incidence of measles in malaysia was reported to be 5.0 per 100,000 population while the mortality rate from measles was 0.02 per 100,000 population [11] . although the diagnosis is usually made based on the characteristic clinical manifestations, confirmation of measles infection may be obtained by detection of measles specific igm antibodies in the serum, and also through measles virus identification from throat-swab and urine specimens [12] . other than fever, the rash and the bcg inoculation site erythema and induration, no other features of kd were present in the patient. the clinical symptoms and signs resolved without kd specific therapy, with no coronary artery complications detected on follow up. kd is an acute vasculitic syndrome of unknown etiology, occurring mainly in children [13] . as there are no confirmatory tests, the diagnosis of kd is made based on the presence of fever lasting for 5 days or more, and 4 of 5 principal clinical criteria that include conjunctivitis without exudates, cervical lymphadenopathy, polymorphous rash, changes in the lips or oral mucosa, and changes of the extremities [13] . a major challenge in the diagnosis and management of kd, however, is the recognition that some infants present with only 2-3 clinical features, and therefore do not fulfill the diagnostic criteria. laboratory investigations may be of some use in this situation of incomplete kd [13] . bcg reactivation has repeatedly been described as an important sign in incomplete kd, although it is not included in any of the diagnostic algorithms [14, 15] . for example, in south korea, 85% of children aged < 1 year who were diagnosed with incomplete kd had erythema, induration or crust formation at the bcg inoculation site [16] . the unexpected finding of bcg reactivation in our patient correctly raised the concern of a possible diagnosis of incomplete kd. although echocardiography was not performed in the initial phase, no additional supporting clinical or laboratory criteria, other than mild anemia, were found. reassuringly, the rapid resolution of symptoms precluded any further concerns with regard to the need for kd therapy in the patient. apart from those to confirm the measles infection, no laboratory investigations were undertaken to determine if additional viral pathogens were present in the patient and contributed to the development of the bcg reactivation. human herpes virus 6 infection has been reported in an infant with a viral exanthem presenting with bcg reactivation [17] . in addition, various respiratory viruses including enterovirus, adenovirus, human rhinovirus and coronavirus have been isolated significantly more frequently in children with kd than in controls [18] , although no direct association with bcg reactivation have been documented. as viral co-infections have been identified in children with measles [19] , a more extensive virology work-up may have been warranted in our patient when the unusual finding of bcg reactivation was discovered. the mechanism leading to the bcg reactivation in our patient with measles is not known. one possible mechanism is the reactivation and multiplication of live but dormant mycobacterium bovis bcg bacilli that may have been present at the inoculation site, facilitated by immune suppression induced by measles infection. in one previous case report, a severely malnourished 2.5year old boy developed ulceration of a healed bcg scar and possible disseminated bcg infection 2 weeks after measles infection [20] . acid-fast bacilli was detected from a swab of the bcg ulcer. this mechanism is, however, unlikely in our patient in view of the rapid onset and resolution of the bcg site erythema/induration with the appearance and resolution of the measles rash. immune suppression induced by measles would normally be expected to persist for a longer duration [21] . in addition, the lack of malnutrition in the patient, the otherwise uncomplicated measles course, and the absence of secondary infections normally seen in severe immunosuppressed states further renders this mechanism unlikely. another possible mechanism for the bcg reactivation, which appears more probable, is an immune-mediated reaction. cross-reactivity between specific epitopes of mycobacterial and human heat shock proteins (hsp), in particular mycobacterial hsp 65 and human homologue hsp 63, have been postulated as the cause of bcg reactivation in children with kawasaki disease [22, 23] . hsp are ubiquitous molecules present in all organisms, including humans, and mediate important functions in protein folding, assembly and transport essential for cell survival [24] . synthesis of hsp are increased during conditions of cellular stress, including infection, ischaemia and other physical stresses. in humans, increased production and serum concentrations of hsp, especially hsp 70, have been reported during viral infections, including measles [25, 26] . as homology between hsp 70 and mycobacterial antigens have been demonstrated [27] , a similar cross-reactivity as thought to occur in children with kawasaki disease could possibly also explain the bcg reactivation in our patient. these mechanisms are especially intriguing as measles infections typically cause suppression of delayed type hypersensitivity and anergy to tuberculin [9] . we report the rare finding of bcg reactivation in a child with confirmed measles infection. although bcg reactivation is known to be an extremely important and highly specific clinical manifestation of kd, this case suggests that bcg reactivation may also occur in other childhood diseases or infections. a thorough search for an infective aetiological agent may be indicated in children presenting with this clinical finding. abbreviations bcg: bacillus calmette-guérin; hsp: heat shock proteins; igm: immunoglobulin m; kd: kawasaki disease effect of bcg vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness protection by bcg vaccine against tuberculosis: a systematic review of randomized controlled trials the bcg world atlas: a database of global bcg vaccination policies and practices other cutaneous bacterial infections revision of diagnostic guidelines for kawasaki disease (the 5th revised edition) reaction at the bacillus calmette-guerin inoculation site in patients with kawasaki disease erythema at bcg inoculation site in kawasaki disease patients. materia socio-medica kawasaki disease patients with redness or crust formation at the bacille calmette-guérin inoculation site measles: not just another viral exanthem world health organization. measles. in: media centre. fact sheets response to measles outbreaks in measles mortality reduction settings diagnosis, treatment, and long-term management of kawasaki disease bacillus calmette-guérin reactivation as a sign of incomplete kawasaki disease incomplete kawasaki disease: the usefulness of bcg reactivation as a diagnostic tool diagnosis of incomplete kawasaki disease in infants based on an inflammation at the bacille calmette-guérin inoculation site human herpes virus type 6 can cause skin lesions at the bcg inoculation site similar to kawasaki disease viral infections associated with kawasaki disease viral coinfections among children with confirmed measles at hospitals in hanoi ulceration of a previously healed bcg scar in suspected disseminated bcg infection measles virus-induced suppression of immune responses heat shock protein as a predisposing and immunopotentiating factor in kawasaki disease t cells recognize an immunodominant epitope of heat shock protein 65 in kawasaki disease role of heat shock proteins in protection from and pathogenesis of infectious diseases elevated serum heat-shock protein 70 levels in patients with acute infection: use of an optimized enzyme-linked immunosorbent assay role for heat shock proteins in the immune response to measles virus infection homology of the 70-kilodalton antigens from mycobacterium leprae and mycobacterium bovis with the mycobacterium tuberculosis 71-kilodalton antigen and with the conserved heat shock protein 70 of eucaryotes publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank all our medical, nursing and laboratory colleagues involved in the diagnosis and care of this patient. we also thank w. nur afiza binti w. mohd. arifin for providing details of the virological methods conducted in the regional laboratory (national public health laboratory, malaysian ministry of health, sungai buloh, selangor, malaysia). authors' contributions sm, lyh, stc and am were involved in the clinical care of the patient. sm drafted the manuscript and kscl, lyh, stc and am provided critical review. all authors read and approved the final manuscript. not applicable.availability of data and materials all relevant data are included within the manuscript.ethics approval and consent to participate not applicable. written informed consent was obtained from the patient's parents for the publication of this case report and images. the authors declare that they have no competing interests. key: cord-003713-n3o8lwu4 authors: min, dong eun; kim, do hee; han, mi young; cha, sung ho; yoon, kyung lim title: high antistreptolysin o titer is associated with coronary artery lesions in patients with kawasaki disease date: 2018-11-07 journal: korean j pediatr doi: 10.3345/kjp.2018.06989 sha: doc_id: 3713 cord_uid: n3o8lwu4 purpose: in kawasaki disease (kd) patients, coronary artery complications, incomplete and refractory types occur more frequently in patients with streptococcal or other bacterial/viral infections. recently, we observed a higher incidence of coronary lesions in kd patients with high anti-streptolysin o (aso) titer. therefore, we hypothesized that kd patients diagnosed with concurrent streptococcal infection have poor prognoses, with respect to treatment response and development of coronary artery lesions. methods: a retrospective review was performed in 723 patients with kd who were admitted to 2 major hospitals between june 2010 and september 2017. results: among 723 patients with kd, 11 initially showed an elevated aso titer (>320 iu/ml) or elevated follow-up aso titer after treatment. of these patients, 5 showed no response to the first intravenous immunoglobulin treatment, 3 had abnormalities of the coronary arteries. this is a significantly higher proportion of patients with a high aso titer (n=3, 27.3%) than those with a normal aso titer (n=53 [7.4%], p=0.047). a severe clinical course was seen in 81.8% of patients in the high aso group versus 14.5% of patients in the normal aso group. conclusion: it is not certain whether acute streptococcal infection may cause kd, but this study revealed that kd with high aso titers showed higher rates of severe clinical course. it may be helpful to analyze concurrent streptococcal infection in patients with a severe clinical course. kawasaki disease (kd) is an acute systemic inflammatory disease involving multiple organs and tissues. 1) children <5 years old of age are most susceptible to kd. 2) the diagnosis of kd depends on the clinical manifestations according to the defined criteria of the presence of fever for at least 5 days, with at least 4 of the 5 following clinical features: (1) erythema and changes in the lips and oral mucosa, (2) bilateral nonexudative bulbar conjunctival injection, (3) polymorphous maculopapular rash (not petechial, bullous, or vesicular lesions), (4) changes in the extremities, including erythema and edema of the hands and feet in the acute phase and/or desquamation starting around the nail bed, and (5) cervical lymphadenopathy, usually unila teral (diameter>1.5 cm). 24) incomplete kd is defined as prolonged unexplained fever without meeting at least three of the above five criteria. 2) despite many investigations and many candidates, no unique infectious agents have been identified as the sole etiologic agent responsible for kd. the role of viral infections in the pathogenesis of kd has been controversial. 57) the association with super antigens such as staphylococci or streptococci has been constantly argued. 810) in kd, incomplete type of the diagnosis of kd depends on the clinical manifestations ac cording to the defined criteria of the presence of fever for at least 5 days, with at least 4 of the 5 principal clinical features. 2) incomplete kd is defined as prolonged unexplained fever without meeting at least three of the 5 criteria. 2) we enrolled patients if their aso titer had increased 4 fold in 2 measurements. 17) this is generally accepted as significant in clinical practice. however, if the aso titer could be measured only once, we enrolled >320 iu/ml, which is the upper normal limit presented in a recent study and many other studies. 1820) if the peak aso titer was <320 iu/ml in a patient who was measured twice, the patient was excluded from the study group. patients who were discharged or transferred without appropriate treatment were also excluded. a good clinical course group is defined as fever subsiding within 36 hours after the end of first ivig treatment without any coronary artery abnormalities. on the other hand, relatively severe kd groups were defined as follows; (1) no response to the first ivig treatment, and a second ivig treatment or methylprednisolone (mpd) pulse therapy were required, or (2) kd patients with coronary artery ab normalities. fisher exact test was used to compare data using ibm spss sta tistics ver. 20.0 (ibm co., armonk, ny, usa), and values of p<0.05 were considered statistically significant. a total of 723 patients were diagnosed with kd between june 2010 and september 2017. patients were admitted to the hospital on average 5.9 days after the onset of fever. these patients' clinical data are summarized in table 1 . of them, 9 (81.8%) had a severe clinical course. only 2 patients (18.2%) had a relatively good clinical course. of the 11 kd patients with elevated aso levels, 5 were boys and 4 were girls (ratio, 0.83:1), with a mean age of 65.5 months (range, 10-131 months) at the time of the kd diagnosis. ten patients had complete kd, while 1 had incomplete kd. one of the patients (female, 73 months) experienced a kd relapse 15 days after the first treatment. at the time of diagnosis, all 11 patients had a fever, (mean dura tion, 9.2 days; range, 5-21 days) and a nonexudative eye injection. 10 patients (90.9%) had a polymorphous rash, 9 patients (81.8%) displayed noticeable changes in the lips or oral mucosa, 8 patients (72.7%) had erythema and edema of the extremities, and 7 patients (63.6%) had cervical lymphadenopathy. the mean fever duration was 9.4 days in the severe kd group and 8 days in the good clinical course group. all patients in the good clinical course group had complete kd, fevers that subsided within 36 hours after the first ivig treatment, and normal coronary arteries. at the time of diagnosis, kd and coronary artery complications occur more frequ ently in patients with streptococcal or other bacterial/viral infec tions. 1113) some reports have stated that systemic inflammation is linked to acute coronary events, including endothelial dysfunc tion. 14, 15) we hypothesized that kd patients diagnosed with strep tococcal infec tion have poor prognoses, especially in terms of treat ment response and the development of coronary artery lesions. here, we investigated the coronary artery lesions and response to intravenous immunoglobulin (ivig) in relation to the level of anti streptolysin o (aso) in patients with kd. we retrospectively reviewed kd patients admitted to kyung hee university medical center and kyung hee university hospital at gangdong between june 2010 and september 2017. the clinical data of a total 723 kd patients were reviewed. only patients for whom aso titer and echocardiography data were available were included in the study. the institutional review board of kyung hee university hospital at gangdong approved this study (approval number: 201808047) and waived the need for written informed consent. laboratory data including microbiology results, imaging studies, and echocardiography examinations were collected and reviewed. a standardized set of laboratory tests was performed before and 36 hours after the end of ivig infusion, including complete blood count, white blood cell differential count, erythrocyte sedimentation rate, creactive protein, albumin, alanine aminotransferase, aspa rtate aminotransferase, bilirubin, creatinine, aso, and urine analysis. all except one patient diagnosed with kd received ivig (2 g/kg) for 12 hours and these blood tests were performed 36 hours after the end of treatment. only 1 patient did not receive ivig, because he was referred to our hospital without a fever. blood culture, throat swab, respiratory viral polymerase chain reaction (pcr), and serum mycoplasma antibody tests were performed in patients who were suspected of having an infection. respiratory viral pcr can detect 12 respiratory viruses and subtypes included the following: adeno virus, respiratory syncytial viruses a and b, influenza viruses a and b, parainfluenza 1, 2 and 3, rhinovirus, metapneumovirus, and coro naviruses 229e, nl63, oc43, and hku1. serial echocardio graphy exams were performed during hospitalization by an expert pediatric cardiologist. by correcting for bsa, a z score system provided by kobayashi et al. 16) was used in our study. in this study, z score ≥2.5 was regarded as a coronary artery abnormality. 4 patients (36.4%) had a confirmed concurrent infection, the most common pathogens being mycoplasma pneumoniae (n=2), rhino virus (n=1), and influenza b (n=1), confirmed by respiratory viral pcr. only 1 patient was confirmed to have streptococcus pyogenes, by a throat culture at diagnosis. blood cultures were all negative in these 11 patients. four patients with a high aso titer did not receive any antibiotics despite a sustained fever, whereas the other 7 did receive antibiotics. however, the prevalence of coronary artery lesions did not differ between them. as for seasonal patterns, 4 cases were diagnosed in early summer (2 in may, 1 in june, and 1 in july), while 3 were diagnosed in win ter (1 in january, 2 in february). no cases were diagnosed in the fall. table 2 shows the numbers and percentages of patients by group. those with a severe clinical course developed coronary lesions, re ceived a second round of ivig, or required mpd pulse therapy. a severe clinical course was seen in 81.8% of patients in the high aso group versus 14.5% of patients in the normal aso group. cardiac involvement was screened for in all patients using echo cardiography. a significantly higher proportion of patients with a high aso titer (n=3, 27.3%) than those with a normal aso titer (n= 53; 7.4%) showed abnormalities of the coronary arteries (p=0.047). a second round of ivig was administered in more patients with an elevated aso titer (45.5%) than patients in the normal aso group (9.8%). here we reported the severity of kd with streptococcal infections among 723 kd patients. among them, 11 had elevated aso levels before or after ivig treatment. of those, 9 had high aso titers or 4fold increased titers, and clinical findings for them were worse than those for the other kd patient. five patients showed no res ponse to the first ivig treatment (45.5%, p=0.003), 3 had abnormali ties of the coronary arteries (27.3%, p=0.047). a severe clinical course was seen in 81.8% of patients in the high aso group versus 14.5% of patients in the normal aso group (p<0.001). jordanvillegas et al. 11) reported that patients with kd who also had respiratory viruses have a higher frequency of coronary artery dilatation and were more often diagnosed with incomplete kd. other researchers have linked streptococcal infection and kd. 21, 22) in particular, the reason might be clinical overlap between strepto coccal infection and kd, such as persistent fever, a de squa mative rash, and erythema of the mucous membranes in streptococcal toxic shock syndrome. a superantigenmediated process might be related to this process. 8) matsubara and fukaya 8) suggest that kd is a response to superantigens in genetically sus ceptible individuals. these all support our results that kd with streptococcal infection had a severe clinical course. in temperate climates, the incidence of group a streptococcal infection peaks during the winter and early spring. in japan, several group a streptococcal serotypes showed a bimodal distribution, with peaks in december to february and again in may to june and a prominent nadir of infections in september. 23) in korea, a seasonal pattern was observed in which kd occurred more often in early summer (may, june, and july) and winter (january and february), and occurred less often in the spring and fall. 24) of the 11 kd diag noses, 4 were made in early summer (2 in may, 1 in june, and 1 in july), and 3 were made in winter (1 in january, 2 in february). no patients were diagnosed in the fall. this may imply that infectious agents might be the trigger of kd and that streptococcus is one of the possible agents is the possible agents. measurement of aso is relatively inexpensive and easy to per form because the proceeds, along with other blood tests. however, there are significant difficulties assigning a "normal" aso titer value. the only upper normal limit is >320 iu/ml, presented in a recent study and many other studies. 20) also, aso titer does not always indicate a recent streptococcal infection. therefore, an in crease in an aso titer is indicative of a preceding group a streptococcus in fection, so sequential measurements are recommended. 1719) we attempted to obtain 2 sequential measurements, but only a single measurement was performed in some patients. ivig contains the pooled immunoglobulins from the plasma of approximately a thousand or more blood donors. as a cocktail of different antibodies against various virulence factors including streptococcus, it can be provided to the patients. in this study, among 11 patients, 5 patients' aso titer was high (range, 506-1,023) at the time of diagnosis, and 6 patients' aso titer elevated after ivig treatment. in our study, 4 of the 11 patients with a high aso titer did not receive any antibiotics despite a sustained fever, whereas the other 7 did receive antibiotics. however, the prevalence of coronary ar tery lesions did not differ between them. in 2018, han and lee 25) report the anbibiotics used in 140 kd patients. the kd patients with antibiotics experienced more hospital days (p=0.045). on the other hand, there was no difference in unresponsiveness to ivig and de velopment of coronary abnormalities between the 2 groups. despite its many limitations, our study's main strength is that we treated all patients using a relatively constant protocol. a series of blood tests was performed at the time of diagnosis, including the aso titer, because the tests are simple and do not require additional specimens. ivig 2 g/kg was administered slowly over 12 hours as soon as kd was diagnosed and discontinued whenever a patient's temperature exceeded 38°c. thirtysix hours after the end of the ivig administration, the blood tests, including the aso titer, were repeated to exclude acute streptococcal infection and the fever pattern was closely observed. in addition, echocardiography was performed by an expert pediatric cardiologist at the admission, 2-3 weeks later, 2 months later, or 1 year later depending on each pati ent's status to monitor for coronary artery or other transient lesions. in this study, we do not know whether acute streptococcal infec tion or past infection caused the kd. however, in kd with acute streptococcal infection, the fever duration was longer than average and the frequency of coronary artery aneurysms was higher. in cases of incomplete kd or prolonged fever, it may be necessary to diagnose acute streptococcal infection using aso titer or culture; therefore, more aggressive therapy is needed to prevent coronary artery lesions. prospective studies with larger samples are needed to further examine the relationship between kd with coronary lesions and elevated aso titers. general pathology of kawasaki disease. on the morphological alterations corresponding to the clinical manifestations diagnosis, treatment, and longterm management of kawasaki disease: a scientific statement for health professionals from the american heart association diagnosis, treatment, and longterm management of kawa saki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis and kawasaki disease, council on cardiovascular disease in the young council on cardiovascular disease in the young; committee on rheumatic fever, endocarditis, and kawasaki disease kawasaki disease: is it caused by an infectious agent? ultrastructural, immunofluorescence, and rna evidence support the hypothesis of a "new" virus associated with kawasaki disease infections and kawasaki disease: implications for coronary artery outcome the role of superantigens of group a strepto coccus and staphylococcus aureus in kawasaki disease superantigens, conventional antigens and the etiology of kawasaki syndrome the etiology of kawasaki disease: superantigen or conventional antigen? respiratory viral infections in children with kawasaki disease factors associated with resource utilization and coronary artery dilation in refractory kawasaki disease (from the pediatric health information system database) epidemiologic features and prognostic factors of coronary artery lesions associated with kawasaki disease based on a 13year cohort of consecutive cases identified by complete enumeration surveys in wakayama acute systemic inflammation impairs endotheliumdepen dent dilatation in humans association between recent group a betahemolytic a new z score curve of the coronary arterial internal diameter using the lambdamusigma method in a pediatric population streptococcal serology: secrets for the specialist clinical use and interpretation of group a streptococcal antibody tests: a practical approach for the pediatrician or primary care physician how to use antistreptolysin o titre antistreptolysin o titer profile in acute rheumatic fever diagnosis simultaneous kawasaki disease and group a streptococcal pharyngitis overlap between kawasaki disease and group a streptococcal infection seasonality and temporal clustering of kawasaki syndrome epidemiologic study on kawasaki disease in korea, 20072014: based on health insurance review & assessment service claims antibiotic use in children with kawasaki disease no potential conflict of interest relevant to this article was re ported. key: cord-292719-n5lg43tr authors: chang, luan-yin; lu, chun-yi; shao, pei-lan; lee, ping-ing; lin, ming-tai; fan, tsui-yien; cheng, ai-ling; lee, wan-ling; hu, jen-jan; yeh, shu-jen; chang, chien-chih; chiang, bor-luen; wu, mei-hwan; huang, li-min title: viral infections associated with kawasaki disease date: 2014-02-01 journal: j formos med assoc doi: 10.1016/j.jfma.2013.12.008 sha: doc_id: 292719 cord_uid: n5lg43tr background/purpose: kawasaki disease (kd) is a disease of unknown cause. to investigate the infectious etiology of kawasaki disease, we initiated a prospective case-control study to investigate possible links between common viral infections and kawasaki disease. methods: we enrolled 226 children with kd and 226 ageand sex-matched healthy children from february 2004 to march 2010. throat and nasopharyngeal swabs were taken for both viral isolation and polymerase chain reaction (pcr) for various viruses. results: the mean age of the 226 kd cases was 2.07 years, and the male to female ratio was 1.43 (133 boys to 93 girls). their mean fever duration was 7.5 days with a mean peak temperature of 39.7°c. in addition to the typical symptoms of fever, neck lymphadenopathy, lip fissure and/or strawberry tongue, skin rash, nonpurulent bulbar conjunctivitis, palm/sole erythema, and induration followed by periungual desquamation, these kd cases also exhibited cough (69%), rhinorrhea (58%), and diarrhea (45%). cases of kd had a significantly higher positive rate of viral isolation in comparison with the control group (7.5% vs. 2.2%, p = 0.02). compared with the control group, cases of kd were more likely to have overall positive rates of viral pcr (50.4% vs. 16.4%, p < 0.001) and for various viruses including enterovirus (16.8% vs. 4.4%, p < 0.001), adenovirus (8.0% vs. 1.8%, p = 0.007), human rhinovirus (26.5% vs. 9.7%, p < 0.001), and coronavirus (7.1% vs. 0.9%, p = 0.003). conclusion: we found that some common respiratory viruses, such as adenoviruses, enteroviruses, rhinoviruses, and coronaviruses, were associated with kd cases. kawasaki disease (kd) is an acute systemic febrile illness of unknown etiology which predominantly affects children under 5 years of age. initially described in 1967 by tomisaku kawasaki, 1 it is now the most common cause of acquired heart diseases in children in the developed world due to the less frequent occurrence of rheumatic heart disease. there have been reports of differing incidence rates in different countries. asian countries are supposed to have higher incidences of kd (30e200/per 100,000 children under 5 years of age) than most of the western countries (3.5e10/per 100,000 children under 5 years of age). 2e10 the etiology of kd is still controversial and infections are considered to be one of the predisposing factors. the infectious evidence of kawasaki disease includes temporal clustering and marked seasonality, geographic clustering, family clustering, a high association between kawasaki disease and infectious disease surveillance, and age distribution, for which the highest incidence rates are seen among 6 monthe2-year-old children who have low maternal antibodies and are most susceptible to infections in general. 11e14 we hypothesize that infections with certain viruses may elicit systemic inflammation, and further small and median sized vasculitis, so-called kawasaki disease, in certain hosts because we found a higher incidence of kd among males, young children, and asian populations. we thus carried out a prospective case-control study to investigate the association of common viral infections with kawasaki disease to test the above hypothesis. we enrolled kawasaki disease cases that had fever for over 5 days and at least four of the following five manifestations: neck lymphadenopathy, lip fissure and/or strawberry tongue, skin rash, nonpurulent bulbar conjunctivitis, palm/sole erythema, and induration followed by periungual desquamation. the onset of kd illness cases was defined as the 1st day of fever onset. after informed consent was obtained from the parents, a questionnaire-styled interview was carried out to solicit clinical symptoms and previous contact history with ill household members or with ill people from outside of the household. the illness included sore throat, rash, fever, conjunctivitis, cough, rhinorrhea, abdominal pain, and diarrhea. clinical laboratory data and coronary arterial lesions were collected from the participants, and all received intravenous immunoglobulin 2 g per kg plus low-dose aspirin (3e5 mg per kg). if fever persisted for 2 days after use of intravenous immunoglobulin, retreatment with intravenous immunoglobulin was administered. two-dimensional echocardiography was performed in all patients during hospitalization and was repeated at convalescence, 2 weeks, and 8 weeks after discharge. coronary arterial lesions were defined as coronary arterial dilatation/ectasia, aneurysm, and increased echogenecity, irregularity of vascular wall, or coronary artery aneurysm. a coronary artery aneurysm was defined as having a lumen diameter (inner border to inner border) of !3 mm in kd cases less than 5 years old and !4 mm in cases less than 5 years old, and giant aneurysm was defined as a lumen diameter of !8 mm for any one echocardiography. we took nasopharyngeal swabs and throat swabs from kd cases on the 1st day of hospitalization. these swabs were processed for both viral isolation and polymerase chain reaction (pcr) for various viruses. for the healthy control group, we enrolled children who were age-and sex-matched with the kd cases, and who did not have preceding illness for the 2 weeks prior to enrollment. the preceding illness included sore throat, rash, fever, conjunctivitis, cough, rhinorrhea, abdominal pain, and diarrhea. these children were kindergarteners or children who visited our baby wellness clinics for vaccination. informed consent was obtained from parents of all children in the control group. we also took throat swabs and nasopharyngeal swabs from the control children for viral isolation and viral pcr. throat or nasopharyngeal swabs were submitted for virus isolation. samples were inoculated into human embryonic fibroblast, llc-mk2, hep-2, and rhabdomyosarcoma cell cultures. when a cytopathic effect involved more than 50% of the cell monolayer, cells were scraped and subjected to indirect fluorescent antibody staining with specific antibodies or typed by specific methods according to the suspected types of viruses. rna and dna extraction from throat swabs, and nasopharyngeal swabs were performed using magna pure lc 2.0 system and magna pure lc total nucleic acid isolation kit (roche applied science, roche diagnostics, indianapolis, in, usa). the primers and probes for enterovirus, adenovirus, influenza b, rhinovirus, metapneumovirus real-time pcr, and coronavirus pcr are presented in table 1 . primers and probes for pan-enterovirus were selected based on highly conserved regions in the 5 0 -untranslated region of the enterovirus genome, and design of primers of other viruses are also based on their most conserved regions. the detection limitation of each virus was 100 copies for enterovirus, 100 for adenovirus, 60 for influenza b virus, 50 for rhinovirus, 50 for metapneumovirus, and 10,000 for coronavirus. if the samples had positive viral isolation or pcr, further molecular typing was done. the detailed method of the viral molecular typing is in the supplementary material online. this study was conducted in taiwan only and institutional review board (irb) approval was obtained from national taiwan university hospital (irb number 9361700624). written informed consent was obtained from the parents of all participants. the c 2 test was used to compare the rates of viral isolation and pcr of various viruses between kd cases and the control children. a p value < 0.05 was considered statistically significant. in total, 226 kd cases as well as 226 age-and sex-matched control children were enrolled. the demographic characteristics of the kd cases and the control children are shown in table 2 . the mean age of kd cases was 2.07 ae 1.76 years, the median (range) was 1.57 (0.12e9.43) and the male to female ratio was 1.43 (133 to 93). their age distribution is shown in figure 1 ; about 62% were younger than 2 years old. the demographic characteristics of the control children were comparable to those of the kd cases. table 3 shows the clinical manifestations. their mean (sd) fever duration was 7.5 (2.4) days with mean peak temperature of 39.7 c. for the typical clinical features of kd, rash was found in 92% of the cases, bcg scar erythema and induration in 44%, palm and/or sole erythema and induration in 72%, desquamation in 96% (96% of periungual desquamation and 24% of peri-anal desquamation) and bulbar conjunctivitis in 97%, red lip with fissure and/or strawberry tongue in 95%, and neck lymphadenopathy in 40% of cases. kd cases also had other clinical features including cough (69%), rhinorrhea (58%), and diarrhea (45%). during the acute stage, 14 (6.2%) children required intravenous immunoglobulin retreatment, 116 (51%) patients had coronary arterial lesions, and 28 (12%) patients had coronary arterial aneurysm. for the contact history and the rate of household transmission, 60.8% of the cases had positive contact history: 51.7% of cases had contact with ill household members and 9.1% had positive contact with extra-familial ill people 1e10 days prior to their kd illness. in 129 (57%) of the 226 families, at least one of the other family members had an illness after the onset of disease in the kd cases. table 4 shows the results of viral isolation and table 5 shows the results of viral pcr between the kd cases and the control participants. kd cases had significantly higher rates of viral isolation (7.5% vs. 2.2%, p z 0.02) than the control children. they also had significantly higher positive rates of pcr (50.4% vs. 16 table 6 . as for further typing, only one case of echovirus 6 and one case of ev71 were identified among the 40 enteroviralpositive kd cases and the other enterovirus serotyping failed due to low viral titer. for adenovirus, six cases of 28 (12) data are presented as n (%), unless otherwise indicated. kd z kawasaki disease; sd z standard deviation. a coronary arterial lesions were defined as coronary arterial dilatation/ectasia, aneurysm, increased echogenicity or irregularity, and coronary artery aneurysm. b a coronary artery aneurysm was defined as having a lumen diameter (inner border to inner border) of !3 mm in kd cases <5 years old and !4 mm in cases !5 years old. serotype 3, five cases of serotype 5, three cases of serotype 2, one case of serotype 1, and one case of serotype 4 were identified in kd cases, whereas two cases of adenovirus serotype 2, one case of serotype 3, and one case of serotype 1 were identified in the control children. for coronavirus, 12 cases of human coronavirus nl63, three cases of human coronavirus 229e, and one case of human coronavirus oc43 were identified in kd cases whereas two of human coronavirus 229e were identified in the control children. for rhinovirus, 36 serotypes were identified and type c was the most common (7 cases) in the 60 rhinoviruspositive kd cases whereas 14 serotypes were identified and the antwerp rv 98/99 type was the most common (5 cases) among the 22 rhinovirus-positive control children. overall, 119 (52.7%) kd cases had positive viral results by either viral isolation or pcr. however, kd cases with positive viral results did not have significantly higher percentages of needing intravenous immunoglobulin retreatment (4% vs. 8%, p z 0.18), coronary arterial lesions (53% vs. 50%, p z 0.70), or coronary arterial aneurysm (11% vs. 14%, p z 0.45) than kd cases without positive viral results. this was a prospective study to investigate the association of common viruses with kawasaki disease. we found that cases of kd frequently had a cough (69%), rhinorrhea (58%), and diarrhea (51%) in addition to the typical symptoms of kd; several common respiratory viruses were also more frequently detected in cases of kd than in the control children. we propose that heterogeneous infectious agents, such as common viruses found in our study, may trigger kawasaki disease in young children with certain genetic backgrounds or susceptibility. the leading theory of kd etiology is that a ubiquitous infectious etiologic agent, that usually results in asymptomatic or mild infection in most people, causes kd in a small subset of genetically predisposed children. in our study, approximately 60% of kd cases had a preceding contact history with people of febrile, respiratory, or gastrointestinal illness, and kd cases frequently had cough (69%), rhinorrhea (58%), and diarrhea (45%), which supported certain kinds of viral infections. a winterespring predominance of kd cases in non-temperate climates also suggests the association of kd with some kinds of viral infections, 11 particularly a respiratory infection, and this theory is supported by the two articles which reported a preceding history of respiratory illness in some kd patients. 7, 8 the other infectious evidence of kawasaki disease includes geographic clustering, family clustering, high association between kawasaki disease and infectious disease surveillance, and age distribution, with the highest incidence rates among children aged from 6 months to 2 years old who have low maternal antibodies and are most susceptible to infections in general. 11e14 many studies worked on a certain single pathogen to be associated with kd. various infectious agents including bacterial (staphylococcus aureus, group a streptococcus, yersinia pseudotuberculosis, klebsiella pneumoniae, pseudomonas aeruginosa), viral (parvovirus b19, eps-teinebarr virus, cmv, hhv6, retrovirus, rotavirus, para-influenza virus, new haven coronavirus, measles, chickenpox, dengue fever), chlamydiae pneumoniae, mycoplasma pneumoniae, rickettsial organisms, and so-called kd agent, a viral etiology characterized by intracytoplasmic inclusion bodies, have been found to be associated with kd. 15e39 however, at present, links between any of these individual agents and kd have not been irrefutably established. although kd had temporal clustering, different seasonality was found in different countries. for example, studies from europe and canada reported a higher incidence in winter, 40 whereas taiwan and korea have the highest incidence rates of kd during the summer, 11, 41 beijing and hong kong in the spring and summer, and japan in january and summer. 3, 42, 43 such seasonality and temporal clustering of kd suggests that different infectious diseases in different countries might trigger this clustering presentation. in the summer, enterovirus infection was one of the most common infections in young children in taiwan. we also detected enterovirus most frequently in kd cases, which links enterovirus with kd in the summer. other respiratory viruses, such as adenoviruses, may play an important role during other seasons because adenoviruses circulate all year-round in taiwan. we proposed that it was not the same infectious etiology, but rather heterogeneous infectious agents in different areas and different seasons, which trigger kd; there was no single pathogen reported to be associated with kd worldwide. that is to say, different pathogens might be responsible for kd in different countries or different seasons. this may explain why no single pathogen was consistently found in cases with kawasaki disease. for example, jordan-villegas et al 44 reported that 8.8% of kd patients had documented respiratory viral infections including rhinovirus, adenovirus, influenza, parainfluenza, and respiratory syncytial virus. a recent article also reported a case of kd associated with parainfluenza type 3 viral infection, 45 and another article reported adenovirus detection in some kd cases. 46 however, kim et al 47 reported that there was no significant association between the presence of any of the 15 respiratory viruses and the incidence of kd. new tests or techniques for specific microorganisms may help us find the etiology of kd. 48, 49 in conclusion, we found that common respiratory viruses, such as enteroviruses, adenoviruses, rhinoviruses, and coronaviruses, were associated with kd. heterogeneous infectious etiologies may be responsible for kd in different countries as well as during different seasons. pediatric acute febrile mucocutaneous lymph node syndrome with characteristic desquamation of fingers and toes: my clinical observation of fifty cases epidemiologic pictures of kawasaki disease in japan: from the nationwide incidence survey in 1991 and 1992 epidemiologic study on kawasaki disease in beijing from kawasaki syndrome hospitalizations in the united states kawasaki syndrome hospitalizations and associated costs in the united states incidence of henocheschonlein purpura, kawasaki disease, and rare vasculitides in children of different ethnic origins epidemiologic study of kawasaki disease in korea, 1997e1999: comparison with previous studies during 1991e1996 kawasaki disease in australia kawasaki disease in sweden: incidence and clinical features kawasaki disease in finland in 1982e1992 epidemiological features of kawasaki disease in taiwan from changes in epidemic patterns of kawasaki disease in japan validity of the infectious disease surveillance system on comparison of nationwide surveys of kawasaki disease during a 10-year period temporal and geographic clustering of kawasaki disease in japan the pathogenesis of kawasaki disease and superantigens lack of association between kawasaki syndrome and chlamydia pneumoniae infection: an investigation of a kawasaki syndrome lack of association between kawasaki syndrome and infection with parvovirus b19, human herpesvirus 8, tt virus, gb virus c/hepatitis g virus or chlamydia pneumoniae kawasaki syndrome: description of two outbreaks in the united states an epidemic of kawasaki syndrome in hawaii mucocutaneous lymph node syndrome (kawasaki disease) in israel. a review of 13 cases: is pseudomonas infection responsible? staphylococcal scalded skin syndrome, toxic shock syndrome, and kawasaki disease coronary aneurysms in a patient with atypical kawasaki syndrome and a streptococcal infection trial of isolation of a virus from sera of patients with kawasaki disease kawasaki syndrome: a controlled study of an outbreak in wisconsin epsteinebarr virus genome-positive t lymphocytes in a boy with chronic active ebv infection associated with kawasaki-like disease kawasaki syndrome: issues in etiology and treatment human herpesvirus 6 infection and kawasaki disease prevalence of antibodies to human herpesvirus 6 in different age groups, in children with exanthema subitum, other acute exanthematous childhood diseases, kawasaki syndrome, and acute infections with other herpesviruses and hiv epsteinebarr virus and other herpesvirus infections in kawasaki syndrome adenovirus infection in patients with kawasaki disease possible role of streptococcus pyogenes in mucocutaneous lymph node syndrome. xii. variable responses of platelets in mcls seem to be explainable by streptococcal pyrogenic exotoxin kawasaki disease and epstein-barr virus viruslike particles with reverse transcriptase activity associated with kawasaki disease toxic shock syndrome toxin-secreting staphylococcus aureus in kawasaki syndrome kawasaki disease associated with streptococcal infection within a family serologic evidence that streptococcal superantigens are not involved in the pathogenesis of kawasaki disease kawasaki syndrome associated with group a streptococcal and epsteinebarr virus co-infections lack of association between kawasaki syndrome and infection with rickettsia conorii, rickettsia typhi, coxiella burnetii or ehrlichia phagocytophila group cytoplasmic inclusion bodies are detected by synthetic antibody in ciliated bronchial epithelium during acute kawasaki disease kawasaki syndrome hospitalizations in ireland kawasaki disease in korea kawasaki disease in hong kong seasonality and temporal clustering of kawasaki syndrome concomitant respiratory viral infections in children with kawasaki disease kawasaki disease associated with parainfluenza type 3 virus infection human adenovirus infection in kawasaki disease: a confounding bystander detection rate and clinical impact of respiratory viruses in children with kawasaki disease a highly specific elisa for diagnosis of 2009 influenza a (h1n1) virus infections seroprevalence of hepatitis virus infection in men who have sex with men aged 18e40 years in taiwan supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jfma.2013.12.008. key: cord-323202-kcy8xoos authors: burns, jane c.; dehaan, laurel l.; shimizu, chisato; bainto, emelia v.; tremoulet, adriana h.; cayan, daniel r.; burney, jennifer a. title: temporal clusters of kawasaki disease cases share distinct phenotypes that suggest response to diverse triggers date: 2020-09-22 journal: j pediatr doi: 10.1016/j.jpeds.2020.09.043 sha: doc_id: 323202 cord_uid: kcy8xoos objective: to test the hypothesis that cases of kawasaki disease within a temporal cluster have a similar pattern of host response that is distinct from cases of kawasaki disease in different observed clusters and randomly constructed clusters. study design: we designed a case-control study to analyze 47 clusters derived from 1332 patients with kawasaki disease over a 17-yr. period (2002-2019) from a single clinical site and compared the cluster characteristics with two control groups of synthetic kd clusters. we defined a “true” kd cluster as at least 5 patients within a 7-day moving window. the observed and synthetic kd clusters were compared with respect to demographic and clinical characteristics and median values for standard laboratory data using univariate analysis and a multivariate, rotated empirical orthogonal function analysis (reofs). results: in a univariate analysis, the median values for age, coronary artery z score, white blood cell count, erythrocyte sedimentation rate, c-reactive protein, and age-adjusted hemoglobin for several of the true kd clusters exceeded the 95th percentile for the two synthetic clusters. reofs revealed distinct patterns of demographic and clinical measures within clusters. conclusions: cases of kawasaki disease within a cluster were more similar with respect to demographic and clinical features, and levels of inflammation than would be expected by chance. these observations suggest that different triggers and/or different intensity of exposures result in clusters of cases of kawasaki disease that share a similar response pattern. analyzing cases within clusters or cases who share demographic and clinical features may lead to new insights into the etiology of kd. kawasaki disease, a pediatric self-limited vasculitis that affects the coronary arteries, has eluded attempts to discover its etiology for over four decades. 1 epidemiologic clues have provided valuable insights into the nature of the disease including the genetic predisposition that underlies susceptibility. 2 the elucidation of the distinct seasonality, the lack of documented person-toperson spread, and the spatiotemporal clustering of cases all suggest a fluctuating exposure that triggers the disease. 3 clinical features of the illness, including mucosal inflammation of the lips, tongue, and upper airway coupled with cervical lymphadenopathy and hoarseness, all point to a trigger that enters through the nasopharynx. 4, 5 specific atmospheric patterns have been linked to clusters of cases of kawasaki disease that may increase exposure to the causative trigger. 3 although kd is conceptualized as a monomorphic disease, it may be more accurate to characterize it as a syndrome with subtle variation among clinical sub-groups. certain clinical features are not universal among patients with kawasaki disease. these include the "node-first" presentation with fever and cervical lymphadenopathy, the specific injury pattern to the tongue usually associated with bacterial toxins (strawberry tongue), and the characteristic periungual desquamation in the convalescent phase. 5, 6 the prospective collection of detailed demographic and clinical details on cases of kawasaki disease treated at rady children's hospital san diego allowed statistical analysis of the temporal pattern of cases of kawasaki disease over many years, revealing clustering of cases beyond what would be expected due to kd seasonality and trends alone. analysis of demographic and clinical characteristics of cases within these temporal clusters was compared with synthetic control clusters derived from either re-shuffling members of clusters or creating clusters of same-season cases that did not occur within observed clusters. the results highlighted the shared features within a cluster and suggest that future research on etiology should prioritize the separate analysis of cases that share similar sub-phenotypes. j o u r n a l p r e -p r o o f we enrolled 1,332 patients with kd who met american heart association (aha) guidelines for complete or incomplete kd and were diagnosed and treated at rady children's hospital san diego (rchsd) between january 1, 2002 and march 31, 2019. 7 the worst ca z score was defined as previously published. 8 the collection of data was approved by the institutional review board at the university of california san diego and parents and participants gave signed informed consent or assent as appropriate. we computed the distribution density of case onsets (cases per 7-day period) across the entire sample. we took the value associated with the high tail of the 95% confidence interval (97.5 th percentile) of the density distribution as the starting definition for a temporal cluster, which was 5 or more cases in 7 days (figure 1 ). across the time series, any day that was part of a moving window in which case density equaled or exceeded 5 cases in 7 days was classified as a cluster day (irrespective of whether or not it had a case onset), and any kd onset falling in those windows was classified as a "cluster" case. cases outside of that window were classified as "non-cluster" cases of kawasaki disease. we used a set of 14 clinical and demographic quantities to calculate cluster-level characteristics (names used in figures shown in bold). patient residence longitude and latitude -due to the very large geographic catchment area, we used geospatial coordinates to understand potential spatial dependence of clinical clusters. for cluster-level summaries, we used median longitude and latitude. because of the uneven j o u r n a l p r e -p r o o f distribution of ethnic/racial groups in our region, we considered these geospatial coordinates as a surrogate for race/ethnicity. patient age at date of onset with the first day of fever designated as illness day 1. for clusterlevel summaries, we used median age at onset. laboratory data prior to ivig infusion and within the first 15 days after fever onset: white blood cell count (wbc), platelet count (plt), erythrocyte sedimentation rate (esr), c-reactive protein (crp), and age-adjusted hemoglobin (zhemo). maximal coronary artery z score for the right coronary artery (rca) and left anterior descending artery (lad) was determined by echocardiography (zworst). for cluster-level analysis, we used median values for each of these quantities. hepatic enzyme elevations were analyzed as a dichotomous variable (alt_abnormal) with normal defined as below the age-adjusted upper limit of normal for alanine amino transferase (alt) (< 60 iu), and abnormal values defined as >100 iu. for cluster-level analysis, mean values were used. patient sex and the presence of a strawberry tongue (strawberry), enlarged cervical lymph nodes >1.5 cm (lymphnode), and convalescent peeling fingers or toes (peeling). for cluster-level summaries of these characteristics, we used mean values. we also computed the variance of each attribute for each cluster as a metric of similarity of patients within a cluster. for any clusters that included cases who presented beyond illness day 15, we calculated cluster-level values excluding these cases to prevent skewing of the data from patients diagnosed later in the illness when laboratory values of inflammation might be normalizing. overall, there were 18 cases whose laboratory data were excluded from analysis because of diagnosis beyond day 15. j o u r n a l p r e -p r o o f created 100 sets of synthetic clusters of the same size distribution as the observed clusters, hereafter called true clusters; we created synthetic clusters by shuffling cluster membership among the 315 cluster cases of kawasaki disease (shuffled clusters). the universe of cluster cases was randomly re-allocated to 47 groups of the same size as the true observed temporal clusters. we also created a set of synthetic clusters drawn from non-kd cluster cases that occurred in any year, but within the same season (control clusters). individual clusters as outliers: we assessed the degree to which each individual cluster was anomalous relative to both sets of synthetic clusters by testing whether the cluster-average value for each clinical characteristic lay outside the range of averages among the comparison groups (e.g., we compared median age of true cluster #7 to the distribution of median age in 100 shuffled cluster #7s and 100 control cluster #7s). we calculated a p-value for each true cluster compared to these groups. we also compared the variances of attributes in the true clusters compared to the synthetic comparison clusters (e.g., we compared variance in age of true cluster #7 to the variance in age in 100 shuffled cluster #7s and 100 control cluster #7s). we also compared the full distribution of average values and variances in the true clusters with a sample drawn from each of the comparison groups. this allowed us to assess whether the true clusters as a whole represented a departure from the comparison groups: that is, does the temporal clustering overall produce a different distribution of traits, beyond individual clusters? we took a random draw of 1 of each of the 47 groups of 100 shuffled clusters and 1 of each of the 47 groups of 100 control clusters, and compared, for example, the j o u r n a l p r e -p r o o f distribution of 47 true cluster median ages to the distributions of these two groups of 47 synthetic clusters. a key question is whether existing sets of clusters differ repeatedly from other clusters by combinations of clinical or demographic characteristics either in addition to or in lieu of, individual characteristics. to assess this, we conducted a rotated empirical orthogonal function (reof) analysis. 9 this is similar to principal component analysis, extracting statistically independent "modes" of kd, wherein the first few explain a relatively large portion of the variance of the entire data sample. varimax rotation was used to identify patterns of unusually high or low expression in the demographic or clinical characteristics in subsets of the clusters. details of reof generation are in supplemental methods. the dataset contained 47 clusters consisting of 315 cases of kawasaki disease. (figure 1 ) to determine if more cases of kawasaki disease had their onset in clusters than would be expected at random, we used a monte-carlo analysis to create 100 timeseries with an equivalent number of cases from all days in the study period, which would account for seasonality and diagnosis trends over time. we tallied the clusters in these timeseries according to the same cluster definition and calculated the distribution of clusters. although a certain number of clusters of 5 or more cases in 7 days occurred at random, a larger number of clusters of 6-7 cases in 7 days occurred in the true data compared with the monte carlo simulation. (figure 1 , e) this indicated that more cases of kawasaki disease were included in clusters than would be expected j o u r n a l p r e -p r o o f by chance. however, grouped together, the demographic and clinical characteristics of the 315 cluster cases of kawasaki disease were compared with the 1,017 non-cluster cases of kawasaki disease and no significant differences were noted (table) . in the univariate analysis, cluster-level averages of demographic and clinical characteristics were compared between the set of 47 true kd clusters and 100 sets of 47 synthetic clusters of equal size created either by randomly shuffling membership of cluster cases (referred to as shuffled clusters) or by randomly creating clusters from non-cluster cases of kawasaki disease within the same season as the true cluster (referred to as control clusters). (figure 2 ; available at www.jpeds.com) striking differences were noted between individual true clusters and synthetic clusters for the following variables: age, esr, and the presence of enlarged lymph nodes or strawberry tongue. for all of the characteristics, the difference in the true cluster distribution versus either set of synthetic clusters was highly significant (appendix figure 1 ; available at www.jpeds.com). we next analyzed the coherence of characteristics of cases within true clusters. we calculated the intra-cluster correlation (icc) coefficient, which shows the percentage of the variance that occurs between versus within clusters (appendix table; available at www.jpeds.com). in this analysis, lymph node, wbc, esr, age, and plt were significantly more similar within true clusters than between true clusters (p=0.007, 0.008, 0.009, 0.035, and 0.045, respectively). to help visualize the variation within and between clusters, individual cluster distributions for the true clusters are shown for several characteristics in appendix figure 2 (available at www.jpeds.com). in the multivariable analysis, the first four reofs together explained 55% of the total variance of the true clusters: reof1 explained 18%, reof2 explained 13%, j o u r n a l p r e -p r o o f and reof3 and reof4 each explained 12%. for each of these four reofs, the highest weightings on the 14 characteristics were identified to determine the defining characteristics presented in the true clusters (figure 3, a) . several of the defining characteristics in the multivariable analysis also were identified as strongly expressed features in the univariate analysis. for reof1, the defining characteristics (the characteristics with a weight larger than one standard deviation) were esr, crp, and zhemo. clusters that loaded strongly (positively or negatively) onto this reof had a higher than average esr and crp and a lower than average zhemo or had a lower than average esr and crp and a higher than average zhemo (appendix the prevalence of these defining characteristics can be seen in figure 3 , b, evaluating this pattern from reofs obtained in a monte carlo sampling of the true clusters versus those from the shuffled and control clusters. from the true set of monte carlo samples, an reof was found with the defining characteristics esr, crp and zhemo almost 50% of the time, whereas from the shuffled clusters, this relationship occurred less than 25% of the time, and from the control clusters it occurred less than 15% of the time. this indicated that the true clusters expressed a much stronger relationship amongst these three characteristics than would be expected by chance. the defining characteristics of reof2 were age, sex, and wbc, with age and fraction male presenting in the same direction and wbc in the opposite direction. thus, some clusters had older patients with a higher percentage of males and lower white blood count and other clusters had younger patients with a lower percentage of males and higher white blood count. because reof2 captured less variability in the overall cluster universe than reof1, these defining characteristics were less prevalent than the reof1 defining characteristics, but still occurred j o u r n a l p r e -p r o o f over 20% of the time in the true cluster population. as with reof1, this relationship was much stronger in the true clusters than in the synthetic clusters --both shuffled clusters and control clusters produced this combination in only about 3% of the 3000 monte carlo trials. reof3 described a relationship between age, lymph nodes, and alt_abnormal in one direction and plt in the other. reof4 described a relationship between lymph nodes, periungual peeling, and location of patient residence (positive latitude with negative longitude indicated clusters from the northwest portion of the catchment area). although these reofs were less prevalent than reof1 and reof2, the monte carlo trials yielded such patterns significantly more frequently in the true clusters than in either the control or shuffled clusters. historically, kd has been thought of as a monomorphic disease, with research efforts focused on these patients as a homogenous group. however, our clinical experience in diagnosing and treating patients with kawasaki disease has suggested that many of the "classic" features of kd are not universal and that patients with certain sub-phenotypes are not evenly distributed over time, even after accounting for seasonality. our analysis focused on temporal kd clusters and examined the characteristics of cases within and across clusters, as well as non-cluster cases, in the rchsd time series. a series of tests indicated that individual clusters exhibited distinctive clinical and demographic characteristics. first, temporal clusters occurred more often than would be expected by chance. second, in assessing whether cases of kawasaki disease within these true clusters were different from cases of kawasaki disease not in clusters, we found that the overall central tendencies between cluster and non-cluster cases were similar (table) . thus, it was not simply a question of clustered cases being different than non-clustered cases. third, the data revealed important in the univariate analysis, esr and crp, both markers of systemic inflammation, were markedly elevated in certain clusters but not others. in the multivariable reof analysis, it was further revealed that these measures of inflammation when elevated were more likely to be associated with low hemoglobin levels and vice versa (lower measures of inflammation associated with normal hemoglobin). although this makes sense biologically, the important finding was that some clusters had this composite feature whereas other clusters did not. with respect to clinical features, cases manifesting "strawberry tongue" or "lymph node first presentation" also clustered, as did cases without these clinical features (figure 2) . strawberry tongue is a specific mucosal injury pattern that involves the sloughing of the cornified tips of the filiform papillae and is associated with bacterial toxin-mediated disease. 11 overall in our time series, only 477/805 (59.3%) patients had this phenotype at the time of diagnosis, but strawberry tongue registered quite strongly as one of the important characteristics in true clusters, wherein its distribution differed from that in synthetic clusters (appendix figure 1, m) . the lymph node first presentation suggests an exaggerated immune response in regional lymph nodes to an antigenic stimulus that enters through the mucosal surfaces of the posterior oropharynx. children presenting with only fever and enlarged cervical lymph nodes during the first week of illness have been described and represented 32.6% of patients from our center. 5 the clustered presence or absence of these phenotypes in patients with kawasaki disease differed significantly from the two groups of synthetic clusters, which might suggest that the patients with kawasaki disease within these clusters were responding to different stimuli leading to these different clinical presentations. similarly, laboratory evidence of inflammation was either high or low in different clusters, again suggesting a non-random distribution of these features. in the reof analysis, certain laboratory and clinical features were associated within the true clusters more often than expected by chance. some of these statistical findings were consistent with our understanding of the biology of kd. for example, higher inflammatory markers (esr and crp) were linked to more pronounced anemia and vice versa. similarly, in reof 5, higher z max was linked to higher esr and platelet count. however, other relationships, such as reof 3 that described a relationship between older age, enlarged lymph nodes, and elevated liver enzymes with lower platelet count were unexpected. thus, new relationships of features revealed by the analysis could be used to group patients for study of genetic susceptibility and molecular investigations of potential etiologic agents. these observations suggest that different triggers or different intensity of exposures may operate to produce cases of kawasaki disease that cluster temporally and share a similar response pattern. important insight into the different etiologies of kd may be gained by focusing on patients who share the demographic and clinical phenotypes identified in these analyses. (e) monte carlo simulation drawing 100 time series of 1,332 randomly-selected dates with the same time trend and seasonality as the true data (blue squares) and comparing that to the true data (black dots) shows more clusters of 6-7 cases in the true data than would be expected from a random distribution of established trends and seasonality. illness day of lab data 5 (4-7) 6 (4-7) laboratory data j o u r n a l p r e -p r o o f a new infantile acute febrile mucocutaneous lymph node syndrome (mlns) prevailing in japan the genetics of kawasaki disease clustering and climate associations of kawasaki disease in san diego county suggest environmental triggers hoarseness as a presenting sign in children with kawasaki disease lymphnode-first presentation of kawasaki disease compared with bacterial cervical adenitis and typical kawasaki disease periungual desquamation in patients with kawasaki disease term management of kawasaki disease: a scientific statement for health professionals from the american heart association kawasaki disease outcomes and response to therapy in a multiethnic community: a 10-year experience rotation of principal components clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 of subjects with the finding/no. of subjects for whom the observation of the presence or absence of the finding was made abbreviations: ln: lymph node; wbc: white blood cell count; z-hemoglobin: hemoglobin concentration normalized for age; alt: alanine aminotransferase; esr: erythrocyte sedimentation rate; crp: c-reactive protein; ns: not significant key: cord-280280-9jr7ekbu authors: bertoncelli, deborah; guidarini, marta; della greca, anna; ratti, chiara; falcinella, francesca; iovane, brunella; dutto, mauro luigi; caffarelli, carlo; tchana, bertrand title: covid19: potential cardiovascular issues in pediatric patients date: 2020-05-11 journal: acta biomed doi: 10.23750/abm.v91i2.9655 sha: doc_id: 280280 cord_uid: 9jr7ekbu the novel severe acute respiratory syndrome coronavirus 2 (sars-cov 2) has rapidly spread worldwide with increasing hospitalization and mortality rate. ongoing studies and accumulated data are detailing the features and the effects of the new coronavirus disease 19 (covid 19) in the adult population, and cardiovascular involvement is emerging as the most significant and life-threatening complication, with an increased risk of morbidity and mortality in patients with underlying cardiovascular disease. at present, though the limited data on the effects of covid 19 in pediatric patients, children seem to count for a little proportion of sars-cov 2 infection, and present with less severe disease and effects however infants and toddlers are at risk of developing critical course. the disease has a range of clinical presentations in children, for which the potential need for further investigation of myocardial injury and cardiovascular issues should be kept in mind to avoid misdiagnosing severe clinical entities. overlapping with kawasaki disease is a concern, particularly the incomplete and atypical form. we aim to summarize the initial considerations and potential cardiovascular implications of covid-19 for children and patients with congenital heart disease. (www.actabiomedica.it) coronavirus disease 19 (covid-19) is a severe acute respiratory syndrome for which the etiologic agent is the novel beta coronavirus sars-cov-2, first described in december 2019 in china in a cluster of patients presenting with pneumonia. in the past few months, the disease has spread worldwide and become a pandemic. since the outbreak began, the virus has raised concerns among medical professionals worldwide because of the increasing rates of patient hospitalization and mortality. the main presenting clinical feature of the disease is pneumonia, ranging from asymptomatic or mildly symptomatic to severe acute respiratory distress syndrome, but cardiovascular involvement is emerging as one of the most significant and life-threatening complications of sars-cov-2 infection (1, 2) . in addition, patients with underlying cardiovascular diseases (cvds) may be subject to an increased risk of death (1, 2, 3) . at present data are limited regarding the incidence and effects of covid-19 in pediatric patients, but it seems that children present with less severe effects and disease. we aim to summarize the initial considerations and potential cardiovascular implications of covid-19 for children and patients with congenital heart disease. viral infection has been widely described as one of the most common infectious causes of myo-carditis. some reports suggest that sars-cov and middle east respiratory syndrome-related coronavirus (mers-cov) share similar pathogenicity with sars-cov-2 (1), and since the previous coronavirus epidemics (sars-cov and mers-cov), known cases of myocarditis have been caused by these viruses (4) (5) (6) . furthermore, patients with underlying heart disease (both congenital or acquired) seem to have increased morbidity and mortality related to viral infections (7) . the pathogenesis of cardiac involvement associated with sars-cov-2 may reflect a process of replication and dissemination of the virus through the blood and/or the lymphatic system from the respiratory tract. sars-cov-2 may lead to cardiac injury via several hypothetical mechanisms: -the sars-cov-2 virus uses ace2 as a receptor for entry into the cell; this enzyme is widely expressed in the lungs but also in the heart and blood vessels. it is unclear at this time, however, whether the sars-cov-2 binding alters ace2 expression or causes dysregulation of the raas (renin-angiotensin-aldosterone system) pathway (8) (9) (10) (11) . -viral invasion may lead to an unbalanced response by type 1 and type 2 t helper cells, triggering an exaggerated inflammatory and immune response and a cytokine storm. the mechanism by which cytokines damage the myocardium is still unknown (12) (13) (14) (15) (16) (17) . -the acute lung injury caused by the virus leads to acute respiratory damage and subsequent severe hypoxia, which may result in oxidative stress, endothelial shedding, microvascular damage, and myocardial injury due to increased myocardial oxygen demand (14, 18, 19) . -direct viral toxicity to cardiomyocytes has been shown in other viral infections, such as coxsackievirus or influenza-induced myocarditis, but in the setting of sars-cov-2 infection, though cases of myocarditis have been described (20) (21) (22) (23) , of cardiomyocytes viral invasion and direct damage have not yet been proven in pathology studies. sars-cov-2 infection facilitates the induction of endotheliitis as a direct consequence of viral involvement and of the host's inflammatory response. endothelial dysfunction is the main determinant of microvascular dysfunction because it shifts the vascular equilibrium toward more vasoconstriction, inflammation with associated tissue edema, and a procoagulant state, contributing to vessel thrombosis and subsequent organ ischemia (18, 19, 24) . studies have shown that a significant percentage of patients affected with covid-19 displayed evidence of myocardial injury (2, 3, 7, 13, 14, 17, 18) . sars-cov-2 cardiac involvement mainly manifested as an increase in the levels of biomarkers of myocardial injury: high-sensitivity cardiac troponin i, n-terminal pro b-type natriuretic peptide, and ck-mb (1, 2, 7, 24, 25, 26) . patients with covid-19 can present with chest pain, dyspnea, palpitations, dysrhythmia, and acute left ventricular dysfunction (1, 2, 18, 21, 28) . dysrhythmias may occur in the setting of viral illness due to hypoxia, inflammatory stress, and abnormal metabolism, but no specific ecg changes have been described in patients with sars-cov2 infection. myocardial injury may be drug-related. although currently no specific effective therapies for covid-19 exist, various pharmacologic agents are under active investigation, mainly antivirals (remdesivir, lopinavir/ritonavir, favilavir), antimalarials (chloroquine, hydroxychloroquine), corticosteroids, monoclonal antibodies and antibiotics (azithromycin) (29) (30) (31) (32) (33) . many antiviral drugs can cause cardiac insufficiency, arrhythmia, or other cardiovascular disorders (1, 2, 17, 34, 35) . antimalarials and some antibiotics can cause qt interval prolongation and malignant arrhythmias (35, 36) . children do not seem to count for a large proportion of covid-19 disease infections. numbers gathered from different studies suggest a great deal of variation in incidence, 2% in the largest series from china, 1.2% in the pediatric cohort from italy, 4.8% in korea, and 1.7% in the united states (37, 38, 39, 40) . it is possible that protective measures, especially social distancing from children and community closure, have impacted the incidence in pediatric patients. only limited data detail the effects of covid-19 on the pediatric population. preliminary evidence suggests children are just as likely as adults to become infected with sars-cov-2 but are less likely to be sympto-matic or develop severe symptoms. in the largest series published to date, 94.1% of the children were either asymptomatic or had mild to moderate disease (37, (41) (42) (43) (44) . information about pediatric patients requiring intensive care is scarce. the largest pediatric series showed 5.2% of children with respiratory distress or hypoxia and 0.6% who progressed to acute respiratory distress syndrome or multiple organ dysfunction (37) . children under 5 years of age are at risk of developing severe disease, with infants presenting the highest risk (37, 42, 45, 46) . laboratory findings do not show a tendency toward immune dysregulation and blood count and pro-inflammatory markers may be normal, but altered liver function test results are common, as are d-dimers, especially in severe cases (38, 43, 44, 46) . children with sars-cov-2 may present with flu-like features, fever, cough, and shortness of breath, as the most frequent symptoms (38, 42, 43, 47) . chest pain may be present in some cases, while others may show vomiting, abdominal pain, and diarrhea as the only symptoms (48) . infants and children with severe forms may present looking very ill, with cold extremities, weak peripheral pulses, and hepatomegaly (45, 46, 48) . tachycardia is seen as a result of multiple, simultaneous causes (fever, dyspnea, pain, anxiety, etc.) and is usually sinus tachycardia without any other significant signs on an ecg (48) . acute myocardial injury is rare in children and adolescents. it is usually associated with either an acute inflammatory condition of the myocardium or the coronary arteries, or an anomalous origin in the left coronary artery. myocardial injury may derive from myocarditis, an inflammatory disease of the myocardium, or pericarditis, irritation or inflammation of the pericardial layers, with viral infection as the most commonly identified cause (epstein-barr virus, adenovirus, parvovirus b19, coxsackievirus, influenza virus, enterovirus, and echovirus) (49) (50) (51) . children with sars-cov-2 may present with another viral agent coinfection (48) . the clinical manifestations of myocarditis and pericarditis can range from mild nonspecific symptoms to chest pain to cardiogenic shock. myocarditis in children may present with flu-like symptoms, shortness of breath, tachycardia, dyspnea, nausea, and decreased appetite, or poor feeding and tachypnea in infants (50, 51) . in the fulminant form, the children are critically ill with cold extremities, weak peripheral pulses, a gallop rhythm, and hepatomegaly more commonly than rales and edema. pericarditis, most common in adolescents, classically presents with chest pain exacerbated when supine, when coughing, or with inspiration and relieved by the sitting position (50, 51) . elevated cardiac biomarkers such as creatine kinase muscle-brain isoenzyme, troponin i, and troponin t (reported to have specificity of 86% and sensitivity of 71% in children) (51) and ecg anomalies (st segment and t wave changes, qrs complex voltage) confirm the diagnosis of cardiac injury. troponin i and t levels are more frequently elevated in acute myocarditis than are creatine kinase musclebrain levels (50, 51) . however, normal biomarker levels do not completely exclude myocarditis. covid-19 may sometimes present with the clinical features of vasculitis, mimicking characteristics of kawasaki disease, an acute febrile illness with cardiac involvement and a predilection for the coronary arteries, for which we can distinguish a typical, atypical and an incomplete form. in the typical form, kawasaki disease is characterized by enanthem (mucous membrane rash), bulbar conjunctivitis, rash, lymphadenopathy, and extremity changes (52, 53) . the incomplete form is diagnosed when the patient presents with typical fever, two or three of the principal clinical features, and suggestive laboratory findings such as elevated erythrocyte sedimentation rate, elevated creactive protein, hypoalbuminemia, anemia, elevated alanine aminotransferase, thrombocytosis, or leukocytosis (52, 53) . atypical form is characterized by typical fever and clinical features different from the main signs and symptoms of kawasaki disease (pneumonia, acute abdomen, central nervous, system involvement, nephritis, myositis, etc.…) (52, 53) . although decades of investigation, and some evidence suggesting for an infectious trigger, etiology of kawasaki disease remain unknown. association of kawasaki disease with viral respiratory infections have been described in several studies, including human coronavirus (54) (55) (56) (57) . initial hypothesis of dr tomisaku kawasaki was that a coro-navirus was the etiologic cause of the mucocutaneous lymph node syndrome he was describing. several clinical signs of kawasaki disease providing important diagnostic clues have not been included in the diagnostic criteria, myocarditis, sterile pyuria, peripheral arthritis, and may also present with covid-19 confounding furthermore the diagnosis. the cytokine storm present in a phase of sars-cov 2 disease recall the role of inflammatory biomarkers in kawasaki disease, particularly interleukine 6. in some cases, covid-19 presentation may raise doubts, mainly related to incomplete or atypical kawasaki disease, and differentiating the entities may be challenging but fundamental because of the potential serious cardiac sequelae. we learn from the adult cohort that patients with preexisting cardiovascular diseases have increased morbidity and mortality. according to a morbidity/mortality report by the centers for disease control of the united states, among the pediatric cases with information on underlying conditions, the most common underlying condition after chronic lung disease was cardiovascular disease (58, 59) . up to now, no studies detail the risk of individual cardiovascular complications in patients with underlying cardiovascular disease who are infected with sars-cov-2, neither have any studies included patients with congenital heart disease standing on what is known some patients with congenital heart disease are at high risk, depending on the complexity of the lesion and their clinical and surgical status. syndromic patients, especially those with reduced immunity, including heterotaxy syndrome, down syndrome, digeorge syndrome, and asplenia, may be at even higher risk (7, 60) . children with congenital heart disease who may be at higher risk for serious illness from sars-cov 2 include: -patients with single heart physiology: hypoplastic left heart syndrome, tricuspid atresia, pulmonary atresia, unbalanced atrioventricular canal, glenn anastomosis, fontan procedure -patients with surgical aorto-pulmonary connection, modified blalock-taussig shunt, waterson anastomosis, potts anastomosis, pulmonary artery banding -patients with pulmonary hypertension -patients who are due to have surgery in the near future, large ventricular septal defect, atrioventricular septal defect, tetralogy of fallot, total anomalous pulmonary venous return. any child with a cardiopathy requiring medication for heart failure, may experience a worsening of their clinical status because of the hemodynamic impact of the lung involvement and/or myocardial injury of sars-cov-2 infection. children who have had previous heart surgery without sequelae and are not taking any heart medications may follow basic preventive indications. covid-19-related issues such as fever, electrolyte disturbance, and current treatment may have a pro-arrhythmic effect, making it challenging to manage the illness in children with inherited (long qt syndrome, brugada syndrome, short qt syndrome and catecholaminergic polymorphic ventricular tachycardia) or acquired arrhythmias, sometimes associated with repaired or unrepaired congenital structural heat lesions. active studies are evaluating different agents to determine the best treatment, most of which may have serious undesired cardiovascular effects (2, 7, (34) (35) (36) . very few of these studies involve children, so data will have to be extrapolated from adult studies. actual ongoing trials include (see table 1 ) -antivirals, especially lopinavir, ritonavir, and ribavirin; -antimalarials, namely chloroquine and hydroxychloroquine; other studies, in contrast, show that aceis/arbs may potentiate the lung-protective function of ace2, which is an angiotensin ii inhibitor (61, 62) . it remains controversial whether patients with covid-19 under treatment with an ace inhibitor or angiotensin-receptor blocker should switch to another drug, and further evidences are required. as such, the heart failure society of america, american college of cardiology, american heart association, and european society of cardiology released a statement recommending continuation of renin-angiotensin-aldosterone system inhibitors for patients currently taking them for "indications for which these agents are known to be beneficial". cardiovascular issues are emerging as one of the most significant and life-threatening complications of sars-cov-2 infection in adult patients. though pediatric critically ill covid-19 patients remain rare, the disease has a range of clinical presentations in children, for which the potential need for further investigation of myocardial injury and cardiovascular issues should be kept in mind to avoid misdiagnosing severe clinical entities. data are lacking for covid-19 in some pediatric subpopulations, including in patients with underlying conditions, but some reports indicate that these populations are at increased risk of morbidity and mortality. children with preexisting complex cardiovascular conditions may be at higher risk. if they require careful monitoring and follow-up in case of infection, extensive preventive measures must be taken with these patients. frequent handwashing, social distancing measures, proper and appropriate use of masks and other personal protective equipment, and the use of technology should be prominent in their management to minimize the risk of nosocomial infections. each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article covid-19 and the cardiovascular system cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (covid-19) pandemic clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china cardiovascular complications of severe acute respiratory syndrome coronavirus associated fulminant myocarditis successfully treated with intravenous immunoglobulin and extracorporeal membrane oxygenation acute myocarditis associated with novel middle east respiratory syndrome coronavirus the cardiovascular burden of coronavirus disease 2019 (covid-19) with a focus on congenital heart disease ace2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia 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position statement of the european society of cardiology working group on myocardial and pericardial diseases myocarditis in the pediatric population: a review acute myocarditis and pericarditis in children disease: a scientific statement for health professionals from the american heart association kawasaki disease: guidelines of the italian society of pediatrics, part i -definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase kawasaki disease associated with parvovirus b19 infection concomitant respiratory viral infections in children with kawasaki disease detection rate and clinical impact of respiratory viruses in children with kawasaki disease concurrent respiratory viruses and kawasaki disease cdc covid-19 response team. coronavirus disease 2019 in children -united states preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 -united states covid-19 and patients with congenital heart disease. indications and suggestions from the italian society of pediatric cardiology and congenital heart diseases. by the board of the italian society of pediatric cardiology and congenital heart diseases www angiotensin-converting enzyme 2 protects from severe acute lung failure angiotensin receptor blockers as tentative sars-cov-2 therapeutics key: cord-259996-uhrhsrky authors: lee, seul bee; choi, han seul; son, sejung; hong, young mi title: cardiac function in kawasaki disease patients with respiratory symptoms date: 2015-07-16 journal: korean circ j doi: 10.4070/kcj.2015.45.4.317 sha: doc_id: 259996 cord_uid: uhrhsrky background and objectives: respiratory symptoms are often observed in children with kawasaki disease (kd) during the acute phase. the association of respiratory viruses in children with kd was investigated using multiplex reverse transcriptase-polymerase chain reaction (rt-pcr) and tissue doppler echocardiography. subjects and methods: 138 kd patients were included from january 2010 to june 2013. we compared 3 groups (group 1: n=94, kd without respiratory symptoms; group 2: n=44, kd with respiratory symptoms; and group 3: n=50, febrile patients with respiratory symptoms). laboratory data were obtained from each patient including n-terminal pro-brain natriuretic peptide (nt-probnp). echocardiographic measurements were compared between group 1 and group 2. rt-pcr was performed using nasopharyngeal secretion to screen for the presence of 14 viruses in groups 2 and 3. results: the incidence of kd with respiratory symptoms was 31.8%. the duration of fever was significantly longer, and coronary artery diameter was larger in group 2 than in group 1. tei index was significantly higher and coronary artery diameter larger in group 2 than group 1. coronary artery diameter, c-reactive protein levels, platelet count, alanine aminotransferase levels, and nt-pro bnp levels were significantly higher and albumin levels lower in group 2 compared with group 3. conclusion: nt-pro bnp was a valuable diagnostic tool in differentiating kd from other febrile viral respiratory infections. some viruses were more frequently observed in kd patients than in febrile controls. tei index using tissue doppler imaging was increased in kd patients with respiratory symptoms. respiratory symptoms are frequently observed in children with kd during the acute phase. 5)11) jordan-villegas et al. 12) reported that patients with kd who carry respiratory viruses more frequently showed coronary artery dilatation and were more often diagnosed with incomplete kd. some studies 5)10)12) determined that specific respiratory viruses were associated with kd. however, other authors insisted that the detection of viruses in kd may not have any associative implications. 13) tissue doppler imaging (tdi) may be a superior method to measure the tei index in children because it is less affected by heart rate variability. 14) the myocardial performance index (tei index) evaluates global left ventricle (lv) systolic and diastolic function. it is correlated with severity and clinical outcome in children with cardiac disease. 14) there haven't been any reports about an association between respiratory infection and cardiac function in kd patients. in this study, we compared laboratory findings in kd patients with febrile patients having a viral infection. another purpose of this study was to investigate the association of respiratory viruses and cardiac function in children with kd. this prospective study was performed on 138 kd patients (80 males, 58 females) at ewha womans university mokdong hospital from january 2010 to june 2013. we compared 3 groups (group 1: n=94, kd without respiratory symptoms; group 2: n=44, kd with respiratory symptoms; and group 3: n=50, febrile patients with respiratory symptoms). respiratory symptoms included cough, rhinorrhea, sputum, and sore throat. to diagnose kd, we used the american heart association criteria. 15) diagnosis of the complete type of kd included fever of more than 5 days and at least four of the following: 1) changes in extremities including palm and sole erythema or edema, 2) polymorphous exanthema, 3) bilateral bulbar conjunctival injection without exudates, 4) changes in the lips and oral cavity including erythema, cracked lips, strawberry tongue, and diffuse injection of oral and pharyngeal mucosa, and 5) cervical lymphadenopathy over 1.5 cm in diameter. children who had a fever lasting 5 or more days and fulfilled two or three principle clinical criteria were regarded as having incomplete kd after other possible causes of fever were excluded. all kd patients were treated with a single dose of intravenous immunoglobulin (ivig, 2 g/kg for 10-12 hours) and high dose aspirin (30 mg/kg three times per a day) until having an afebrile status for more than 2 days, after which low dose aspirin (5 mg/kg/day) was administered. the ethics committee of ewha womans university mokdong hospital institutional review board approved this study. written informed consent was obtained from the parents of all patients. laboratory data obtained from each patient included complete blood count, erythrocyte sedimentation rate (esr), and levels of alanine aminotransferase (alt), aspartate aminotransferase (ast), serum total protein, albumin, c-reactive protein (crp), n-terminal pro-brain natriuretic peptide (nt-probnp). echocardiography was performed using an ie33 machine (philips medical system, andover, ma, usa) with an s8 transducer on kd patients and febrile patients who were suspected of having kd during their admission period. standard parasternal and apical views were acquired. complete 2d and m-mode echocardiogram, pulsed color-flow doppler, and tdi were obtained. we measured the following lv parameters by m-mode echocardiography: interventricular septal wall thickness, posterior wall thickness, and lv end diastolic dimension at the chordae tendinae level. ejection fraction was determined by using the biplane simpson formula, and fractional shortening was calculated using lv internal dimensions. the diastolic function was assessed with pulsed doppler mode from the apical window. early diastolic velocity (e), late diastolic velocity (a), e/a ratios, and deceleration time were measured using conventional pulsed wave doppler echocardiography (ie33 machine, philips medical system, andover, ma, usa). tdi velocities were obtained at the basal septum from the apical four-chamber view. the doppler beam was aligned as parallel as possible to the direction of the maximum annular motion. tdi was performed to obtain longitudinal myocardial velocity with high quality. a narrow sector angle was used, and image depth was adjusted to allow for a high frame rate (130-160 frames/s) with care taken to avoid angulations. the sweep speed was at least 100 mm/s. the peak systolic myocardial velocity (s'), early diastolic myocardial velocity (e'), and late diastolic myocardial velocity (a') were obtained. we calculated the tei index using tdi, which combines systolic and diastolic lv time intervals, using the formula (a-b)/b, where a is the interval between the closing and the opening of the mitral valve, and b is equal to the left ventricle ejection time (lvet) (fig. 1 ). isovolumetric relaxation time (ivrt) was measured from the end of the s' wave to the onset of the e' wave, and isovolumetric contraction time (ivct) was measured from the end of the a' wave to the onset of the s' wave. the coronary artery was measured at the parasternal short axis view (fig. 2) . coronary arteries were defined as abnormal if the internal lumen diameter was greater than 3 mm in children younger than 5 years old, 5) if the internal diameter of a segment measured at least 1.5 times that of an adjacent segment, or if the coronary lumen was clearly irregular. 16) a giant aneurysm was defined as an internal lumen diameter of greater than 8 mm. 17) we collected the nasopharyngeal secretion of kd patients with respiratory symptoms and control febrile patients with respiratory symptoms using nasal and throat swabs on the first day of hospitalization. reverse transcriptase-polymerase chain reaction (rt-pcr) was ibm spss statistics version 18.0 (spss inc., chicago, il, usa) was used for all statistic analyses. data were expressed as mean±standard deviation. echocardiographic findings were represented as adjusted mean±standard deviation after adjustment for covarients such as crp and fever duration. the kruskal wallis test and the wilcoxon rank sum test were used to compare laboratory data between kd patients and the control group. a p value of less than 0.05 was considered statistically significant. a total of 138 kd patients diagnosed with kd were enrolled in the study. the clinical characteristics of kd patients with and without respiratory symptoms are shown in table 1 . in this study, 94 patients (68.1%) were included in the kd group without respiratory symptoms (group 1), and 44 patients (31.8%) were included in the kd group without respiratory symptoms (group 2). there were no significant differences in age and sex between group 1 and group 2. fever duration was significantly longer in group 2 than in group 1 (6.2±2.1 days vs. 5.3±1.6 days). in group 2, conjunctival injection was found in 80.9% of the patients, cervical lymphadenopathy over 1.5 cm in 33.0%, skin rash in 71.3%, lip and/ or oral mucosal abnormality in 75.5%, palm and/or sole erythema and edema in 62.8%, and bacillus calmette-guérin (bcg) site injection in 29.8% of cases. in group 2, conjunctival injection was found in 72.7% of the patients, cervical lymphadenopathy in 18.2%, skin rash in 52.3%, lip and/or oral mucosal abnormality in 31.8%, palm and/or sole erythema and edema in 22.7%, and bcg site injection in 22.7% of cases. other features, such as polymorphous skin rash, lip and oral mucosal abnormalities, hand or foot erythema, and edema, were more frequently observed in group 1 (p<0.05), and the rate of incomplete type kd was significantly higher in group 2 than group 1 (61.6% vs. 81.8%, p=0.019) ( table 1) . there were no significant differences in age and sex between group 2 and group 3 (data not shown). there were no significant differences in laboratory tests including those for hemoglobin (hb), white blood cell count (wbc), percentage of segmented neutrophils (seg %), platelet count, esr, crp, and levels of ast, serum total protein, albumin, and nt-pro bnp between groups 1 and 2. alt was significantly higher (56.7±84.2 iu/l vs. 93.2±133.7 iu/l) in group 2 compared with group 1. the nt-pro bnp value was higher in group 2 compared with group 3 (698.9±907.7 pg/ml vs. 156.5±112.0 pg/ml, table 2 ). platelet count (301.3±53.4x10 9 /l vs. 239.4±74.9x10 9 /l), crp (5.9±4.4 mg/dl vs. 3.0±2.8 mg/dl), and alt (93.2±133.7 iu/l vs. 25.7±43.8 iu/l) were also significantly higher in group 2 than in group 3. albumin level was significantly lower in group 2 than in group 3 (3.6±0.3 g/dl vs. 4.0±0.3 g/dl). other laboratory tests including those for hb, wbc, seg %, esr, ast, and total protein showed no significant differences between group 2 and group 3 ( table 2 ). there were no significant differences in positive rates of pcr between group 2 and group 3 (72.7% vs. 78.0%). group 2 had a higher positive rate for adenovirus than group 3 (54.5% vs. 30.0%, p=0.027). the control group had a significantly higher positive rate for viral pcr for parainfluenza virus 3 (0% vs. 24.0%, p=0.001). for other various viruses including coronavirus, parainfluenza virus (1 and 2), influenza (a and b), respiratory syncytial virus (a and b), rhinovirus (a, b, and c), metapneumo virus, and bocavirus, there were no significant differences in positive rates of respiratory virus pcr ( table 3) . ejection fraction and fractional shortening were not significantly different between group 1 and group 2. there were no significant differences in late diastolic myocardial velocity (a') ( (table 4) . however, ivct (61.4±8.9 ms vs. 49.5±15.9 ms) and tei index (0.44±0.06 vs. 0.34±0.07) were significantly higher in group 2 compared with group 1. coronary artery abnormality was more frequent in group 2 compared with group 1 (70.5% vs. 40.4%, not shown in the table 4 ), and coronary artery diameter was significantly higher in group 2 compared with group 1 (3.3±1.1 mm vs. 2.7±0.9 mm) ( table 4) . response to intravenous immunoglobulin between kawasaki disease patients without respiratory symptoms and those with respiratory symptoms ivig responders showed improvement in fever and other symptoms after ivig administration. if kd patients showed fever (higher than 38 o c) after 36 hours of ivig infusion, they were regarded as non-responders, then retreated using a second ivig. there were no significant differences in the number of ivig responders, family history, recurrence, and retreated cases of kd between group 1 and group 2 ( table 5 ). kd is the most common cause of acquired heart disease among children in developed countries, but the etiology of kd remains unknown. among many factors that might be associated with kd, infections are considered to be one of the predisposing factors of kd. 5) burns et al. 18) reported significant and consistent seasonal variations in kd patients with a higher incidence in winter and a lower incidence in late summer and fall. in korea, kd showed the highest incidence in summer and winter and the lowest incidence in february and october. 4)16) the monthly fluctuation in the incidence of kd and the detection of viruses suggests the etiologic importance of the precedence of infection in the development of kd. according to tsai et al. 19) during the acute stage of kd, 61% of family members of kd patients had acute illnesses, and 92% of them had clusters of infectious disease. these results provide more evidence that kd is strongly associated with infectious disease. it appears that some pathogens are a cause of kd, but no specific pathogen has been found to be a definite cause of kd. 5)20) 21) many studies have been carried out to identify the infectious agents responsible for kd. 5)10) chang et al. 5) have suggested that several viruses, such as enteroviruses, adenoviruses, rhinoviruses, and coronaviruses, are associated with kd. the kd patients in their studies had significantly higher positive rates for virus isolation and pcr for those viruses compared with the control group (50.4% vs. 16 .4%, p<0.001). jordan-villegas et al. 12) stated that respiratory symptoms were frequently observed in children with kd during the acute phase. the association rate of kd with antecedent respiratory illness, including rhinovirus, adenovirus, influenza, parainfluenza, and respiratory syncytial virus, has been reported to range from 56.0% to 83.0%. in our study, adenovirus, respiratory syncytial virus, rhinovirus, and bocavirus were found in kd patients. group 2 had a higher rate of positive results for adenovirus than group 3 (54.5% vs. 30.0%, p=0.027). the control group had a significantly higher positive rate for parainfluenza virus 3 (0% vs. 24.0%, p=0.001). in this study, we assumed that some viruses were strongly associated with kd occurrence. the etiology of kd is still being debated, but the evidence suggests the following: 1) monthly clustering and seasonality, 18) 2) geographic prevalence, 3) ethnic tendency, 4) a high association between kd and infectious disease, and 5) higher incidence rates among 6-month to 2-year-old children who have low maternal antibodies and are more susceptible to infections in general. 22)23) chang et al. 5) found that heterogeneous infectious agents, such as common viruses, may trigger kd in young children with certain genetic backgrounds or susceptibility. on the other hand, kim et al. 13) reported that virus detection rates using multiplex rt-pcr were 32.7% in kd patients and 30.8% in the control group. there was no significant association between respiratory viruses and kd. kd with respiratory viruses is frequently misdiagnosed as a simple viral infection before other symptoms appear, so the diagnosis can be delayed. kd may be misdiagnosed as another febrile disease such as adenoviral infection, measles, rubella, and scarlet fever. 9) according to ye et al. 24) nt-pro bnp had the highest diagnostic value for kd among other factors including cytokines, crp, and esr, which were recommended indexes by the american heart association. they found that nt-pro bnp is a reliable marker for the diagnosis of kd and the prediction of ivig treatment effect. dahdah et al. 25) reported that nt-pro bnp level was significantly higher in incomplete kd groups than in febrile patients (p<0.05). nt-pro bnp was a useful marker for the diagnosis of kd in patients less than 3 months of age. 26) our study demonstrated that nt-pro bnp is a valuable diagnostic tool in differentiating kd from other febrile table 2 ). the clinical manifestations of adenovirus, especially conjunctival injection, throat injection and prolonged fever, are somewhat like those of kd. kd is frequently misdiagnosed as pharyngoconjunctival fever caused by adenovirus because of the clinical similarity of the two diseases, 10) so infusion of ivig may be delayed. jordan-villegas et al. 12) has shown that 2.4% of kd patients had adenovirus in their respiratory tract, and 5 of 6 kd patients with concomitant adenovirus infection had incomplete kd. although virus pcr shows higher sensitivity and detects a relatively low level of virus, viral quantification was not done in this study. jordan-villegas et al. 12) found that children with kd who had respiratory virus infections had a higher incidence of coronary artery dilatation than kd patients without viral infections, and the former group were more often diagnosed with incomplete kd. according to vijayan et al. 27) coronary artery dilatation was more frequently observed in incomplete kd than in classical kd (91.7% vs. 41.1%, p<0.001). these findings were similar with our study. fever duration was significantly longer, and coronary artery diameter was larger in group 2 than in group 1. the rate of incomplete kd was significantly higher in group 2 compared with group 1. we could not find other articles studying the relevance of respiratory infection and cardiac function in kd patients. the tei index combines the systolic and diastolic functions of ventricles in an index of global myocardial performance. 14) it correlates with the severity and clinical outcome in children with cardiac disease. 14)28) the tei index could be used as an accurate tool for estimating myocardial function in kd patients. 29) according to ajami et al. 30) after ivig treatment in kd patients, the tei index changed from 0.43±0.08 to 0.35±0.06. the tei index could be used to detect early global myocardial dysfunction when other cardiac function indexes are in the normal range. 30) there are several limitations to our study. first, diagnosis of kd was mostly dependent on clinical manifestations since not every patient had coronary artery dilatation. also, we could not collect nasopharyngeal swab samples from all kd patients with respiratory symptoms because the respiratory virus pcr test was quite expensive. kd patients with respiratory symptoms whose parents did not agree to have their kids test for virus pcr were excluded in this study. group 1 patients were assumed not to have concomitant viral infections. rt-pcr results for all kd patients would help identify the relationship between respiratory viruses with echocardiographic findings in kd patients. second, adenoviral infection could not be distinguished from kd by laboratory tests. although there are other ways to diagnose viral infection, including adenovirus, such as by using a virus culture or a neutralized antibody, we only used virus pcr to detect respiratory viruses in this study. third, the sample size was relatively small. pcr is a relatively easy way to detect respiratory viruses in children, but in this study, whether a virus coexists with or causes kd cannot be distinguished. viral culture and the quantification of viral loading could help distinguish whether a specific virus simply coexists with or causes kd. in conclusion, nt-pro bnp is a valuable diagnostic tool in differentiating kd from other febrile viral respiratory infections. kd patients with respiratory symptoms had a higher tei index than kd patients without respiratory symptoms, suggesting myocardial dysfunction. further studies are needed to clarify this relevance. a new infantile acute febrile mucocutaneous lymph node syndrome (mlns) prevailing in japan kawasaki syndrome kawasaki disease in children evaluation of the temporal association between kawasaki disease and viral infections in south korea viral infections associated with kawasaki disease kawasaki syndrome results of the nationwide epidemiologic survey 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disease: a global perspective transmission of acute infectious illness among cases of kawasaki disease and their household members the role of infection in kawasaki syndrome kawasaki disease: what is the epidemiology telling us about the etiology? epidemiological features of kawasaki disease in taiwan temporal and geographical clustering of kawasaki disease in japan value of the n-terminal of prohormone brain natriuretic peptide in diagnosis of kawasaki disease natriuretic peptide as an adjunctive diagnostic test in the acute phase of kawasaki disease clinical characteristics and serum n-terminal pro-brain natriuretic peptide as a diagnostic marker of kawasaki disease in infants younger than 3 months of age coronary artery dilatation in incomplete kawasaki disease tei-index in patients with mildto-moderate congestive heart failure doppler echocardiographic index for assessment of global right ventricular function evaluation of myocardial function using the tei index in patients with kawasaki disease key: cord-253056-765rs3e7 authors: dionne, audrey; le, cathie-kim; poupart, steffany; autmizguine, julie; meloche-dumas, léamarie; turgeon, jean; fournier, anne; dahdah, nagib title: profile of resistance to ivig treatment in patients with kawasaki disease and concomitant infection date: 2018-10-17 journal: plos one doi: 10.1371/journal.pone.0206001 sha: doc_id: 253056 cord_uid: 765rs3e7 introduction: kawasaki disease (kd) can be associated with concomitant viral or bacterial infections. children with persistent or recurrent fever 36 hours after the end of intravenous immunoglobulin (ivig) are considered to be resistant to treatment and are at increased risk for coronary complications. although concomitant infection does not affect coronary outcome, it is unknown how it influences the response to ivig treatment. methodology: retrospective cohort study between 2008 and 2016 in a tertiary pediatric university hospital, including 154 children, of which 59 (38%) had concomitant infection. results: children with concomitant infection were more likely to have fever 48 hours after initial ivig treatment (36% vs 20%, p = 0.05) and to be treated with a second dose (33% vs 18%, p = 0.04). children with infection had higher c-reactive protein at the time of diagnosis (148 vs 112 mg/l, p = 0.04), and 48 hours after ivig administration (111 vs 59 mg/l, p = 0.003). nevertheless, there was no statistically significant difference in the prevalence of coronary complications (z-score > 2.5) between children with and without concomitant infection (36% vs 39%, p = 0.68). conclusion: children with kd and concomitant infection are more likely to have persistent fever and elevated inflammatory markers after treatment. this association increases the likelihood of receiving a second dose of ivig but not the risk of coronary complication. accordingly, prospective studies to distinguish true ivig resistance from infection induced persistent fever is warranted. a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 kawasaki disease (kd) is an acute systemic vasculitis mostly affecting children younger than 5 years old. it is the most important cause of acquired heart disease in children in developed countries [1] . concomitant respiratory viral infections have been described in 8-42% of patients, and bacterial infections were found in 33% of patients [2] [3] [4] [5] [6] [7] [8] . the clinical presentation of patients with and without concomitant infection is similar [2, 8] . in one study, bacterial coinfection alluded to a trend towards a higher rate of resistance to intravenous immunoglobulin (ivig), without reaching statistical significance (26% vs 15%, odds ratio 1.77 (95% confidence interval 0.71-4.41)) [8] . the accepted definition of ivig resistance is based on the persistence or recrudescence of fever 36 hours after the end of ivig infusion [1] . however, it is unclear how concomitant infection influences the resolution of fever and response to ivig treatment. the aim of this study was to determine the impact of concurrent infection on the prevalence of ivig resistance and coronary outcome. this retrospective study included children with a diagnosis of kd between 2008 and 2016 followed at the sainte-justine's university hospital center (montreal, canada). inclusion criteria were a diagnosis of kd maintained at discharge based on current clinical practice and recommendations [1] ; and echocardiography measurements of the coronary artery (ca) at onset, 1-2 weeks and >3 months after diagnosis. the main outcome was resistance to ivig treatment in children with, versus those without concurrent infection. secondary outcomes included duration of fever, progress of inflammatory markers and coronary artery complications. this study was approved by the institutional research ethics committee of the chu sainte-justine. the institutional research ethics committee waived the requirement for informed consent. medical charts were reviewed for demographic characteristics, clinical course, laboratory values and infectious workup. clinical kd criteria were reviewed and children classified as complete or incomplete kd, in the presence of fever and �3 clinical criteria for the latter. delay in ivig administration was defined as > 10 days between onset of fever and ivig administration; and ivig resistance as persistent or recrudescent fever (> 38.5˚c) 36 hours after the end of ivig infusion. concurrent infection was defined as a clinical diagnosis and proven concurrent infection as patients with a positive microbiologic testing or imaging study in the presence of clinical symptoms. testing for concomitant infection was based on clinical symptoms. urinary tract infection was diagnosed according to current american academy of pediatrics guidelines [9] . gastroenteritis was defined as gastrointestinal symptoms with positive stool cultures for virus or pathogenic bacteria. children with respiratory symptoms and a positive respiratory virus multiplex reverse transcription polymerase chain reaction (influenza, parainfluenza, coronavirus, enterovirus, rhinovirus) were diagnosed with upper respiratory tract infection (urti). otitis media was diagnosed according to current american academy of pediatrics guidelines [10] . children with clinical signs of exudative pharyngitis in the presence of a positive group a streptococcus culture were diagnosed with concurrent infection. bacterial adenitis was diagnosed in the presence of clinical symptoms with signs of abscess formation and/or necrosis on ultrasound. children with positive serology for acute infection (igm) with epstein-barr virus (ebv), cytomegalovirus (cmv), measles, parvovirus and mycoplasma before ivig administration were considered to have concurrent infection. pneumonia was diagnosed when chest x-ray, interpreted by a pediatric radiologist, confirmed the presence of a consolidation, in the presence of respiratory symptoms. echocardiographic ca size was reviewed for all children at onset of the disease, with follow-up studies for a minimum of 3 months and up to one year after diagnosis of kd. ca zscores were calculated for the right coronary artery, left main coronary artery, left anterior descending artery and circumflex artery. ca aneurysm was defined as a localized dilatation of a portion with adjacent normal measurements, or an obvious saccular deformation of the ca. ca dilatation of non-aneurysmal segments was defined as a ca z-score > 2.5 [1] , calculated according to dallaire and dahdah [11] . early ca dilatation was defined as ca dilatation at onset up to one week following kd diagnosis, and late ca dilatation when persisting at 3 months' follow-up. quantitative variables were summarized as mean ± sd and categorical variables as frequencies and percentages. the shapiro-wilk test was used to test for normal distribution. comparison of clinical and laboratory data between patients with and without concurrent infection was performed using the student's t-test for continuous variables with normal distribution or the mann-whitney u test for continuous variables with non-normal distribution. anova for repeated measures was used to describe the variation of temperature and laboratory values over time. the fisher or the χ 2 tests were used for comparison of categorical variables. logistic regression was used to examine the association between concomitant infection and ca complications, controlling for confounder variables (ivig resistance). all analyses were performed with spss statistics version 23 (ibm, chicago, illinois). a two-tailed p value of <0.05 was deemed significant. the study included 154 children (101 male; 66%) aged 3.4±2.8 years. the median number of diagnostic criteria was 5 (range 2-6), with 59 (38%) children having incomplete kd criteria. ivig were administered to 150 (97%) patients, 6.7±2.6 days after onset of fever. delay in ivig administration occurred in 10 (7%) patients, and ivig resistance in 36 (23%). concurrent infections were diagnosed in 59 (38%) patients, of which 20 (34%) were viral and 39 (66%) bacterial. urti was diagnosed in 19 (32%) children, caused by respiratory syncytial virus (n = 3), parainfluenza (n = 3), rhinovirus (n = 4), influenza (n = 2), enterovirus (n = 2) and adenovirus (n = 4). three children had multiple viruses detected. two (7%) children were diagnosed with viral gastroenteritis. three (5%) children had a clinical and biological profile suggestive of acute cmv infection (positive igm and negative igg), and 2 (3%) of acute mycoplasma infection. otitis media was diagnosed in 7 (12%) of patients, and pneumonia in 8 (14%) children. group a streptococcus pharyngitis was diagnosed in 13 (22%). four (7%) patients had bacterial adenitis, complicated by retropharyngeal pharyngitis in one child. one child was diagnosed with perforated appendicitis and underwent surgery, with pathology confirming the diagnosis. one child had escherichia coli pyelonephritis. concomitant infection was proven by microbiologic testing and/or imaging in 48 (81%) of patients. characteristics of patients with viral versus bacterial infections are described in table 1 . during hospitalization, antibiotics were empirically initiated in 95 (62%) children, and completed in 36 (23%). antibiotics were initiated on average 2±5 days prior to ivig treatment, with antibiotics initiated prior to ivig treatment in the majority of cases (55, 67%). only a minority (4, 9%) were started on antibiotics after non-response to initial ivig treatment. age was similar between children with and without infection (3.5±2.7 versus 3.4±2.9 years, p = 0.94), with a similar proportion of male (34 (58%) versus 67 (71%) patients, p = 0.10). there was a similar proportion of children with incomplete clinical criteria among children with and without infection (20 (34%) versus 39 (41%), p = 0.38). there were 50 (58%) children with infection who received antibiotics compared to 45 (47%) without infection who received antibiotics (p<0.001). of the former, 29 (58%) completed antibiotic treatment versus 7 (16%) of the latter (p<0.001). most children with and without concurrent infection received ivig (57 (97%) and 93 (98%) patients; p = 0.63). delay in diagnosis and ivig administration occurred in 4 (7%) children with concurrent infection versus 6 (7%) without concurrent infection, p = 0.89 (table 2) . finally, there was no difference in delay of ivig administration whether patients presented with complete versus incomplete clinical criteria (7% and 7%; in general, basic laboratory values were similar between children with and without concurrent infections. c-reactive protein was however higher in cases with concurrent infections compared to cases without concurrent infection (148±96 versus 112±65 mg/l, p = 0.03) ( table 3) . similar results were found between patients with proven infection on microbiologic testing and/or imaging versus those without and results are presented in table 4 . overall, ivig resistance occurred in 36 (24%) patients. children with concurrent infection had higher rates of ivig resistance (19 (33%) versus 17 (18%) patients, p = 0.04), and higher temperature at 48 hours (fig 1) . they were also more likely to have fever > 38.5˚c at 48 hours, than those without concurrent infection (16 (36%) versus 15 (20%) patients, p = 0.05). this was accompanied with higher crp at time of diagnosis, remaining similarly higher in the first 72 hours after treatment (fig 2) . ivig resistance was higher in patients with proven infection on microbiologic testing and/ or imaging than those without (16 (35%) versus 20 (19%) patients, p = 0.04). there was no difference in response to treatment between patients who had a proven infection on microbiologic testing and/or imaging study versus those with clinical diagnosis of infection (16 (35%) versus 3 (27%) patients, p = 0.64). resistance to initial ivig treatment in patients with bacterial infection was nearly double that in patients with viral infection, although not reaching statistical significance (12 (46%) versus 4 (24%) patients, p = 0.12). there was no difference in response to treatment between patients with complete and incomplete clinical criteria (25 (28%) versus 10 (17%) patients, p = 0.12). patients who received antibiotics during their hospital course, independent of infection status, were at higher risk of ivig resistance than those who did not (27 (29%) versus 9 (16%) patients, p = 0.05). however, neither receiving antibiotics prior to ivig therapy (15 (27%) versus 11 (41%) patients, p = 0.22) nor completing antibiotic course (13 (36%) versus 14 (25%) patients, p = 0.25) were associated with response to treatment. there was no significant difference in coronary artery complications (fig 3) between patients with and without infection (21 (36%) versus 37 (39%), p = 0.68). this remained true even after adjusting for ivig resistance and number of ivig treatment (p = 0.47). resistance to ivig treatment was associated with an increased risk of ca complication both as a univariate (53% versus 34%, p = 0.037), and when adjusting for the presence of infection (p = 0.039). coronary artery dilation at time of diagnosis was found in 58 (38%) patients, similarly distributed according to the presence or absence of concurrent infection (20 (34%) versus 38 (40%) patients, respectively; p = 0.45), and persisted in 17 (11%) patients (in 5 (9%) versus 12 (13%) patients, respectively; p = 0.42). coronary aneurysms were diagnosed in 17 (11%) patients, without significant difference between patients with and without infection neither (7 (12%) versus 10 (11%) patients, p = 0.80). while the risk of coronary aneurysm was similar between patients with viral versus bacterial infection (5 (19%) versus 2 (12%) patients, p = 0.69), patients with bacterial infection were more likely to have coronary artery dilation (13 (48%) versus 3 (18%) patients, p = 0.04). in this retrospective series, the presence of a concomitant infection was associated with a higher rate of resistance to ivig treatment. patients with concomitant infection were more likely to have persistent fever and slower normalization of inflammatory markers after ivig treatment. the administration of antibiotics did not decrease this risk of resistance to ivig therapy. however, concomitant infection was not associated with an increased risk of coronary artery complications. more precisely, the higher likelihood of repeated ivig treatment when concurrent infection was present is defined as recrudescence of fever 36 hours after the end of ivig infusion based on expert opinion [1] . our results challenge this definition since fever may be maintained by an infection, either viral or bacterial, that is not likely to respond to ivig. inflammatory markers are often used to help guide the decision about the need for additional treatment in kd. in our series, patients with concurrent infection presented higher crp levels at baseline, as well as 48 hours after initial treatment. this is consistent with a retrospective study on the variability in response to ivig, which showed a higher rate of concomitant infection and higher crp levels in complete non-responders to ivig treatment compared to partial nonresponders and responders [12] . thus, both the persistence of fever after ivig treatment and elevated inflammatory markers contribute to the increased likelihood of "ivig resistance" in patients with concomitant infections. interestingly, non-response to ivig therapy was associated with the use of antibiotics in a prior single-center retrospective study [12] . one would have expected patients with concomitant infection, at least bacterial, to have lower rate of ivig resistance if the infection was controlled by antibiotics. both in prior reports and this series [12] , the use of antibiotic was found to be associated with non-response to ivig treatment, independent of whether or not an infection was confirmed. however, it is not clear if it is just reflecting the underlying infection, or kd that is resistant to initial treatment. another hypothesis would be that the presence of infection triggers an additional inflammatory response at the molecular levels that impact response to treatment and outcomes. il-1α and il-1β have been shown to be essential in the development of kd [13] . the il-1 pathways play a critical part of the host defense against microbial pathogens through activation of toll like receptors [14, 15] . moreover, inositol-triphosphate 3-kinase c (itpkc) has a critical role in mediating nlrp3 expression and intracellular calcium, which is then responsible for il-1β production [16] . genetic polymorphism in itpkc is associated with higher il-1β cytokines and treatment failure [16] . this raises the question if concomitant infection increases resistance to ivig treatment by increasing levels of il-1β cytokines. this could be very important as new treatment strategies are targeting il-1 blockade in recalcitrant kd. persistence of fever after ivig treatment is a strong risk factor for development of coronary aneurysms [1, 17] . in this series, patients with resistance to ivig treatment had a higher risk of developing ca complication. notwithstanding, the rate of ca complication was statistically independent of the presence of infection in our series and in previous series [8] . thus, the lack of increased risk of ca complication in the setting of persistent fever in patients with kd and concomitant infection argues for infection as the cause of fever as opposed to ivig resistance. it questions whether this "excessive" diagnosis of ivig resistance is well justified when there is a concomitant infection, and if the current definition of treatment resistance should be modified. retreatment with ivig or other immunosuppressive therapies may also have had a protective effect on the development of ca complication. however, the rate of ca complication was similar between patients with and without infection, even after accounting for the number of ivig treatment received. thus, other criteria need to be used to help with decision for retreatment of patients with persistent fever and concomitant infection. coronary artery dimensions may be a more useful marker for the need for additional treatment in this at risk population. in general, patients who are resistant to initial treatment receive a second dose of ivig (2 g/ kg) [18] . notwithstanding, at least 5% of children remain febrile despite multiple dose of ivig [18] . these particular patients are at even greater risk of ca complications, and additional therapies are usually administered [19] , including corticosteroids [20] [21] [22] , anti-tnf alpha agents [23, 24] , cyclosporine [25] , cyclophosphamide [26] and more recently anakinra (anti-interleukine1) [27, 28] . the use of these additional therapies is based on effectiveness in other vasculitis, with no prospective clinical trials to show effectiveness on coronary artery outcome. in patients with concerns for concurrent infection, the benefit of those additional therapies should be carefully balanced against the increased risk of infection. it is important to make this distinction, in order to 1) avoid using aggressive immunosuppressive therapies in patients with persistent fever due to uncontrolled infection and 2) avoid not treating aggressively a patient with kd that is resistant to initial treatment and at increased risk of serious coronary artery complications. however, this distinction can be clinically very difficult to answer, and caution should be exercise to prevent both cardiac complications and adverse side effects of therapies. there are limitations to this study essentially related to the retrospective methods, and the diagnosis of concomitant infection. on one hand, in the absence of systematic testing for infections there is a potential underestimation of the actual concurrent infection rate, as some infections could not be identified. on the other hand, inclusion of only children with infectious workup at time of initial kd diagnosis could have falsely increased the rate of concurrent infection. however, the rate of concomitant infection in this series was similar to those previously published [8] . moreover, positive testing for virus and/or throat culture in children could reflect a carrier status rather than actual concurrent infection. however, because infectious workup was performed based on children's symptoms, the positive results most likely represent an actual infection. serologies for different viral infections (cmv, ebv, mycoplasma) can be difficult to interpret in an acute inflammatory setting, with igm cross-reactivity. these infections could not be confirmed by pcr due to the retrospective nature. however, this could only have affected 3 children, and statistical analysis excluding these children did not affect the results. moreover, whereas the aha definition of resistance to ivig treatment is based on persistent fever 36 hours after the end of ivig infusion [1] , other factors are considered in the decision whether or not to retreat patients, including inflammatory markers and ca dimensions. thus, some patients were classified as resistant to treatment based on the definition, but were not retreated and had favorable evolution. small sample size of sub-groups analysis and secondary aims limit the statistical power, and results should be interpreted in light of these limitations. in this study, patients with concomitant infection had a higher rate of resistance to ivig treatment. patients with concomitant infection had longer duration of fever and slower normalization of inflammatory markers after initial treatment. however, the presence of infection was not associated with an increased risk of ca complication. accordingly, the persistence of fever in kd and the definition of resistance to ivig should be regarded speculatively when concurrent infection is present. decision to intensify treatment in patients with concurrent infection should not only be based on persistent fever. coronary artery dimensions may be a more useful indication for treatment in this patient population. prospective studies are needed to better refine which children truly require additional therapies. conceptualization: audrey dionne, nagib dahdah. diagnosis, treatment, and long-term management of kawasaki disease. a scientific statement for health professionals from the american heart association concurrent respiratory viruses and kawasaki disease influenza infection and kawasaki disease evaluation of the temporal association between kawasaki disease and viral infections in south korea detection rate and clinical impact of respiratory viruses in children with kawasaki disease concomitant respiratory viral infections in children with kawasaki disease viral infections associated with kawasaki disease infections and kawasaki disease: implications for coronary artery outcome urinary tract infection: clinical practice guideline for the diagnosis and management of the initial uti in febrile infants and children 2 to 24 months the diagnosis and management of acute otitis media new equations and a critical appraisal of coronary artery z-scores in healthy children variability in response to intravenous immunoglobulin in the treatment of kawasaki disease il-1 signaling is critically required in stromal cells in kawasaki disease vasculitis mouse model: role of both il-1α and il-1β inflammasome activation and il-1β and il-18 processing during infection the tlr and il-1 signaling network at a glance inositol-triphosphate 3-kinase c mediates inflammasome activation and treatment response in kawasaki disease predictive risk factors for coronary artery abnormalities in kawasaki disease intravenous gamma-globulin treatment and retreatment in kawasaki disease. us/canadian kawasaki syndrome study group treatment options for resistant kawasaki disease coronary artery complication in kawasaki disease and the importance of early intervention: a systematic review and meta-analysis effects of steroid pulse therapy on immunoglobulin-resistant kawasaki disease steroid pulse therapy for children with intravenous immunoglobulin therapy-resistant kawasaki disease: a prospective study infliximab treatment of intravenous immunoglobulin-resistant kawasaki disease infliximab for intravenous immunoglobulin resistance in kawasaki disease: a retrospective study cyclosporin a treatment for kawasaki disease refractory to initial and additional intravenous immunoglobulin initial intravenous gammaglobulin treatment failure in kawasaki disease rational and study design for a phage i/iia trial of anakinra in children with kawasaki disease and early coronary artery abnormalities (the anakd trial) usefulness and safety of anakinra in refractory kawasaki disease complicated by coronary artery aneurysm key: cord-017245-kxqh32ip authors: sharma, avinash; singh, surjit title: kawasaki disease date: 2016-06-02 journal: pediatric rheumatology doi: 10.1007/978-981-10-1750-6_35 sha: doc_id: 17245 cord_uid: kxqh32ip to learn about the epidemiology, aetiopathogenesis, clinical features and differential diagnosis of kawasaki disease (kd) 1. to learn about the epidemiology, aetiopathogenesis, clinical features and differential diagnosis of kawasaki disease (kd) 2. to learn about the acute and long-term management of kd a 2-year-old boy presented with high-grade fever for 8 days. the baby had been irritable and fretful and was refusing feeds. the mother consulted a paediatrician who prescribed amoxicillin. the fever, however, persisted and the baby developed swelling over the dorsum of hands and feet. the mother also noticed a rash over the trunk along with red lips and red tongue. both eyes were con-gested and there was a swelling on the left side of the neck. as the fever was continuing, she sought consultation from another paediatrician who opined that the baby needed hospitalization for further workup. he ordered an infection workup, obtained blood and urine cultures and started intravenous ceftriaxone. the baby continued to run fever. investigations showed a neutrophilic leucocytosis, raised c-reactive protein levels and an elevated erythrocyte sedimentation rate. blood and urine cultures were sterile. at this time a clinical review suggested a possibility of this being kawasaki disease. 2d echocardiography did not reveal any coronary artery abnormality. the parents were counselled and a decision was taken to administer intravenous immunoglobulin (ivig) 2 g/kg along with aspirin 30 mg/kg/day. the baby showed prompt clinical improvement. the irritability disappeared within a few hours and the fever was passive by the next day. the mother noticed that the skin over fi ngers and toes had started to peel. a repeat haemogram at this time showed thrombocytosis. the dose of aspirin was reduced to 3 mg/kg/day and the baby was discharged with a follow-up appointment after 2 weeks. kawasaki disease (kd) is an acute, self-limiting, childhood medium-vessel vasculitis. initially described in 1967 by dr. tomisaku kawasaki in japanese children as an acute mucocutaneous lymph node syndrome [ 1 -3 ] , kd may lead to coronary artery abnormalities (caas) in up to 25 % of patients if left untreated. it is for this reason that kd is considered a medical emergency. kd is the most common cause of an acquired heart disease in children in developed countries. it is now often considered to be the most common vasculitic disorder in children. the three highest incidence fi gures of kd in the world come from the far east, viz., japan, korea and taiwan. in these countries, not only is the incidence very high, it is continuing to show a rise on a year-toyear basis [ 4 -10 ] . nationwide surveys conducted in japan since 1970 show that there have been three epidemics of kd in japan and also that the incidence of kd has increased by more than two times in the last two decades [ 6 -9 ] . japan reports the highest incidence of kd in the world -the present fi gure being 265/100,000 children below the age of 5 years. korea has the second highest incidence at 134.4/100,000 children below fi ve. in taiwan the current incidence is 82.8 per 100,000 [ 3 ] . based on statistical projections, it is estimated that by 2030, there will be 1 in 700 people living in taiwan with a history of kd. the corresponding fi gure for the usa is 1 in 1600 [ 4 -6 ] . the incidence of kd, however, has remained static in europe as well as north america. in india, anecdotal reports suggest that the recognition of kd has increased signifi cantly over the last two decades, but confi rmatory epidemiologic data on incidence are not available. a hospitalbased study from chandigarh showed that the incidence was 4.54/100,000 children below 15 years, but this fi gure is, in all likelihood, a gross underestimate [ 11 ] . there is no doubt, however, that over the years awareness of kd amongst paediatricians in india has increased signifi cantly. in the years to come, kd may soon replace rheumatic fever to become the leading cause of acquired heart disease in children in india, just as in japan, europe and north america. kd affects the young with 85 % of cases being below 5 years. although it is uncommon in children below 3 months, kd has been reported in neonates as well. in india, however, the median age of occurrence of kd is higher than in japan probably because kd in infancy and young children is being missed in our country. boys seem to be affected more commonly than girls. the male/female ratio at chandigarh has been 1.8:1 [ 2 , 3 , 11 -13 ] . fascinating data on seasonal variations in the incidence of kd have emerged, and these have linked the incidence fi gures of kd in some countries (especially japan and the usa) to tropospheric wind patterns emerging from central asia. such associations have, however, not been proven in other countries, as, for instance, canada [ 14 ] . the causation of kd still remains an enigma. there have been various hypotheses and postulates regarding its aetiology [ 15 , 16 ] . infectious : there are multiple factors which suggest that kd could be an infectious illness. occurrence of the disease in childhood and its virtual absence in adulthood suggest that it may be an infectious disease, and exposure in childhood confers protective immunity, thereby protecting the individuals in adulthood. rarity of its occurrence in early infancy suggests that maternal antibodies may have a protective effect. in addition, clustering of cases in some seasons, few reports suggesting occurrence in families or communities and the clinical presentation with fever, rash and lymphadenopathy, also suggests that it might be an infectious illness. however, till date, no infectious agent has been incriminated with certainty. although several micro-organisms (e.g. streptococcus , staphylococcus , epstein -barr virus , parvovirus , coronavirus ) have been linked with kd, infection alone cannot explain the pathogenesis of the disease. superantigen mediated : the presence of excess of t-lymphocytes with vβ 2 in the coronaries, intestinal mucosa and blood in children with kd suggests that the disease might be superantigen mediated. also, some of the clinical features of kd mimic those of toxic shock syndrome which is a superantigen-mediated disorder. environmental : researchers have also suggested that there might be an environmental trigger which causes this illness. seasonal and geographical clustering can be explained on this basis. genetic : recent evidence based on genomewide association studies suggests that a genetic basis of kd seems entirely plausible. evidence for this hypothesis comes from several epidemiologic data which show that children of certain genetic background seem to have a much higher predisposition to kd. for instance, the incidence of kd amongst children of japanese ancestry in hawaii is much higher than that in other races residing there. in fact, the incidence of kd in children of japanese ancestry there is almost similar to the incidence in japanese children residing in japan. however, till date, no single gene has been implicated, and there is no suggestion of it being an inherited disorder. onouchi et al. have shown the association between kd and itpkc functional polymorphisms [ 15 , 16 ] . it appears that kd is triggered in genetically predisposed children on exposure to some infectious or environmental agent. kd is a systemic medium-vessel vasculitic disorder with a striking predilection for the coronary arteries. this preferential involvement of the coronary arteries is unique to this condition. the infl ammation involves primarily the intima and media leading to damage of the internal and external elastic lamina. the affected vessel may subsequently become ectatic or may show aneurysmal dilatation. healing of these vessels may, in due course, result in stenosis and coronary thrombosis. large coronary aneurysms, and especially giant aneurysms, may never regain normal anatomy [ 2 , 3 ] . the clinical correlates of these changes should be borne in mind. on echocardiography, a coronary artery that gets dilated in the acute phase may regain its normal diameter during convalescence. however, intravascular ultrasound studies have shown that the vessel wall may never regain its recoil and elasticity even when echocardiography suggests a normal anatomy. coronary artery involvement can also be studied by doing computerized tomography (ct) angiographic studies ( fig. 35.1 ) . coronary vessels affected in kd have a predisposition to develop calcifi cation during the healing phase. this calcifi cation may render the affected vessels unsuitable for procedures such as angioplasty and stent placement later in life. kd can also affect other arteries like the femoral and axillary. these would, however, get involved only if there has been coronary artery 1. fever : this is often high grade, may exceed 40 °c and lasts for more than 5 days. the fever typically does not respond to antimicrobials and is associated with irritability which may at times be extreme. fever >5 days plus at least four of the following: • bilateral conjunctival injection • changes in oropharyngeal mucous membranes • changes in peripheral extremities • polymorphous rash • cervical lymphadenopathy illness not explained by any other disease condition hands followed by desquamation which starts from the periungual regions of hands and feet is a characteristic sign. these changes are seen in about 90 % of children with kd. later in the course of disease, beau's lines may develop over the nails which are transverse ridges more easily felt than seen over the nails. 5. rash : an erythematous, morbilliform, nonpruritic rash can occur which begins from the trunk and involves the perineal area. the rash is transient and fades by itself. the rash of kd can be polymorphous but is never vesicular. reported to be present in more than 90 % of affected children from developed countries, it may be diffi cult to perceive in children with dark skin. 6. lymphadenopathy : unilateral, tender, cervical lymphadenopathy occurs in about 60 % of children with kd. a diagnosis of kd can be made if a child with fever for more than 5 days fulfi ls four of the aforementioned fi ve criteria. if a child has fever for less than 5 days or has less than four criteria, the presence of coronary artery abnormalities (caas) detected on 2d echocardiography would also suggest a diagnosis of kd [ 17 ] . the diagnosis of kd can be very challenging and it may test the clinical acumen of even the most astute physician. it must be clearly understood that as there is no gold standard for diagnosis of kd, one does not know the sensitivity and specifi city of the diagnostic criteria for this condition [ 18 ] . from clinical experience, it is clear that if one applies the criteria very strictly, the specifi city would be high, but this would be at the cost of sensitivity. there is no doubt whatsoever that many children with kd may not fulfi l these criteria. further, as the clinical spectrum of kd evolves over a few days, the clinical fi ndings which may have been present during the fi rst few days of the illness may no longer be evident subsequent in the course [ 19 ] . in addition to these characteristic features, some additional fi ndings suggest the possibility of kd. perianal desquamation which appears earlier than the periungual desquamation is also characteristic, and its presence should be looked for in every child having fever for more than 5 days. a transient arthritis may be seen in a quarter of the patients and may, at times, be the presenting feature of kd. reactivation of the bcg scar can be noted in some infants with kd but this is extremely uncommon in our experience. hydrops of the gallbladder may be seen during the acute phase of kd. asymptomatic anterior uveitis is not uncommon during the fi rst few days of the illness. the clinical course in kd is divided into three phases [ 2 , 13 ] : acute febrile phase : this lasts from the onset of illness to 10-14 days and is characterized by high-grade fever, irritability, rash, strawberry tongue, red cracked lips and limb changes. signs of myocarditis may appear in this phase, which include tachycardia, s3 gallop and congestive cardiac failure. subacute phase : this lasts up to 4-6 weeks and ends with return of the acute phase reactants to normal. the caas fi rst appear in this phase. convalescent phase : this lasts for months to years during which healing of the vessels occurs with remodelling and scarring. beau's lines occur during this phase. if a child does not fulfi l the criteria and has less than four features, a diagnosis of incomplete kd is proffered. incomplete kd is commonly seen in infants, and ironically this is the group of patients who are at highest risk for the development of caa. the american heart association has suggested an algorithm for identifi cation of children who do not fulfi l the criteria for kd and are suspected to have kd and so have a risk of developing caa [ 17 ] . when a child with kd presents with features that are not usually seen in this condition, a diagnosis of atypical kd is proffered. clinical features which are unusual in kd include, but are not restricted to, nephritis, seizures, acute hepatitis, neurological obtundation or hypertension [ 13 , 17 ] . because of it being an acute febrile illness, the differential diagnosis of kd includes the common infectious illnesses of childhood: scarlet fever measles hhv-6 and hhv-7 toxic shock syndrome stevens-johnson syndrome drug hypersensitivity serum sickness systemic-onset juvenile idiopathic arthritis it cannot be overemphasized that there is no pathognomonic laboratory test for kd. however, there are several investigations which may support a clinical diagnosis of kd. a normocytic, normochromic anaemia with polymorphonuclear leucocytosis is usually seen. thrombocytosis is characteristically seen after day 10 of fever, but thrombocytopenia can also occur, especially when there is an accompanying macrophageactivation syndrome. acute phase reactants like the c-reactive protein (crp) and the erythrocyte sedimentation rate are elevated during the acute phase. sterile pyuria may be found which is of urethral origin; therefore, one may not obtain this fi nding if urine is obtained by suprapubic bladder aspiration. pyuria in a sick and febrile child is liable to be misdiagnosed as a urinary tract infection [ 2 , 3 ] . ultrasonography may reveal hydrops of the gallbladder. the gallbladder may sometimes enlarge to the extent that it becomes palpable on physical examination. cerebrospinal fl uid examination is not indicated in kd. if, however, it has been carried out, one may see fi ndings consistent with aseptic meningitis. lipid abnormalities are not unusual in children with kd. serum triglycerides and low-density lipoproteins are increased and high-density lipoproteins are reduced. these abnormalities begin in acute phase and may take several months to normalize. 2d echocardiography remains the imaging modality of choice for evaluation of coronary artery abnormalities in children with kd. caas include ectasia and/or aneurysms in proximal parts of left main coronary artery, left anterior descending artery, left circumfl ex artery and/or right coronary artery. this examination needs to be carried out by a pediatric cardiologist or a physician who has the requisite training and experience in evaluation of coronary arteries. coronary arteries are said to be dilated if the size is more than 1.5 times that of the adjacent segment. coronaries with diameter of more than 3 mm in a child less than 5 years of age and more than 4 mm in older children are said to be dilated. it is preferable to use z-scores for evaluation of coronaries in children. the use of these z-scores makes the follow-up and comparison easier and more reliable. children with kd can also have several other fi ndings on echocardiography. these include a decrease in ejection fraction (suggestive of myocarditis), mild valvular regurgitation, increased brightness of the coronary vessels and pericardial effusion. all of these are indicative of an ongoing infl ammatory process. it is important to diagnose and treat kd expeditiously as delays in therapy can result in serious morbidity and occasional mortality. the mortality rate of acute kd at chandigarh is approximately 0.8 %. caas can develop in a quarter of untreated patients with kd. every child suspected to have kd should be admitted and evaluated so that close clinical observation can be carried out. it cannot be overemphasized that clinical fi ndings in kd may change from day to day, and it is of the utmost importance that these be observed and recorded methodically. treatment of kd consists of intravenous immunoglobulin (ivig) and aspirin started within the fi rst 10-12 days of illness [ 2 , 3 , 20 -23 ] . ivig is given as a single intravenous infusion of 2 g/ kg. it is generally administered over 8-12 h, but the infusion must be started slowly so as to avoid occurrence of hypersensitivity reactions. ivig has been found to be very effective if given within the fi rst 10 days of onset of illness. in case, however, the child presents late and the acute phase reactants are still elevated or if there are caas on echocardiography, ivig should still be administered. the response to ivig is often dramatic, and the irritability, so characteristic of kd, often disappears within a few hours of initiation of the infusion. fever defervescence usually occurs within 12-18 h. administration of ivig can, on occasions, be associated with signifi cant adverse effects like headache and vomiting. these are thought to be secondary to a mild aseptic meningitis which is known to be associated with administration of ivig. these can usually be managed quite easily with symptomatic treatment. ensuring adequate hydration and a slow rate of infusion of ivig is said to decrease the occurrence of these adverse effects [ 22 -25 ] . aspirin in anti-infl ammatory doses (30-50 mg/kg/day) is started along with ivig and is continued till the child becomes afebrile. thereafter, aspirin is continued in antiplatelet doses (3-5 mg/kg/day) till a follow-up echocardiography is done and found to be normal at 6-8 weeks of illness. if caas are found in follow-up echocardiography, then aspirin needs to be continued for prolonged periods. additional anticoagulation (with warfarin or low molecular weight heparin) may be required in children with large aneurysms. while therapy with ivig and aspirin has dramatically reduced the occurrence of caas in kd, a small proportion of patients (approximately 3-5 %) still go on to develop caas despite seemingly appropriate therapy having been administered. approximately 10-20 % of patients with kd either do not respond or have a recrudescence of fever that recurs within 36 h of completion of ivig infusion. such patients are said to have refractory kd. several japanese investigators [ 22 -24 ] have put forth risk scoring systems for predicting refractory kd. ogata et al. [ 22 , 23 ] showed that children who were predicted to be ivig resistant on the basis of one such scoring system showed earlier defervescence of fever when treated pre-emptively with a combination of ivig and iv methylprednisolone as compared to the group given ivig alone. the occurrence of caas was also less in the former group. miura et al. [ 24 ] showed that iv methylprednisolone, when used along with ivig in children with refractory kd, does lead to faster defervescence. the effect, however, is not long-lasting. further, the incidence of development of caas is not signifi cantly different in two groups, and the occurrence of adverse effects was signifi cantly higher in the group treated with iv methylprednisolone plus ivig. it must be noted that these scoring systems do not seem to yield reliable results in populations other than japanese and therefore may have limited utility in day-to-day clinical practice in other countries. there is no consensus on the best modality for treatment of refractory kd. therapeutic options include a repeat dose of ivig, intravenous pulse methylprednisolone or anti-tnfα agents (e.g. infl iximab). cyclosporin and plasmapheresis have also been used in such circumstances [ 2 , 3 ] . children with kd who have no caa or have only transient coronary artery ectasia require lowdose aspirin (3-5 mg/kg/day) for initial 6-8 weeks. children with a single small coronary artery aneurysm should be given aspirin at least until the disappearance of aneurysm. however, in a child with giant coronary artery aneurysm, or one with multiple coronary aneurysms, long-term antiplatelet therapy along with antithrombotic therapy in the form of oral warfarin or low molecular heparin is mandated. male sex age less than 6 months thrombocytopenia at presentation neutropaenia, hyponatraemia and hypoalbuminaemia prolonged fever or recrudescence of fever failure to respond to ivig a landmark study by kato et al. [ 25 ] showed that up to 50 % of small-to medium-sized aneurysms resolve on follow-up. giant aneurysms (>8 mm size), however, do not resolve and are associated with signifi cant long-term morbidity. even when the coronary aneurysm appears to have resolved anatomically, functional vessel wall abnormalities are known to persist and may result in myocardial ischaemia/infarction later in life. kd can be associated with signifi cant long-term sequelae. this has been conclusively borne out through recently published long-term follow-up studies carried out at san diego, usa [ 26 ] . it is obvious that kd is no longer considered to be merely a one-time disease of childhood. considering the fact that the incidence of this disease is showing a steady increase in several countries, it is likely to emerge as the commonest cause for acquired heart disease in children the world over. many of these children would grow up to be adults with coronary sequelae. kd, therefore, needs to be considered as a disease of public health importance, and health planners need to be made aware of these facts. acute febrile mucocutaneous syndrome with lymphoid involvement with specifi c desquamation of the fi ngers and toes in children text book of pediatric rheumatology nelson textbook of pediatrics epidemiology of kawasaki disease in asia, europe, and the united states epidemiologic features of kawasaki disease in acute stages in taiwan, 1997-2010: effect of different case defi nitions in claims data analysis epidemiologic features of kawasaki disease in japan: results of the 2009-2010 nationwide survey changes in epidemic patterns of kawasaki disease in japan results of 12 nationwide epidemiological incidence surveys of kawasaki disease in japan epidemiologic pictures of kawasaki disease in japan: from the nationwide incidence survey in 1991 and 1992 monitoring the occurrence of kawasaki syndrome in the united states is kawasaki disease incidence rising in chandigarh a comparison of the clinical profi le of kawasaki disease in children from northern india above and below 5 years of age kawasaki disease -an indian perspective tropospheric winds from northeastern china carry the etiologic agent of kawasaki disease from its source to japan a replication study for association of itpkc and casp3 two-locus analysis in ivig unresponsiveness and coronary artery lesion in kawasaki disease a genome-wide association study identifi es three new risk loci for kawasaki disease diagnosis, treatment, and longterm management of kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis and kawasaki disease, council on cardiovascular disease in the young kawasaki disease: issues in diagnosis and treatment -a developing country perspective delayed diagnosis of kawasaki syndrome: an analysis of the problem prediction of intravenous immunoglobulin unresponsiveness in patients with kawasaki disease prediction of resistance to intravenous immunoglobulin treatment in patients with kawasaki disease corticosteroid pulse combination therapy for refractory kawasaki disease: a randomized trial the strategy of immune globulin resistant kawasaki disease: a comparative study of additional immune globulin and steroid pulse therapy adverse effects of methylprednisolone pulse therapy in refractory kawasaki disease long-term consequences of kawasaki disease. a 10-to 21-year follow-up study of 594 patients acute myocardial ischemia in adults secondary to missed kawasaki disease in childhood 1. kd is the most common cause of acquired heart disease in children in developed countries. 2. the incidence of kd varies across the world; the highest has been reported from japan. 3. there is no gold standard for diagnosis of kd, it is to be considered in a child with prolonged pyrexia, irritability and sequential appearance of clinical signs of kd. 4. the management is with ivig and aspirin. the latter is used initially in antiinfl ammatory doses initially and then reduced to antiplatelet dose. the duration of treatment depends on the coronary artery involvement. 5. there are no clear guidelines for resistant kd, most centres would use a second dose of ivig, and other choices are steroids and infl iximab. key: cord-030192-ebsh62ll authors: winant, abbey j.; blumfield, einat; liszewski, mark c.; kurian, jessica; foust, alexandra; lee, edward y. title: thoracic imaging findings of multisystem inflammatory syndrome in children (mis-c) associated with covid-19: what radiologists need to know now date: 2020-07-30 journal: radiol cardiothorac imaging doi: 10.1148/ryct.2020200346 sha: doc_id: 30192 cord_uid: ebsh62ll the covid-19 global pandemic is an ongoing public health emergency, with over 4 million confirmed cases worldwide. due to the novel nature of this coronavirus and our evolving understanding of its pathophysiology, there is continued uncertainty surrounding diagnosis and management of covid-19, especially in pediatric patients. in addition, a new febrile hyperinflammatory kawasaki-like syndrome (also known as multisystem inflammatory syndrome in children, or mis-c) has emerged in pediatric patients with temporal association to covid-19 infection. this review article aims to provide an up-to-date review of the clinical and imaging findings of pediatric mis-c associated with covid-19, compared with typical acute pediatric covid-19 infection, with an emphasis on thoracic imaging findings. originating in wuhan, china in december 2019, the covid-19 global pandemic is an ongoing public health emergency, with more than 4 million confirmed cases and over 285,000 reported deaths, as of may 15, 2020. 1 as of april 20, 2020 , in the united states, there were an estimated 2572 pediatric covid-19 cases (1.7% of total us covid-19 cases). 2 although no published estimates currently exist on the worldwide prevalence of pediatric covid-19 infection, based on prior us and chinese cdc data, an extrapolated estimate may be approximately 2% of overall worldwide cases. 2, 3 still, knowledge of the thoracic manifestations of pediatric covid-19 infection is limited. in adults, covid-19 is typically characterized by severe pneumonia and hyperactivation of the inflammatory cascade. [4] [5] [6] [7] several early studies suggested that covid-19 infection in children was relatively mild compared with adults, with very few pediatric fatalities reported and the majority of critically ill children possessing underlying medical comorbidities. 2, [8] [9] [10] [11] however, chao et al recently found a higher than previously recognized rate of severe illness in pediatric patients with covid19. 12 furthermore, emerging new evidence suggests that covid-19 infection in children and adolescents is associated with a multisystem inflammatory syndrome (mis-c), with features similar to kawasaki disease and toxic shock syndrome, frequently requiring intensive care unit (icu) admissions. 1 in light of these new findings, it is clear that our understanding of the manifestations of pediatric covid-19 infection is dynamic and evolving. for example, increasing evidence suggests that the respiratory tract is not the only organ system susceptible to infection. 13 furthermore, innate host immunity, possibly due to inflammatory hyperactivation and cytokine storm, may mediate much of the tissue damage in acute covid-19 infection and drive the multisystem hyperinflammation in mis-c. 4, 5, 14, 15 therefore, it is becoming clear that covid-19 is much more than simply a viral pneumonia, but rather a multiorgan systemic disease. 4, 5, 13, 16 given the current lack of available information related to the thoracic imaging findings of pediatric mis-c associated with covid-19 infection, the purpose of this article is to provide an up-to-i n p r e s s date review of the clinical and imaging features of pediatric mis-c associated with covid-19 infection, compared with acute pediatric covid-19 infection, with an emphasis on thoracic imaging findings. in april 2020, after the peak of covid-19 in many european countries, new reports from western europe warned of a new pediatric febrile hyperinflammatory syndrome, affecting children with temporal association to covid-19 infection. 15, 17, 18 for example, clinicians in the united kingdom reported increased incidence of a severe inflammatory syndrome with kawasaki disease-like features in mostly previously healthy children. 17 similarly, verdoni et al reported a 30-fold increase in incidence of a kawasaki-like disease in children in bergamo, italy in the months following the peak of the covid-19 pandemic. 18 children manifesting similar illness have also been recognized in the united states, especially in new york city area. [19] [20] [21] as of may 12, 2020, the new york state department of health has identified 102 pediatric patients with similar hyperinflammatory illness. 21 referred to as pediatric covid-associated multisystem inflammatory syndrome (pmis) or multisystem inflammatory syndrome in children (mis-c) associated with covid-19, this hyperinflammatory syndrome occurs in children testing positive for current or recent infection with sars-cov-2 (rt-pcr or serologic assay) or had an epidemiologic link to a known or suspected covid-19 positive patient. 1, 21 temporally, mis-c cases have been clinically manifesting approximately one month or more after the peak of covid-19 cases in a geographic region. 15 although the etiology is unknown, mis-c is presumed to reflect a postinfectious cytokine-mediated hyperinflammatory process, triggered by covid-19 infection. 15, 22 although a causal link between covid-19 infection and the presumed post-viral hyperinflammation of mis-c has not yet been definitively established, it is strongly suggested by the temporal association and history of covid-19 exposure in mis-c patients. 23 proposed mechanisms i n p r e s s include direct triggering of autoinflammatory response, possibly by molecular mimicry or unknown mechanism, and/or dysregulation of immune responses after covid-19 infection, which could result in other environmental insults triggering a hyperinflammatory pathology in predisposed patients. 23 although the clinical features of mis-c resemble kawasaki disease, there are important demographic differences between mis-c patients and kawasaki disease patients, including older age of onset and differences in ethnicity predisposition. first, although mis-c associated with covid-19 affects pediatric patients of all ages (reported cases range from 6 months to 16 years), the majority of mis-c patients are school age children, with mean age of 7.5-10 years. [17] [18] [19] [20] 22 in contrast, the vast majority of kawasaki disease patients present before five years of age, most under 2 years of age. 24 in addition, while the incidence of kawasaki disease is highest in asia, strikingly, there have been no reported cases of mis-c in asia, despite being an early hotspot of covid-19 infection, with some of the earliest published series on acute pediatric covid-19 infection emerging from china. 15, 24, 25 two series have found a predilection of mis-c to affect children of afro-caribbean descent. 17, 26 although the cause for difference in distribution of mis-c worldwide is not definitively known, genetic predisposition has been suggestive as a factor in this predisposition for development of mis-c. 23 different strains of the virus, due to mutation, could also possibly account for the increased incidence of mis-c in western europe and north america compared with asia. similar to kawasaki disease, two series of pediatric cases of mis-c associated with covid-19 have reported a male predilection (62.5-70%), although a larger series found males and females to be equally affected. 17,18, 22 the most commonly reported comorbidities in children with mis-c associated with covid-19 were overweight status (bmi 25, 17-38%) and asthma (8.5%). 17, 22 clinical presentation i n p r e s s children affected by mis-c associated with covid-19 typically present with persistent high fever (> 3 days) and systemic hyperinflammation, reflected in a constellation of symptoms involving multiple organ systems, frequently manifesting abdominal pain and gastrointestinal symptoms, kawasaki disease-like features, and cardiogenic shock. in published series, the most common presenting signs and symptoms include prolonged high fever (94-100%), weakness/malaise (100%); prominent gastrointestinal symptoms (60-100%), typically abdominal pain, vomiting, and diarrhea; and less commonly, variable maculopapular rash (37-57%) and respiratory distress (0-65%). 17,18,22,26-29 a small number of reported mis-c patients have presented with such severe abdominal pain that laparoscopy was performed for suspected appendicitis (n=3), two of which were found to have mesenteric adenitis and one was found to have aseptic peritonitis. 22, 26 clinical features of kawasaki disease, including non-vesicular skin rash, extremity changes, adenopathy, conjunctivitis, cheilitis, and meningeal signs, are frequently reported, however only six reported patients have met criteria for the classical form of kawasaki disease. 18, 19, 22, 30 the vast majority of mis-c patients present with cardiogenic shock requiring icu admission. all the united states cdc has presented the following case definition for a diagnosis of mis-c associated with covid-19, with pediatric patients required to meet all three of the following criteria: (1.) individual under 21 years of age presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic); (2.) no alternative plausible diagnosis; (3.) positive current or recent sars-cov-2 infection by rt-pcr, serology, or i n p r e s s antigen test; or covid-19 exposure within four weeks prior to symptom onset. fever is defined as temperature greater than 38.0 o c for greater than 24 hours or a subjective fever greater than 24 hours. laboratory evidence of inflammation is defined as including, but not limited to: elevated c-reactive protein (crp), erythrocyte sedimentation rate (esr), fibrinogen, procalcitonin, d-dimer, ferritin, lactate dehydrogenase (ldh), and interleukin-6 (il-6). 21 the vast majority of children affected with mis-c associated with covid-19 present in cardiogenic shock requiring inotropes (80-100%) and mechanical ventilation (66-88%) for cardiovascular stabilization. 17, 19, 20, 22 over a quarter of children with mis-c with acute heart failure at presentation require mechanical circulatory assistance with venoarterial extracorporeal membrane oxygenation (ecmo). 22 although the cdc and who have not provided treatment guidelines, common treatment 22 this recovery of systolic function after treatment may suggest that the mechanism of heart failure is not myocardial damage as seen in adults i n p r e s s with covid-19 infection, however additional studies will be needed to assess whether long-term cardiac complications arise. 22 mainly due to its recent emergence, knowledge of the thoracic manifestations of mis-c associated with covid-19 is limited. however, the following imaging findings were observed in our 20 pediatric patients with confirmed mis-c. three main thoracic imaging findings have been observed in pediatric patients with mis-c associated with covid-19: heart failure, ards pattern, and pulmonary embolus. we observed that the majority of pediatric patients with mis-c associated with covid-19 present with cardiogenic shock, many with imaging findings of acute heart failure. this is in keeping with several reported series that found the majority of mis-c patients (43-67%) present with myocarditis and heart failure. 18, 26, 28, 29 characterized by impaired left ventricular systolic dysfunction, elevated bnp, and significantly elevated proinflammatory cytokines ("cytokine storm," including il-6, c-reactive protein, and procalcitonin), the acute heart failure that is common in mis-c is hypothesized to be the result of a postviral immune-mediated myocarditis. 22, 26, 27 most mis-c patients have positive sars-cov-2 antibodies (80-100%), rather than positive rt-pcr, supporting a post-viral etiology. 17-20,22 infectious diseases have long been considered a trigger for autoimmune diseases, possibly via molecular mimicry or dysregulated immune response. 23 il-6, specifically, has been implicated in the pathogenesis of myocarditis. 23 chest radiographs typically show cardiomegaly, pulmonary edema, and pleural effusions, in keeping with acute left heart failure (fig. 1) . echocardiography typically reveals left ventricular systolic dysfunction with depressed ejection fraction (movie 1). 22 in mis-c with heart failure, cardiac mri typically demonstrates diffuse left ventricular myocardial t2 hyperintensity, suggesting myocardial edema and hyperemia. 27 late gadolinium enhancement is not typically visualized, arguing against the presence of myocardial necrosis or fibrosis. 27 contrary to adult covid-19-related myocarditis, which is typically characterized by extensive transmural late gadolinium enhancement, suggesting extensive necrosis and/or fibrosis, the absence of myocardial necrosis in mis-c may reflect the difference between post-viral immune-mediated cytokine storm and direct viral myocardial toxicity in adult covid-19-myocarditis. 27, 32 of note, the cardiac imaging abnormalities in pediatric mis-c may be transient. for example, relatively rapid recovery of systolic function and normalization of cardiac mri signal abnormalities has been found in mis-c after appropriate supportive care. 22, 27 recovery of systolic function and the absence of late gadolinium enhancement has led investigators to hypothesize that the left ventricular systolic dysfunction in mis-c is most likely due to transient myocardial stunning or edema, rather than myocardial damage. 22, 27 in adults, respiratory failure from acute respiratory distress syndrome (ards) is the leading cause of mortality due to covid-19 infection. 33 it has been postulated that hyperinflammation and i n p r e s s cytokine storm may contribute to the development of severe manifestations of covid-19 infection, including ards and multiorgan failure. 4, 14 we observed that children with mis-c associated with covid-19 can present with hypoxic respiratory failure and imaging findings of ards. 19 chest radiographs demonstrate bilateral multifocal ground-glass and consolidative airspace opacities (fig. 2) . in some pediatric patients with mis-c associated with covid-19 presenting with an ards pattern, airspace opacities were noted to be asymmetric. a prothrombotic coagulopathy is a hallmark of severe covid-19 in adults. 34 while severe covid-19 infection in adults has been associated with high incidence of thrombotic complications, including dvt, pe, ischemic stroke, and myocardial infarction, this association has not yet been demonstrated in typical pediatric covid-19 infection. 35 although the mechanism for adult thromboembolic complications of covid-19 is not known, it has been suggested that overproduction of proinflammatory cytokines contribute to a prothrombotic coagulopathy. 5 interestingly, some authors have suggested that pediatric mis-c and late-stage severe adult covid-19 are characterized by a similar proinflammatory milieu, both characterized by elevated inflammatory markers, including fibrinogen, ddimer, ferritin and il-6. 15, 18, 20 poyiadi et al found that adult covid-19 patients with elevated d-dimer and crp are significantly more likely to develop pulmonary emboli than patients without elevated inflammatory markers. 36 given that elevations in these inflammatory markers are a hallmark of pediatric mis-c associated with covid-19, it is conceivable that the hyperinflammatory state of mis-c may predispose to a similar prothrombotic coagulopathy and thromboembolic complications, including pulmonary emboli. we observed small segmental pulmonary emboli (pe) in some pediatric patients affected by mis-c associated with covid-19. on ct pulmonary arterial angiography, pulmonary embolus appears as an expansile filling defect in a pulmonary artery in pediatric patients with mis-c associated with covid-19 i n p r e s s (fig. 3) . currently, the clinical significance of these small segmental pulmonary emboli in pediatric mis-c patients is unclear. 37, 38 for example, poyiadi et al found no significant difference in icu admission, requirement for intubation, or duration of intubation between adult covid-19 patients who developed pe and those who did not. 36 further studies on the significance of pe in children with mis-c associated with covid-19 will be important. in addition to the characteristic thoracic imaging findings of mis-c associated with coivd-19, characteristic extrathoracic imaging findings are also emerging in pediatric patients with mis-c associated with covid-19 infection. abdominopelvic mesenteric lymphadenopathy, often most prominent in the right lower quadrant, sometimes with surrounding inflammatory fat stranding, with an overall appearance similar to mesenteric adenitis, is a common finding in mis-c associated with covid-19 (fig. 4) . in fact, belhadjer et al found 2 children with mis-c associated with covid-19 underwent appendectomy for suspected appendicitis, with an ultimate diagnosis of mesenteric adenitis. 22 indeed, mesenteric lymphadenopathy is in keeping with the impressive frequency of gastrointestinal symptoms in children with mis-c as well as the likely propensity of the virus to infect the gastrointestinal tract. 13 additional abdominal findings observed in pediatric patients affected by mis-c associated with covid-19 include echogenic kidneys (fig. 5) , ascites (fig. 5) , hepatomegaly, and gallbladder wall thickening, in keeping with multiorgan involvement. 17 children: what are the differences? the typical chest radiographic findings in typical acute pediatric covid-19 infection include bilateral peripheral and subpleural ground-glass opacities and/or consolidations 39, 40 (fig. 6a ). on ct, the i n p r e s s most common appearance of typical acute pediatric covid-19 infection is bilateral multifocal peripheral ground-glass opacities, with or without consolidations, often with a posterior and lower lobe predominant distribution 25, 39, 40 (fig. 6b ). it has been suggested that there are three imaging phases of typical acute pediatric covid-19 infection: early, progressive, and developed phases. 40 as there is significant clinical and imaging variation between patients, there is, at present, no known timeline for demarcating these phases. typically, the "halo" sign ( fig. 6b) , which denotes a rim of ground-glass opacity surrounding a nodule or consolidation, if often observed in the early phase (reported in up to half of cases), often progressing to ground-glass (progressive phase), and ultimately developing into a confluent consolidation (developed phase). 25, 40 additional ct findings reported in typical acute pediatric covid-19 infection include adjacent bronchial wall thickening and inflammation along the bronchovascular bundle are more frequently reported in pediatric patients compared to adults. 25 fine mesh reticulations and "crazy paving" have also been reported, but with less frequency. 25 pleural effusions and thoracic adenopathy are rare and considered atypical. 39, 40 differences between thoracic imaging findings of typical pediatric covid-19 and mis-c associated with there are some differences between the thoracic imaging findings of typical pediatric covid-19 infection and mis-c associated with covid-19 (table 1 ). such differences may be partially explained by the hypothesis that typical covid-19 reflects an acute infection, whereas mis-c associated with covid-19, which is typically occurs approximately 1 month after covid-19 peak in a geographic region and is most often associated with positive antibodies (suggesting prior infection), most likely reflects post-viral hyperinflammatory process. 15, 18, 22 the main radiologic difference between typical pediatric covid-19 and mis-c associated with covid-19 is the location of imaging abnormalities. typical pediatric covid-19 infection predominantly affects the pulmonary parenchyma, manifesting primarily with bilateral peripheral and subpleural airspace opacities. 25, 39, 40 extrapulmonary abnormalities are rare and unexpected in typical acute i n p r e s s pediatric covid-19 infection. 25, 39, 40 in contrast, pediatric mis-c associated with covid-19 is a systemic hyperinflammatory state characterized by multiorgan system involvement, often with prominent cardiovascular abnormalities, such as heart failure, manifesting with cardiomegaly, pulmonary edema, and pleural effusions. 22 as previously described, the hyperinflammatory state of mis-c associated with covid-19 may contribute to a prothrombotic coagulopathy predisposing to thromboembolic complications, including pulmonary emboli. 14,34-36 furthermore, the hyperinflammatory state of mis-c associated with covid-19 is often associated with adenopathy, which is rare and unusual in typical pediatric covid-19 infection. 22, 26, 28, 40 lastly, ards, a common thoracic imaging pattern in late-stage adult covid-19 infection, is also observed in some pediatric mis-c cases, although much less common in typical pediatric covid-19 infection. [39] [40] [41] [42] as previously described, it has been suggested that mis-c associated with covid-19 and latestage adult covid-19 may be characterized by a similar hyperinflammatory milieu, which may account for some overlap in imaging findings and pathophysiology, although more scientific evidence is needed for validation. 15, 18, 20 the growing number of pediatric cases of mis-c associated with covid-19 suggests that covid-19 is likely far more than just a respiratory illness in the pediatric population. in addition to the previously described pulmonary parenchymal abnormalities seen in typical, presumed acute covid-19 infection, mis-c associated with covid-19, which is likely a post-viral hyperinflammatory process, is now known to cause multiorgan damage, including heart disease, liver injury, kidney failure, gastrointestinal and dermatologic manifestations, among others. this signals an important paradigm shift in our understanding of pediatric covid-19 infection: from a primarily respiratory illness to multi-organ system disease. interestingly, many of the clinical and imaging features of mis-c associated with covid-19 resemble late-stage severe adult covid-19 infection, possibly due to a similar hyperinflammatory i n p r e s s cytokine storm, predisposing to some similar thoracic imaging manifestations, including heart failure, ards, and thromboembolic complications. currently, more scientific evidence is needed to guide clinical and imaging study decisions for mis-c associated with covid-19. however, based on our preliminary observation of mis-c associated with covid-19 in our practice, a judicious approach to imaging pediatric patients, who meet the cdc criteria for a diagnosis of mis-c associated with covid-19 infection or exposure, may need to be broadened to include echocardiography, abdominal imaging, and ctpa in pediatric patients with high clinical suspicion for pe, in addition to typical chest radiographs and/or ct. as knowledge and scientific evidence about the imaging findings of mis-c associated with covid-19 grow, better understanding of the characteristic imaging findings and the need for specific imaging evaluations is expected in the future. in addition, because there is currently a lack of pathologic data explaining the underlying causes and imaging findings of mis-c, future studies focusing on the radiology-pathology correlation will shed light on this new and challenging disorder, unique to the pediatric population. i n p r e s s table table 1 . differences in imaging findings between mis-c associated with covid-19 and typical covid-19 in children typical covid-19 findings multisystem inflammatory syndrome in children and adolescents temporally related to covid-19: scientific brief. world health organization website cdc covid-19 response team. coronavirus disease 2019 in children -united states characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a cases from the chinese center for disease control and prevention covid-19: consider cytokine storm syndromes and immunosuppression covid-19 cytokine storm: the interplay between inflammation and coagulation the science underlying covid-19: implications for the cardiovascular system clinical features of patients infected with 2019 novel coronavirus in wuhan epidemiology of covid-19 among children in china sars-cov-2 infection in children and newborns: a systematic review detection of covid-19 in children in early characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 (covid-19) at a tertiary care medical center evidence for gastrointestinal infection of sars-cov-2 covid-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? pediatric covid-associated multi-system inflammatory syndrome (pmis) on the alert for cytokine storm: immunopathology in covid hyperinflammatory shock in children during covid-19 pandemic an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study covid-19 associated pediatric multi-system inflammatory syndrome cardiac dysfunction and thrombocytopenia-associated multiple organ failure inflammation phenotype in a severe paediatric case of covid-19 multisystem inflammatory syndrome in children (mis-c) associated with coronavirus disease acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic autoimmune and inflammatory diseases following covid-19 epidemiology of kawasaki disease in asia, europe, and the united states clinical and ct features in pediatric patients with covid-19 infection: different points from adults kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in paris, france: prospective observational study cardiac mri of children with multisystem inflammatory syndrome (mis-c) associated with covid-19: case series spectrum of imaging findings on chest radiographs, us, ct, and mri images in multisystem inflammatory syndrome in children (mis-c) associated with covid-19 paediatric multisystem inflammatory syndrome temporally associated with sars-cov-2 mimicking kawasaki disease (kawa-covid-19): a multicentre cohort covid-19 and kawasaki disease: novel virus and novel case cardiac involvement in a patient with coronavirus disease 2019 (covid-19) clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid-19 acute pulmonary embolism and covid-19 children suspected of having pulmonary embolism: multidetector ct pulmonary angiography--thromboembolic risk factors and implications for appropriate use mdct pulmonary angiography evaluation of pulmonary embolism in children covid-19) pneumonia: what radiologists need to know international expert consensus statement on chest imaging in pediatric covid-19 patient management: imaging findings, imaging study reporting and imaging study recommendations tissue plasminogen activator (tpa) treatment for covid-19 associated acute respiratory distress syndrome (ards): a case series acute respiratory failure in covid-19: is it 'typical' ards? i n p r e s s figure 5 9-year-old male with mis-c with acute kidney injury. grayscale sagittal ultrasound image of the right kidney demonstrates increased echogenicity of the right renal parenchyma, in keeping with acute kidney injury, and adjacent small abdominal ascites. figure 6a 13-year-old girl, with a history of sickle cell disease, with rt-pct positive for covid-19, who presented with hypoxia, respiratory distress and chest pain. a. frontal chest radiograph shows bilateral peripheral lung zone-predominant diffuse and patchy ground-glass opacities as well as more focal confluent opacity in the retrocardiac i n p r e s s region, which are typical chest radiographic findings of pediatric covid-19 pneumonia.cardiomegaly, which was stable compared to prior radiographs, due to the patient's underlying sickle cell disease, is also shown. figure 6b 13-year-old girl, with a history of sickle cell disease, with rt-pct positive for covid-19, who presented with hypoxia, respiratory distress and chest pain.i n p r e s s b. axial lung window ct image shows several right lower lobe and right middle lobe peripheral rounded nodular consolidative opacities, with surrounding ground-glass halo ("halo" sign) (arrows), which is often seen in the early phase of pediatric covid-19pneumonia. in addition, more confluent opacity (asterisk) is seen in the left lung, which is typical finding of developed phase of pediatric covid-19 pneumonia. key: cord-353229-k3zerr83 authors: akca, ummusen kaya; kesici, selman; ozsurekci, yasemin; aykan, hayrettin hakan; batu, ezgi deniz; atalay, erdal; demir, selcan; sag, erdal; vuralli, dogus; bayrakci, benan; bilginer, yelda; ozen, seza title: kawasaki-like disease in children with covid-19 date: 2020-09-16 journal: rheumatol int doi: 10.1007/s00296-020-04701-6 sha: doc_id: 353229 cord_uid: k3zerr83 children with coronavirus disease 2019 (covid-19) are being reported to have manifestations of hyperinflammatory states and/or kawasaki-like disease. in this study, we investigated children with typical and atypical kawasaki disease (kd) likely to be associated with covid-19. we have reported four children with kawasaki-like disease probably associated with covid-19. the clinical features were consistent with incomplete kd in three patients. sars-cov-2 rt-pcr was positive in one and the serology was positive in one patient with negative rt-pcr. corticosteroids, anakinra, intravenous immunoglobulin (ivig), and acetylsalicylic acid were used in the treatment. three patients recovered after the treatment while one patient died. the literature review revealed 36 articles describing 320 children with kawasaki-like disease associated with covid-19. sars-cov-2 rt-pcr was negative in 120 (65.5%) of 183 patients while the serology was positive in 130 (83.8%) of 155 patients. the therapeutic options have included ivig, acetylsalicylic acid, tocilizumab, anakinra, enoxaparin, and methylprednisolone. pediatric covid-19 cases may present with atypical/incomplete kawasaki-like disease. thus, pediatricians need to be aware of such atypical presentations resembling kd for early diagnosis of covid-19. coronavirus disease 2019 (covid-19) caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has affected individuals of all ages worldwide. children constituted only a small proportion of patients with covid-19, which was initially reported as 1.7% [1] . the actual incidence is unknown since there are no community-based studies. while more than 90% of children with covid-19 were described to have asymptomatic, mild, or moderate disease, new concerns emerged with reports on hyperinflammatory states or kawasaki-like disease [2, 3] . the resulting phenotypes are a combination of typical/atypical kawasaki disease, kawasaki shock syndrome, toxic shock syndrome, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis [4, 5] . children with hyperinflammatory syndrome and multiorgan involvement were classified as having pediatric inflammatory multisystem syndrome (pims) or multisystem inflammatory syndrome in children (mis-c) [6, 7] . kawasaki disease (kd) is an acute, systemic vasculitis of medium-sized vessels. its etiology has not been clearly elucidated. infectious triggers have been suggested in the etiology of kd due to having an epidemic pattern and marked seasonality [8] . various infectious agents, including bacteria such as streptococcus pyogenes, staphylococcus aureus, and yersinia pseudotuberculosis, and viruses such as adenovirus, enteroviruses, epstein-barr virus and coronavirus (new haven coronavirus/hcovnh) have been implicated in the etiology of kd [9] [10] [11] . recently, along with the covid-19 pandemic, kawasaki-like disease associated with covid-19 has been increasingly reported. large case series of kd related to sars-cov-2 from the united kingdom (uk), italy, the united states of america (usa), and france were published [6, [12] [13] [14] [15] [16] [17] . kawasaki-like disease might be severe and requires more aggressive management. herein, we report the characteristics of four patients with kawasaki-like phenotype associated with covid-19 from turkey and analyze the features of similar published cases through a systematic literature review. we also discussed the effect of the local characteristics such as the presence of bacillus calmette-guérin (bcg) vaccine in the routine vaccination schedule and high mefv mutation carriage rate on disease course. increasing reports of this phenotype from different countries would widen the spectrum of clinical and laboratory features, facilitate the diagnostic process, and provide more clues leading to early and effective treatment. we performed a search through pubmed/medline, scopus and web of science databases using the following keywords: "coronavirus disease-19", "covid-19", "2019 novel coronavirus diseases", "severe acute respiratory syndrome coronavirus 2", "sars-cov-2", "2019-ncov", "kawasaki disease", "incomplete kawasaki disease", "atypical kawasaki disease", "kawasaki-like disease", and "kawasaki-like syndrome" filtered for articles published in english and turkish. we searched the literature from inception to august 20, 2020. the systematic review was performed according to the prisma checklist (www.prism a-state ment.org/). we included all articles that reported children who had kawasaki-like disease associated with covid-19. the schematic overview of the literature review process is shown in fig. 1 . the following parameters were noted from included studies: age, gender, country, diagnosis, and diagnostic tests for covid-19. diagnosis of complete kd was based on the criteria of the american heart association (aha): the presence of fever for at least 5 days accompanied by the presence of at least four of the following five findings: bilateral non-exudative conjunctival injection, unilateral cervical lymphadenopathy, changes in the lips and oral cavity, skin rash, and changes in extremities, including indurative angioedema and desquamation [18] . incomplete kd was diagnosed in the presence of unexplained prolonged fever, two or three diagnostic criteria, and supporting compatible laboratory or echocardiography (echo) findings [18] . a 7-year-old boy presented with fever, cough and an erythematous rash. he had bilateral conjunctival injection, diffuse erythematous maculopapular rash, erosive hyperemia of the oral mucosa, bilateral crackles on chest auscultation and respiratory distress findings in physical examination. respiratory distress developed rapidly, and he was intubated due to hypoxemia. laboratory tests revealed mild elevation of liver transaminases, lymphopenia, thrombocytopenia, elevated d-dimer, and lactate dehydrogenase levels. his ferritin level was within normal range when he was referred to our hospital on the 12th day of fever, but rose to 1336 µg/l (20-336) on day 27. the sars-cov-2 rna was not detected from his nasopharyngeal swab. however, the bronchoalveolar lavage fluid tested positive for sars-cov-2 by real-time reverse transcriptase-polymerase chain reaction (rt-pcr). chest computed tomography revealed bilateral diffuse groundglass density areas. diffuse enlargement in the left coronary artery (diameter of the left coronary artery was 3.3 mm and z score 2.0) with normal systolic function and pulmonary hypertension were reported in echo findings. the patient was diagnosed with incomplete kd and covid-19 pneumonia. intravenous immunoglobulin (ivig), azithromycin, hydroxychloroquine, ritonavir and lopinavir, tocilizumab, and mesenchymal stem cell treatments were applied during his admission in the pediatric intensive care unit. on the 27th day of the onset of the fever, his hypoxia deteriorated under mechanical ventilation. he was started on venovenous extracorporeal membrane oxygenation (vv-ecmo) therapy. disseminated intravascular coagulation, renal, and heart failure were developed in the follow-up. he died from severe hypoxia on the 17th day of vv-ecmo. a 10-year-girl presented with resistant fever for the last 4 days, which was accompanied by vomiting. physical examination was remarkable with one-sided submandibular lymphadenopathy size of 2 × 1.5 cm, changes in the lips and oral cavity, maculopapular erythema around the neck, bilateral non-exudative conjunctival injection, and diffuse abdominal tenderness. she had prolonged capillary refill time with hypotension. inotropic therapy was initiated due to hypotensive values resistant to fluid therapy. her laboratory examination revealed impairment of renal function, high levels of acute phase reactants [c-reactive protein (crp) 26.4 mg/dl (0-0.8), erythrocyte sedimentation rate (esr) 96 mm/h (0-20)], lymphopenia with normal leukocyte count, normal platelet levels (155 × 10 3 /µl), elevated brain-natriuretic peptide, d-dimer, ferritin (1019.6 µg/l) and triglyceride levels. pleural effusion and ground-glass densities were evaluated in favor of covid-19 in the thoracic tomography of the patient who developed respiratory distress in the follow-up. besides, an edematous gall bladder was observed on abdominal tomography. she had no contact history for covid-19, and the rt-pcr test result was negative. she was diagnosed with kd due to the fever and accompanying findings; the conjunctival injection, unilateral cervical lymphadenopathy, changes in the lips and oral cavity, and skin rash. echoc was normal. intravenous immunoglobulin (ivig), recombinant interleukin 1 (il-1) receptor antagonist (anakinra), and corticosteroid therapies (20 mg/day) were administered due to the accompanying hyperinflammatory syndrome. the covid-19 nasopharyngeal swab test result, which was examined for the second time, was negative, while serologic testing for igg antibodies against sars-cov-2 was positive. since the patient still had active symptoms, favipiravir treatment was started. on the 7th day of hospitalization, the inflammatory response and symptoms completely regressed, and the patient was discharged. a 2-year-old girl presented with fever for 8 days. edema of the dorsum of hands and feet accompanied fever. arthritis was present in the proximal interphalangeal joints of the hands and right knee. she did not have a conjunctival injection, skin rash, or changes in the lips and oral cavity. other system examination was unremarkable. the parents were actively working physicians. laboratory tests were as follows: leukocyte count 18 × 10 3 /µl, neutrophil count 8.24 × 10 3 /µl, platelet count the echocardiographic evaluation revealed increased perivascular echogenicity in the right coronary artery. ivig and acetylsalicylic acid treatment were initiated with the diagnosis of incomplete kd. then low-dose corticosteroid treatment was started. she recovered within 2 weeks. sars-cov-2 serology testing could not be performed. a 2-year-old girl with a diagnosis of congenital adrenal hyperplasia presented with resistant fever for 6 days. she had bilateral conjunctival injection at the onset of symptoms and conglomerate lymphadenopathy in the right cervical region. clinical examination revealed no signs of hepatosplenomegaly or lymphadenopathy in other lymphatic regions. she had no skin rash, no changes in the oral cavity, or in the extremities. her father was a physician. laboratory examination revealed elevated acute phase reactants [crp: 13.66 mg/dl (0-0.5), esr 57 mm/h (0-20)], and increased leukocyte count (17.4 × 10 3 /µl). the initial echo examination was normal. covid-19 nasopharyngeal swab test results were negative, two times. after consultations with the departments of pediatric hematology-oncology, infectious disease, and cardiology, antibiotic treatment was initiated for lymphadenitis. at 2-week follow-up, the echo findings revealed an aneurysm in the left coronary artery. the sars-cov-2 serology was negative, either. ivig, acetylsalicylic acid, and corticosteroid treatment were initiated with the diagnosis of incomplete kd. an increasing number of kawasaki-like disease in patients with covid-19 continue to be reported worldwide. we have reported four patients, along with the review of 320 pediatric patients from the systematic literature search (table 1 ) [6, [12] [13] [14] [15] [16] [17] . in addition to these articles presented in the table, six articles reported kawasaki-like disease in children with covid-19 [36, [48] [49] [50] [51] [52] . these articles were not included since there were no details about the reported patients. in our study, the clinical features were consistent with incomplete kd in three patients. sars-cov-2 rt-pcr was negative in all except one while the serology was positive in one patient with negative rt-pcr. corticosteroids, anakinra, ivig, and acetylsalicylic acid were used in the treatment. three patients recovered after the treatment while one patient died. until today, 80 patients were reported from france, 17 patients from italy, 132 patients from the usa, 74 patients from the uk, 3 patients from india, 12 patients from spain, 1 patient from israel, and 1 patient from turkey. sars-cov-2 rt-pcr was negative in 120 (65.5%) of 183 patients while the serology was positive in 130 (83.8%) of 155 patients. the therapeutic options included ivig, acetylsalicylic acid, tocilizumab, anakinra, enoxaparin, and methylprednisolone. all of the reported patients recovered after the treatment except one. hacettepe university is a tertiary reference center for pediatric rheumatology, and we serve a large population of children, probably serving as the reference center for a large geographic area in turkey. iga-vasculitis/henoch-schönlein purpura is the most frequent childhood vasculitis in our region. in our hospital where we diagnosed 129 (complete and incomplete) kd patients between june 2007 and september 2019 (incidence 0.8 per month), 3 patients were diagnosed with kd within a month during the covid-19 pandemic. although an approximately 3.7-fold increase in the incidence of kd was observed in our hospital during the pandemic, it was lower compared to reported incidences from other countries [6, 12] . for instance, in the series reported from italy, a 30-fold increased incidence of kawasaki-like disease was reported, and it is expected to reach similar figures in north america [12] . 3 of our 4 patients had clinical features consistent with incomplete kd. along with the incomplete clinical features, they had very high crp, lactate dehydrogenase, and d-dimer levels, which were different from our classical kd patients. the reported prevalence of incomplete kd is 15 to 36.2% [53, 54] . in the literature review, incomplete kd phenotype was increased to 45.9% (n = 147). thus, the rate of incomplete kd during the pandemic is higher compared to the pre-covid-19 period. the rate could differ in different geographic areas. in our center in the pre-covid period, aydin et al. had reported the prevalence of incomplete kd of our center as 48.0% [55] . the rate increased to 75.0% (n = 3) in patients during the covid-19 pandemic [55] . this finding suggests that we should maintain a high index of suspicion for incomplete kd in covid-19 patients. the underlying mechanisms of cardiovascular involvement in covid-19 are currently unknown. however, varga et al. reported that infected endothelial cells stimulate the inflammatory response and cause endotheliitis as a result of viral exposure [56] . besides the viral effects, host factors are important in the pathogenesis of kd. certain genetic or environmental factors may be suggested for the rather lower frequency of these cases in our center. first, the carrier frequency of mefv mutations is high in our country, with a rate of 1/5 [57] . asymptomatic heterozygous carriers of mefv mutations have been indicated to have more frequent inflammatory symptoms, increased crp, serum amyloid-a protein and the mrnas for proinflammatory cytokines such [58] [59] [60] . in one previous report, the authors also commented on a protective effect of mefv variants against covid-19 [58] . such mefv mutation carriers with subclinical inflammation may be protected against endemic infections due to the increased activity of the pyrin [60, 61] . a selective advantage against some pathogens such as yersinia pestis in mefv mutation carriers has recently been proposed [62] . the jury is out on whether fmf carriage might provide some protection against covid-19 infection. another issue is the possible protective effect of bcg vaccine [63] . bcg vaccine is included in the routine vaccination program in turkey, and it is applied at two months of age. previous studies have shown that the bcg vaccine protects against other viral infections by causing metabolic and epigenetic changes that increase the innate and trained immune response to infections [64] . supporting this information, arts et al. reported that bcg vaccination reduced yellow fever vaccine viremia by 71% [65] . on the other hand, the duration of the bcg effect remains uncertain. long-term studies are needed with a broader analysis of monocyte function [65, 66] . however, the apparent lack of protection against covid-19 was observed in the uk and france, where bcg vaccination was administered to older children [67] . it is hypothesized that when vaccination is done in the early infancy period, it may result in improved immune surveillance for lifelong, resulting in a milder viral disease. but if performed at an older age, this response may be short term or insufficient [67] . finally, early measures such as curfews in children and travel restrictions might have an effect in reducing the spread of viruses and decreased incidence of kd. we have not been able to show covid-19 in two of our patients. both parents of these two patients were actively practicing physicians at the time of the pandemics. rt-pcr-based assays performed on respiratory specimens were positive in 63 of 183 patients (34.5%) with kd and covid-19. the sensitivity of rt-pcr tests is low, and it is affected by many external factors such as the sampling time, whether the sample is taken correctly, and the performance of the kits [68] . ai et al. reported that 413 of 1014 (41%) rt-pcr test results of infected patients were negative at the initial presentation [69] . although waltuch et al. reported negative rt-pcr results of nasopharyngeal swab samples in four patients, serological tests of these patients were positive [25] . serological tests have some advantages compared to rt-pcr tests such as presence of antibodies in the blood for a long time, unlike viral rna, and stable structure of antibodies in sample processing steps. however, serological tests could be negative in the infected patients at an early stage of infection [70] . in our literature review, serologic tests were performed in 155 patients and 130 were positive (83.8%). the sensitivity of covid-19 serology tests ranges from 72.7 to 100% [71] . some children with covid-19 developed a cytokine storm syndrome which may require intensive care [72] . children with persistent fever, inflammation (neutrophilia, high crp, and lymphopenia), and single or multi-organ dysfunction have been identified in the uk as "pediatric multisystem inflammatory syndrome in relation to sarscov-2 (pmis-ts)" regardless of the sars-cov-2 rt-pcr test results [73] . this hyperinflammatory condition was named as "multisystem inflammatory syndrome in children (mis-c)'' by the centers for disease control and prevention [74] . the phenotypes under this category are typical/atypical kd, kawasaki shock syndrome, toxic shock syndrome, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis [4] . in this study, we investigated only the group with typical/atypical kd accompanying covid-19, to compare with our previous figures for kd: our first patient with incomplete kd also developed a hyperinflammatory syndrome. during the covid-19 pandemic, healthcare workers are worried about passing the infection to their families. the parents of two of our patients were healthcare workers who were at high risk to contact with infected patients. similarly, healthcare workers were present in families of one every two patients in the study by licciardi et al. [20] . similarly, in early reports from china, 40 of 138 (29%) patients were healthcare professionals [75] . we present our patients with kd-like disease associated with sars-cov-2 infection. since pediatric cases may come with findings consistent with atypical or incomplete kd, pediatricians need to be aware of such atypical presentations of covid-19 infection for early diagnosis. a high clinical suspicion should be maintained for covid-19-associated kawasaki-like disease since it usually requires aggressive management. we await further studies to explain the clinical course of pediatric patients diagnosed with covid-19 and kd, in particular, to clarify the pathophysiology. whether there are geographic or ethnic factors affecting the occurrence of a kawasaki-like disease in these patients will also be explained with further reports. author contributions dr. uka conceptualized and designed the study, drafted the initial manuscript, reviewed and revised the manuscript. dr. sk conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. dr. yo conceptualized and designed the study, drafted the initial manuscript, reviewed, and revised the manuscript. dr. hha conceptualized and designed the study, drafted the initial manuscript, reviewed, and revised the manuscript. dr. edb conceptualized and designed the study, coordinated and supervised data collection, critically reviewed, and revised the manuscript. dr. ea conceptualized and designed the study, drafted the initial manuscript, reviewed, and revised the manuscript. dr. sd conceptualized and designed the study, drafted the initial manuscript, reviewed, and revised the manuscript. dr. es conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. dr. dv conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. dr. bb conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. dr. yb conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript. dr. so conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript. all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. funding no external funding for this manuscript. conflict of interest the authors have indicated that they do not have any financial and non-financial potential conflicts of interest to disclose. informed consent written informed consent was obtained from the presented patients and their parents. coronavirus disease 2019 in children-united 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and in heterozygous carriers of mefv mutations are carriers for mefv mutations" healthy the pyrin inflammasome in health and disease familial mediterranean fever: assessing the overall clinical impact and formulating treatment plans implications of covid-19 in pediatric rheumatology considering bcg vaccination to reduce the impact of covid-19 bcg vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity non-specific effects of vaccines: plausible and potentially important, but implications uncertain bcg vaccine protection from severe coronavirus disease 2019 (covid-19) challenges in laboratory diagnosis of the novel coronavirus sars-cov-2 correlation of chest ct and rt-pcr testing in coronavirus disease 2019 (covid-19) in china: a report of 1014 cases the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application estimating falsenegative detection rate of sars-cov-2 by rt-pcr covid-19 associated multisystem inflammatory syndrome in children (mis-c) guidelines; a western new york approach covid -19-paedi atric -multi syste m-%2520i nflam mator y%2520s yndro me-20200 501.pdf 74. prevention. cfdca (2020) multisystem infl ammatory syndrome in children (mis-c) associated with coronavirus disease 2019 (covid-19). cdc health alert network publication cdchan-00432 clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan key: cord-301107-0njnjqeb authors: dursun, recep; temiz, selami aykut title: the clinics of hhv‐6 infection in covid‐19 pandemic: pityriasis rosea and kawasaki disease date: 2020-05-31 journal: dermatol ther doi: 10.1111/dth.13730 sha: doc_id: 301107 cord_uid: 0njnjqeb a new type of coronavirus family (sars‐cov‐2), which can be found in humans and animals, with many varieties and clinical symptoms, was first seen in wuhan, china in late 2019, under the name novel coronavirus disease 2019 (covid‐19). in the literature, cutaneous symptoms related to the disease are generally emphasized. however, it is not yet known whether this new sars‐cov‐2 virus, which has entered our lives, plays a role in the etiopathogenesis of dermatological diseases. the patients who were admitted to the dermatology outpatient clinic between 1 april and may 15, 2019, and on 1 april and may 15, 2020 were retrospectively analyzed by searching the hospital automation system and patient files. the reason for the same months to be included in the study was to exclude seasonal effects on the diseases. after pandemic, the number of patients with pityriasis rosea and kawasaki disease increased significantly in patients who applied to the dermatology outpatient clinic. our study is the first study showing pityriasis rosea increase during the pandemic period. we think that this increase is related to hhv‐6 reactivation. herein, we wanted to draw attention to two diseases in which human herpes 6 (hhv‐6) was accused in etiopathogenesis: kawasaki disease and pityriasis rosea. this article is protected by copyright. all rights reserved. a new type of coronavirus family (sars-cov-2), which can be found in humans and animals, with many varieties and clinical symptoms, was first seen in wuhan, china in late 2019, under the name novel coronavirus disease 2019 . it spread to the world very quickly, and was accepted as a pandemic on march 11, 2020 (1) . clinical, therapeutic, vaccination, anti-virus, and anti-spreading studies have been initiated all over the world related to this virus, where human immunity was first introduced. because viral disease was spreading very fast and had a very lethal feature (2) . it is also reported that there are many patients with covid-19 disease asymptomatic. there are many publications about the cutaneous findings of the disease. in the literature, disease-related skin lesions have been reported in approximately 2-20% of covid-19 patients (3) . in the literature, cutaneous symptoms related to the disease are generally emphasized. however, it is not yet known whether this new sars-cov-2 virus, which has entered our lives, plays a role in the etiopathogenesis of dermatological diseases (4) . herein, we wanted to aim to evaluate whether two diseases (pityriasis rosea and kawasaki disease), in which human herpesvirus 6 (hhv-6) was held responsible for etiopathogenesis, after the covid-19 pandemic. this study was conducted at the necmettin erbakan university hospital, a major tertiary hospital, and sees over 1,200,000 patients per year. the patients who were admitted to the dermatology outpatient clinic between 1 april and 15 may 2019, and on 1 april and 15 may 2020 were retrospectively analyzed by searching the hospital automation system and patient files. the reason for the same months to be included in the study was to exclude seasonal effects on the diseases. in the evaluation made based on before and after the covid-19 pandemic, the total number of patients admitted to the outpatient clinic during these periods was determined. the numbers and rates of patients with pityriasis rosea and kawasaki disease among the total patients who applied to the outpatient clinic were calculated. local ethics committee approval was also obtained for the study. data analysis was performed using the spss 22.0 program. mean ± standard deviation and percentage were used for descriptive statistics. chi-square test was performed and the p value of less than 0.05 was accepted as statistically significant. the total number of patients admitted to the dermatology outpatient clinic between 1 april and 15 may 2019 was 6467. female patients had a slight predominance (55.9%). the mean age of patients was 35.7 ± 29.1. the total number of patients admitted to the dermatology outpatient clinic between 1 april and 15 may 2020 was 1292. female patients had a slight predominance (54.8%). the mean age of patients was 36.6 ± 30.2. in terms of age and gender, there was no significant difference in outpatient applications before and after the covid-19 pandemic. table 1 shows the distribution of the patients who applied to the dermatology outpatient clinic before and after the pandemic. among the patients who applied to the dermatology outpatient clinic between april 1 and may 15, 2019, 52 patients (0.8%) were diagnosed with pityriasis rosae. among the patients who applied to the dermatology outpatient clinic between april 1 and may 15, 2020, 50 patients (3.9%) were diagnosed with pityriasis rosae. after pandemic, the number of patients with pityriasis rosea increased significantly in patients who applied to the dermatology outpatient clinic (p:0,000). among the patients who applied to the dermatology outpatient clinic between april 1 and may 15, 2019, 2 patients (0.03%) were diagnosed with kawasaki disease. among the patients who applied to the dermatology outpatient clinic between april 1 and may 15, 2020, 4 patients (0.3%) were diagnosed with kawasaki disease. after pandemic, the number of patients with kawasaki disease increased significantly in patients who applied to the dermatology outpatient clinic (p:0,009). table 2 shows the distribution of patients with pityriasis rosea and kawasaki disease before and after the pandemic. covid-19 has already had many effects on the routine dermatology practice (5) . however, it is clear that there will be many more developments and new information in the relationship between covid-19 and dermatology in the following days. sars-cov-2, which is the cause of covid-19 disease, is not actually a dermatotrophic virus. however, various cutaneous manifestations associated with the disease have been reported to develop during covid-19 disease (3, 6) . cutaneous symptoms can be classified under five main categories (urticarial lesions, livedo and necrosis, maculopapular eruption, vesicular rash, pseudo-chilblain) (3). however, dermatological diseases triggered by sars-cov-2 remain a mystery for now. in our study, it was found that the rate of pityriasis rosae patients who applied to the dermatology outpatient clinic this year during the pandemic period increased approximately 5 times compared to the same time last year. the fact that there was no significant increase in the total number of pityriasis rosae patients was attributed to the low number of total admissions to the hospital during the pandemic period. in our opinion, the increase in the rate of pityriasis rosae patients among polyclinic patients was more important data. previously, a case of pityriasis rosea associated with covid-19 disease has been reported (7) . our findings are the first study in the literature showing the increase of pityriasis rosea patients and their relationship with covid-19. pityriasis rosea has been mostly associated with reactivation of human herpesvirus 6 and 7, but other viral etiology, vaccination, psychological stress, and drugs have also been implicated as the cause of this reaction (8) . hhv-6, a member of the herpes virus family, is usually transmitted in the first two years of life (roseola infantum) and settles in the salivary glands, causing a latent infection (9) . there are two types of hhv-6, a and b (10) . the reactivation of hhv-6 is blamed for many diseases, including pitriasis rosae (11) . it has been argued that one of the factors causing activation of herpes viruses is coronaviruses (12) . along with the covid-19 pandemic, it was thought that reactivation of hhv-6 could explain this obvious increase in pityriasis rosea cases. another possible trigger could be psychological stress caused by the pandemic period. kawasaki disease is a systemic vasculitis of childhood that can affect the coronary arteries. the diagnosis of kawasaki disease is based on clinical features. cutaneous symptoms with diagnostic criteria are: erythema of the mouth or pharynx, strawberry tongue, or stomatitis; polymorphous rash; erythema or edema of the hands or feet (13) . the etiology of kawasaki disease is still unknown. hhv-6 is one of the accused reasons for the etiology (14) . in a study conducted during the covid-19 pandemic, kawasaki disease was found to increase 30-fold compared to previous years (15). in our study, there was a 10-fold increase in the rate of patients with kawasaki disease who applied to the dermatology outpatient clinic compared to the previous year. we think that this increase in kawasaki disease during the covid-19 pandemic may be due to coronavirus triggering of hhv-6, which is responsible for the etiology. the covid-19 disease caused by sars-cov-2 still contains great mysteries for dermatology. in order to solve the mysteries about the disease, a lot of data are published about the clinical symptoms caused by the disease, the effects and side effects of drug treatments, and the associated diseases. kawasaki disease has been reported to increase compared to previous years. however, there is no data to show the increase of pityriasis rosae patients in which hhv-6 plays a role in etiopathogenesis, as in kawasaki disease. our study is the first study showing pityriasis rosea increase during pandemic period. we think that this increase is related to hhv-6 reactivation. herein, we wanted to draw attention to two diseases in which human herpes 6 (hhv-6) was accused in etiopathogenesis: kawasaki disease and pityriasis rosea. genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding clinical characteristics of 2019 novel coronavirus infection in china classification of the cutaneous manifestations of covid-19: a rapid prospective nationwide consensus study in spain with 375 cases viral exanthem in covid-19, a clinical enigma with biological significance evaluation of dermatology consultations in the era of covid19 cutaneous manifestations in covid-19: a new contribution pityriasis rosea as a cutaneous manifestation of covid-19 infection pityriasis rosea recurrence is much higher than previously known: a prospective study molecular epidemiological studies of human herpesvirus 6 in families a populationbased study of primary human herpesvirus 6 infection additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and-7 shedding light on the effect of natural anti-herpesvirus alkaloids on sars-cov-2: a treatment option for covid-19 kawasaki disease: part i. diagnosis, clinical features, and pathogenesis reactivation of human herpesviruses 6 and 7 in kawasaki disease key: cord-299870-4ulmbn1r authors: ferrara, giovanna; giani, teresa; caparello, maria costanza; farella, carla; gamalero, lisa; cimaz, rolando title: anakinra for treatment-resistant kawasaki disease: evidence from a literature review date: 2020-09-03 journal: paediatr drugs doi: 10.1007/s40272-020-00421-3 sha: doc_id: 299870 cord_uid: 4ulmbn1r kawasaki disease (kd) is one of the most common vasculitides of childhood and the main cause of acquired heart disease in developed countries. intravenous immunoglobulin (ivig) in association with aspirin represents the main treatment for kd. however, 10–20% of patients fail to respond to standard treatment and have an increased risk of cardiac complications. there is currently no accepted protocol for treatment of resistant cases. several authors highlighted the role of interleukin-1 (il-1) as a mediator of inflammation in kd and suggested the possibility of using il-1 or its receptor as a target of therapy. the use of il-1 inhibitors in patients with kd has been reported in the scientific literature, but data are largely limited to individual case reports and small case series. we summarized the scientific literature related to the use of anakinra, analyzing preclinical and clinical data. thirty-eight patients have been described so far, most of them with kd-related complications. twenty-two were described in case reports and case series, while 16 were patients from the completed kawakinra phase iia study. almost all patients received clinical benefit, and no relevant side effects were noted. based on this evidence, in our opinion, anakinra may be considered as an option after the failure of the first ivig infusion, especially in patients with coronary involvement. kawasaki disease (kd) is an acute medium vessel vasculitis of childhood, typically involving coronary arteries, and represents in this age group the first cause of acquired heart disease in developed countries. classically, kd is diagnosed in the presence of a high fever lasting for at least 5 days associated with at least four of the five principal features: changes in the peripheral extremities, cervical lymphadenopathy, bilateral non-exudative conjunctivitis, changes in the oral cavity, and polymorphous exanthema [1] . in the presence of fever and four or more principal clinical features, the diagnosis of complete kd can be made; experienced clinicians who have treated many patients with kd may also establish the diagnosis without waiting for the full clinical picture and even with < 4 days of fever [1] . the diagnosis is clinical, and there are no confirmatory laboratory or imaging investigations. if coronary artery abnormalities are detected, the diagnosis of kd is considered confirmed also in those cases that lack the full clinical features of classic kd and that would otherwise be considered as incomplete kd cases [1] . intravenous immunoglobulin (ivig) in association with aspirin represents the main treatment for kd, and administration of these treatments within the first 10 days following fever onset has been associated with a fivefold reduction in the risk of coronary artery aneurysms (caa) [1] . however, 10-20% of patients do not respond to standard treatment and have an increased risk of cardiac complications and death [2] . the current evidence to guide treatment of resistant kd is of moderate to low quality [2] , which is unfortunate given the potential severity of adverse outcomes of both kd itself and the treatments, and the cost of some proposed agents. the latest guidelines of the american heart association [1] suggest that reasonable therapy for resistant kd includes a second dose of ivig or a short course of high-dose steroids or infliximab. the guidelines also mention the anti-interleukin-1 (anti-il-1) anakinra among the different drugs that can be used in refractory forms, but leave the choice of the drug to individual physicians. interleukin-1 (il-1) has been shown to play a key role in the development of caa, leading to a potential use of il-1 blockade in patients with kd [3] . our aim was to review the literature in order to report the scientific evidence coming from both experimental and clinical studies that support the use of anakinra in refractory kd. a careful search using pubmed and the cochrane library for human studies published in english up to the present time and the platform clinicaltrials.gov for ongoing trials was conducted. the key words used in the search were "kawasaki" and "anakinra" (kawasaki [all fields] and "interleukin 1 receptor antagonist protein"[mesh terms] or "interleukin 1 receptor antagonist protein"[all fields] or "anakinra"[all fields]). in the last few decades, biological disease-modifying antirheumatic drugs have been developed to interfere with il-1 signaling. the activation of il-1 signaling requires the combination of il-1 with type i il-1 receptor and il-1 receptor accessory protein, which ultimately activates the transcription factor nuclear factor kappa light-chain enhancer of activated b cells (nf-κb) [4] . the three drugs currently available either block the il-1 binding to the il-1 receptor (anakinra) or bind directly to il-1 (rilonacept and canakinumab). anakinra is an il-1 receptor antagonist, and was approved by the us food and drug administration (fda) for the treatment of rheumatoid arthritis in 2001 and cryopyrin-associated periodic syndrome in 2013 [5] . it is a non-glycosylated homolog of human il-1 receptor antagonist (il-1ra), manufactured from cultures of genetically modified escherichia coli using recombinant dna technology, and differs from the native human il-1ra in an extra methionine residue on its amino terminus [5] . anakinra, unlike canakinumab and rilonacept, acts as a competitive inhibitor of both il-1α and il-1β, blocking signal transduction by il-1 type i receptor; of note, it has been demonstrated that il-1α also has a major role in coronary lesions [6] . a big advantage of this drug over the other anti-il-1 agents is the rapid onset of action and the short half-life of 4-6 h; these aspects confer the advantages of being able to quickly test the response and limit the effects in the case of a serious adverse event [7] . this makes the drug an extremely manageable treatment in clinical practice. on the contrary, for long-term illnesses, the daily subcutaneous injections represent a major disadvantage. anakinra is now used in numerous diseases such as hereditary autoinflammatory syndromes, and was recently approved for systemic onset juvenile idiopathic arthritis and still's disease. in children weighing less than 50 kg, the starting dosage is 1-2 mg/kg/day; patients weighing 50 kg or more are dosed with 100 mg/day. in children with inadequate response, the dosage can be escalated up to 4 mg/kg/day. rilonacept is a fully human dimeric fusion protein consisting of both il-1 receptor components required for il-1 signaling (il-1 type i receptor and il-1 receptor accessory protein) combined with the fc portion of human immunoglobulin g1. it acts by blocking both il-1α and il-1β. the drug was first approved by the us fda in 2008 for the treatment of cryopyrin-associated periodic syndrome. it has a half-life of 8 days, and is administered by subcutaneous weekly injections (160 mg/week) [8] . canakinumab is a recombinant, human monoclonal, highly selective anti-il-1β antibody, able to prevent the binding of endogenous il-1β to its cognate receptor. the drug was first approved by the us fda in june 2009 for the treatment of familial cold autoinflammatory and muckle-wells syndromes. serum clearance of canakinumab is slow after subcutaneous injection, with a long half-life of 21-30 days. it therefore offers the advantage of monthly injections [9] . the first studies demonstrating high levels of il-1 in patients with kd during the acute phase date back to more than 30 years ago [10] . a more recent study confirms this finding, showing significantly increased plasma levels of il-1β, il-18, and their antagonists (il-1ra and il-18bp) in acute kd patients compared with age-matched control patients with viral or bacterial infections [11] . in the last decade, several studies demonstrated the key role of il-1 in the pathogenesis of kd. weng et al. enrolled 156 children with kd (136 responders and 20 non-responders to ivig) and showed that polymorphisms in the genes coding for il-1 (-31 cc and -511 tt) were associated with a greater risk of resistance to ivig treatment [12] . similar results were obtained by another group, who evaluated il-1-related gene transcripts in patients with ivig-resistant kd. again, considering 20 kd patients (12 responders and eight resistant) and nine controls, the authors confirmed a significant abundance of transcripts in ivig-resistant patients, demonstrating an increased expression of the coding genes for proteins implicated in the il-1 pathway. the authors therefore highlighted the role of il-1 as a mediator of inflammation in kd and suggested the possibility of using il-1 or its receptor as a target of therapy [13] . the same conclusions came from a study comparing the gene expression of 146 patients with kd in the acute and subacute phase with that of subjects suffering from other acute infectious diseases and healthy controls [14] . the efficacy of anti-il-1 treatment was studied by lee et al. in a mouse model of coronary arteritis developed using intraperitoneal injection of lactobacillus casei cellwall extract (lccwe). the mice developed a focal, localized coronary arteritis that histopathologically mimics the coronary artery lesions found in human kd [15] . in a first experiment, mice lacking caspase-1 (caspase-1 −/−), an enzyme of the inflammasome that activates il-1, were unable to trigger the inflammatory response to lccwe and did not develop coronary arteritis; similar results were obtained in mice without the il-1 receptor (il-1r −/−). in a second experiment, mice treated with anakinra daily, from the day before exposure to lccwe until day 5, and then sacrificed on day 7 for anatomical search of coronary damage, showed a significantly lower incidence of vasculitis than controls. the same experiment was also conducted with a tumor necrosis factor inhibitor, infliximab. also in this case, there was a reduced incidence of coronary lesions compared to controls, but not of myocarditis. in addition, treatment with anakinra showed greater efficacy than infliximab (protection in 8/9 vs. 5/9) [16] . in mice models of severe forms of kd, the same group evaluated il-1 blockade in preventing and reducing systemic vascular inflammation, in particular, of the abdominal vessels (renal arteries and aorta) [17] . a recent study by the same authors showed how blocking il-1 also prevents the long-term consequences of kd. in particular, in order to verify the development of ventricular dysfunction and to study the volume of the left ventricle, the authors performed serial echocardiograms on lccweexposed mice, up to 43 days after the injection of lccwe. three weeks following the injection, mice exposed to the lysate began to show a reduced ejection fraction compared to controls. in those who had been pre-treated with anakinra, however, these changes did not occur. the authors concluded on the effectiveness of anakinra in preventing not only acute damage, but also long-term sequelae, and proposed a wider use of the drug, not only for difficult cases [18] . moreover, it was recently shown that il-1 signaling in intestinal epithelial cells increased intestinal permeability, as deleting il-1r specifically in those cells not only prevented increased permeability, but also reduced heart inflammation and aortic aneurysm development in lccwe-injected kd mice [19] . several case reports of kd patients treated with anakinra have been published (nine single cases, a series of two, and a series of 11); their main characteristics are summarized in table 1 . the first report on the use of anti-il-1 in kd dates back to 2012 [20] and described a 2-year-old boy with classic kd who developed myocarditis with reduction of the ejection fraction to 20%, without coronary artery inflammation, 2 days after the first dose of ivig. despite a second dose of ivig and three boluses of methylprednisolone, echocardiography showed a dilatation of the left descending coronary and right coronary arteries. on the 14th day, the patient was intubated and supported with extracorporeal membrane oxygenation (ecmo) for respiratory distress and cardiogenic shock. on the 18th day, anakinra 1 mg/kg was started, with prompt resolution of the fever and a significant clinical improvement. three days after the withdrawal of anakinra (on the 29th day), fever reappeared, ivig therapy was readministered, and methylprednisolone was resumed. on the 53rd day, echocardiography showed a giant aneurysm of one coronary artery. anakinra was re-administered for 6 weeks, in combination with aspirin and anticoagulants to prevent thrombosis. after 6 months from disease onset, echocardiography showed a complete normalization of the cardiovascular findings. in this case, the close correlation between the rapid relapse of the disease with the drug withdrawal and the immediate clinical recovery on its reintroduction support the effectiveness of the anti-il-1. shafferman et al. [21] in 2014 reported on an 11-weekold infant with classic kd who developed respiratory failure. the patient was intubated, and a lumbar puncture was performed, showing a sterile pleiocytosis. laboratory data revealed anemia, thrombocytopenia, and elevated inflammatory markers. echocardiography showed a slight dilatation of the coronary arteries, and abdominal ultrasound showed hydrops of the gallbladder. therapy with ivig and aspirin was started, but with a sudden increase in ferritin and a further decrease in platelet count, with suspicion of macrophage activation syndrome (mas), methylprednisolone intravenous (iv) therapy was started. despite treatment, coronary dilatation increased. anakinra 3 mg/kg was administered twice a day for 3 days, with immediate improvement of respiratory function and subsequent disappearance of the rash; clinical conditions and inflammation markers improved. however, a third echocardiograph showed diffuse dilatation of all coronaries, with the following z scores: left anterior descending (lad) = 11, right coronary artery (rca) = 6.5, and left main coronary artery (lm) = 5.6. so, the patient also received infliximab 5 mg/kg and iv steroids, with clinical improvement. the patient received anakinra for 5 months at a dosage of 8 mg/kg/day split in two doses. echocardiography 8 months later showed an almost complete normalization of previous abnormalities (z scores: lad = 0.84, rca = 2.8, and lm = 1.6). the third case [22] described a 3-year-old girl with typical kd treated with ivig 2 g/kg and aspirin 100 mg/kg. anakinra 2 mg/kg/day was started on the 14th day from onset for persistent fever and increase of inflammatory markers despite two other doses of ivig and two steroid boluses, with clinical and laboratory response within 24 h. echocardiography was normal. anakinra was administered for 2 weeks. after withdrawal, no relapses were observed and echocardiography remained normal. in 2018, guillaume et al. [23] reported on an 18-monthold boy with typical kd who received a first dose of ivig on the sixth day of fever. on the seventh day, echocardiography revealed diffuse and fusiform aneurysms of all coronary arteries [z scores: rca = 6.89, left coronary artery (lca) = 6.06, lad = 8.12, and left circumflex (lcx) = 2.12]. fever subsided, but relapsed on the ninth day; therefore, ivig was re-administered, along with three boluses of iv methylprednisolone. despite therapy, on the 25th day, the aneurysms worsened (z scores: rca = 9.10, lca = 7.47, lad = 9.94, and lcx = 2.97). anakinra 6 mg/ kg/day was started for 10 weeks then tapered to 6 mg/kg every 2 days for 4 weeks and finally 6 mg/kg every 3 days for another 4 weeks up to withdrawal. apyrexia was obtained in 24 h from anakinra injection, and c-reactive protein (crp) normalized in 7 days; progressive reduction of aneurysm size allowed anticoagulation to be stopped after 4 months. seven months from the onset of the disease, angio-ct showed a also in 2018, the effectiveness of anakinra was reported in a 16-year-old caucasian boy with complete kd [24] . echocardiography on the 12th day of fever revealed a slight dilatation of all coronary arteries; n-terminal pro b-type natriuretic peptide (nt-probnp) blood levels were increased 2.5-fold. the boy underwent a first ivig infusion, without benefit; so, on the 15th day, he received anakinra at the dosage of 100 mg/day. resolution of fever and decrease of crp and nt-probnp occurred within 12 h. anti-il-1 was continued for 4 weeks. coronary angio-ct, which on the 19th day showed bulky aneurysms (diameters 0.8-0.9 cm) and multiple stenosis of all coronaries throughout their course, was definitely improved at 6 months, with the disappearance of the stenosis and persistence of slight dilatation only in the proximal portion of the main vessels. in 2018, kone-paut et al. [25] described the largest case series to date, reporting on 11 patients (eight males and three females), with an average age of 22 months (range 4 months-9 years), followed in seven european centers, affected by resistant kd, all successfully treated with anti-il-1. nine of them had a complete form and two an incomplete form; two developed a kd shock syndrome and were transferred to intensive care unit. seven patients had coronary anomalies on the first evaluation performed between the third and 12th day; three patients developed coronary artery abnormalities during the disease course; in two cases, myocarditis occurred, in one, there was evidence of valve dysfunction; only one patient had no cardiac complication. all patients had been treated with a first dose of ivig at the standard dose of 2 g/kg and aspirin 50 mg/kg/day and had received at least a second-line treatment. in particular, three patients had received anakinra after two ineffective treatments, four patients after three ineffective treatments, two patients after four ineffective treatments, and two other patients after five ineffective therapeutic attempts. the second line of treatment was a second ivig infusion in five patients, infliximab in three patients, and methylprednisolone boluses in three other patients. as a third-line treatment, six patients received methylprednisolone, one oral prednisone, and one ivig. other drugs used (single patients) were cyclosporine, methotrexate, and infliximab. all patients received anakinra at a dosage between 2 and 8 mg/kg/day, on average 25 days after onset (range 8-87 days) and for an average period of 15 days (range 6-87 days). the main reason for the use of anakinra was persistent fever (8/11), followed by gradual dilatation of the coronary arteries (7/11), persistence of clinical (2/11) or laboratory abnormalities (6/11), and severe myocarditis with kd shock syndrome in one case. the effectiveness of anakinra was assessed in terms of resolution of fever (100% of cases), reduction of inflammation indexes (100% of cases), and reduction of the z score (10/11 patients). a patient died suddenly, probably from a giant aneurysm rupture. the authors concluded by emphasizing the immediate clinical and laboratory response to anti-il-1 (in most cases in 24 h, and in one case, within 6 days), in particular in the case with kd shock syndrome (dramatically improved after the first injection of anakinra 6 mg/kg). in another retrospective series, involving 32 kd patients, flinn et al. [26] described a single patient with giant aneurysms, treated with several pharmacological treatments, and among them anakinra, but the authors did not specify the sequence nor the dose, nor the duration of the treatment. however, they did not report side effects. gamez-gonzale et al. [27] also used anakinra in two patients with kd shock syndrome refractory to ivig, but no further details on the clinical picture and outcome were provided. in the last year, we found three other case reports on the use of anakinra in kd refractory to standard therapy. lind-hoist et al. [28] reported on a 12-week-old infant with a history of vomiting for 10 days and irritability, who progressively developed respiratory distress, pericarditis, and severe dilatation of the coronary arteries (z scores: lca = 12.68 and rca = 9). with the suspicion of atypical kd, he was treated with ivig, with only transient clinical improvement. assuming a refractory form of kd, infliximab was administered on the third day, followed by a second dose of ivig and three boluses of methylprednisolone. on the 15th day, due to a considerable increase in ferritin (3349 ng/ml), triglycerides (487 mg/dl), and transaminases [alanine aminotransferase (alt) 457 u/l] and the detection of hemophagocytosis in bone marrow aspiration, the diagnosis of mas was made. the child was treated with anakinra at increasing dosages (from 5 to 10 mg/kg/day), with gradual resolution of the clinical symptoms and normalization of laboratory tests. he was discharged on the 53rd day, on oral corticosteroids, aspirin, and anakinra, which were tapered and withdrawn over a period of 6 months. maggio et al. [29] described two siblings with parvovirus infection who subsequently developed two different clinical features of kd, one of whom was treated with anakinra. in particular, the case of interest concerns a 9-month-old girl who initially presented with fever, pharyngitis, conjunctivitis, vomiting, and diarrhea, with neutrophilic leukocytosis and severe anemia, initially attributed to parvovirus infection (positive igm). however, on the 26th day, she developed coronary aneurysms (z scores: rca = 6 and lca = 5.72); therefore, the diagnosis of incomplete kd was made a posteriori. the patient received ivig without improvement; so, anakinra was started at the dosage of 4 mg/kg/day, with progressive resolution of the cardiological findings up to normalization of the z score 25 days after the onset of anti-il-1 therapy. in the last case report, gambacorta et al. [30] described a 9-month-old boy with classic kd. he received a first dose of ivig on day 9, with benefit, and then, after clinical deterioration, a second dose of ivig on day 14. on day 20, since the patient developed a new febrile peak and inflammatory markers increased, methylprednisolone pulses (30 mg/kg for 3 days) were administered, obtaining again a resolution of the symptoms. on day 25, for the first time, the patient developed dilatation of the coronary arteries, with the appearance of small aneurysms involving the lca, rca, and the lad. despite a dose of infliximab (5 mg/kg) and the improved clinical conditions, the patient underwent serial echocardiograms that showed a progressive increase of the size of coronary arteries and eventually the development on day 37 of medium aneurysm of lca (z score 7.53) and giant aneurysms of rca (z score 11.49) and lad (z score 11.2). on day 40, the infant presented with a new increase of inflammatory markers, edema of the hands and feet, and low-grade fever; so, anakinra 6 mg/kg/day was administered, and was followed by progressive clinical improvement with normalization of inflammatory markers and platelet count, and gradual reduction of the size of the coronary arteries and resolution of aneurysms. in all these cases, the authors support the efficacy of anakinra in patients with refractory kd. in particular, anakinra was effective for severe and potentially fatal complications of kd, such as mas [21, 28] and kawasaki shock syndrome [20, 25, 27] , but was also able to achieve the complete resolution of coronary dilatation and aneurysms or to prevent their worsening [20, 21, 23, 25, 26, 29, 30] . in no case were side effects reported. the first open-label, phase iia clinical trial (kawak-inra, eudract number: 2014-002715-41, clinicaltrials. gov nct02390596) on anakinra in kd was performed in france and has been recently published [31] . the primary aim of the study was to determine the safety of blocking il-1 in patients with kd unresponsive to ivig. sixteen patients were included, and they received subcutaneous anakinra at a starting dosage of 2 or 4 mg/ kg/day (depending on age and body weight), increased to 6 mg/kg if their temperature remained > 38 °c. treatment duration was 14 days. the main outcome was abatement of fever; 75% of patients in the intention-to-treat group and 87.5% in the per-protocol group became afebrile within 48 h of the last escalation dose of anakinra. disease activity measures, including physician's and parents' evaluations as well as crp levels, improved in almost all cases. at screening, 12 out of 16 patients had a coronary z score maximum of > 2 and ten out of 16 had > 2.5. at day 45, five out of ten and six out of 12 patients reached a z score maximum of < 2.5 and < 2, respectively. three patients had serious adverse events, which were resolved at the last evaluation. no severe infections occurred. this study supports the early use of anakinra in cases refractory to ivig, demonstrating that it is quickly effective on kd symptoms, inflammation parameters, and dilatation of the coronary arteries in most patients, with good tolerability. the anakid trial (clinicaltrials.gov nct2179853) [32] , an american phase i/iia dose-escalation study whose primary objective is to assess the safety and tolerability of anakinra in the acute phase of kd in patients not responsive to a first cycle of ivig and aspirin, is currently underway. the secondary objective of the trial is to evaluate the pharmacokinetics of the drug. eligibility criteria are the following: american heart association criteria for kd, age > 1 month, and z score ≥ 3 within 20 days of onset. the treatment schedule consists of at least 2 weeks of therapy, with the first two doses administered intravenously (4 mg/kg/day). patients with a z score ≥ 2.5 or an aneurysm after 2 weeks will complete 6 weeks of therapy. we are awaiting conclusion of the study and publication of full results. another study (anacomp, a randomized, phase iii, multicenter trial comparing the efficacy and safety of anakinra versus ivig retreatment in patients with kd who failed to respond to initial standard ivig treatment) has been planned and approved, and will start soon in france. to date, guidelines for the treatment of kd resistant cases are not based on strong evidence, and sometimes a second infusion of ivig is used in clinical practice. however, this strategy has not yet been proven to be effective in a prospective controlled trial, and new treatments are now available. of note, a new disorder possibly linked to sars-cov-2 infection has been described both in europe and in the usa; it has been termed pediatric multi-inflammatory syndrome temporally associated with covid-19 (pims-ts) or multisystem inflammatory syndrome associated with coronavirus disease 2019 (mis-c). this condition shares features with kd, i.e., fever, rash, and mucositis, but also has several differences, such as older age at onset and a high prevalence of myocarditis and gastrointestinal involvement. case series have been published. also, on the basis of previous experience in adults with covid-19 [33] anakinra has been used in resistant cases [34, 35] even though a lack of controlled trials in this setting does not allow firm conclusions yet. in this review, we have summarized the preclinical studies related to il-1 involvement in the pathogenesis of kd and the clinical experience regarding anakinra treatment for this disorder published so far. the clinical cases described show that anakinra has been used in most cases after at least two ineffective treatments, in cases of coronary aneurysms already at diagnosis, and in cases of major complications of kd such as mas or kd shock syndrome, without relevant side effects. with regard to cost, in italy, using a mere economic comparison, the cost of a second ivig dose for refractory patients as a therapeutic alternative to a 4-week cycle of anakinra is more expensive, up to 80% more (counting only drug costs). while awaiting the results of the trials currently finished and of those which are ongoing or planned, we acknowledge the possible role of anakinra for kd patients who do not respond to a first ivig infusion. funding we received no funding for this article. there are no conflicts of interest. there are no competing interests. ethics approval not applicable. availability of data and material not applicable. code availability not applicable. author contributions all authors contributed to the planning and writing of the manuscript. diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association treatment options for resistant kawasaki disease il-1 inhibition may have an important role in treating refractory kawasaki disease regulation of interleukin-1 activity is enhanced by cooperation between the interleukin-1 receptor type ii and interleukin-1 receptor accessory protein anakinra for the treatment of rheumatoid arthritis: a safety evaluation sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α unveiling the efficacy, safety, and tolerability of anti-interleukin-1 treatment in monogenic and multifactorial autoinflammatory diseases rilonacept in the treatment of chronic inflammatory disorders pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1β monoclonal antibody endothelial cell activation and high interleukin-1 secretion in the pathogenesis of kawasaki disease inositol-triphosphate 3-kinase c mediates inflammasome activation and treatment response in kawasaki disease il-1b polymorphism in association with initial intravenous immunoglobulin treatment failure in taiwanese children with kawasaki disease transcript abundance patterns in kawasaki disease patients with intravenous immunoglobulin resistance global gene expression profiling identifies new therapeutic targets in acute kawasaki disease coronary arteritis in mice following the systemic injection of group b lactobacillus casei cell walls in aqueous suspension il-1β is crucial for induction of coronary artery inflammation in a mouse model of kawasaki disease role of interleukin-1 signaling in a mouse model of abdominal aortic aneurysm associated with kawasaki disease the il-1 receptor antagonist, anakinra, prevents myocardial dysfunction in a mouse model of vasculitis and myocarditis of kawasaki disease intestinal permeability and iga provoke immune vasculitis linked to cardiovascular inflammation a child with severe relapsing kawasaki disease rescued by il-1 receptor blockade and extracorporeal membrane oxygenation high-dose anakinra for the treatment of severe neonatal kawasaki disease: a case report a child with resistant kawasaki disease successfully treated with anakinra: a case report usefulness and safety of anakinra in refractory kawasaki disease complicated by coronary artery aneurysm severe late-onset kawasaki disease successfully treated with anakinra the use of interleukin 1 receptor antagonist (anakinra) in kawasaki disease: a retrospective cases series kawasaki disease-a review of treatment and outcomes in an irish pediatric cohort 2010-14 kawasaki disease shock syndrome: a unique and serious subtype of kawasaki disease high-dose anakinra as treatment for macrophage activation syndrome caused by refractory kawasaki disease in an infant kawasaki disease triggered by parvovirus infection: an atypical case report of two siblings resolution of giant coronary aneurisms in a child with refractory kawasaki disease treated with anakinra open label, phase ii study with anakinra in intravenous immunoglobulin-resistant kawasaki disease. arthritis rheumatol motivation and study design for a phase i/iia study of anakinra in children with kawasaki disease and early coronary artery anomalies use of anakinra to prevent mechanical ventilation in severe covid-19: a case series intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 (pims-ts) in the uk: a multicentre observational study multisystem inflammatory syndrome in u.s. children and adolescents key: cord-018638-4pyjhpbk authors: pilania, rakesh kumar; singh, surjit title: kawasaki disease date: 2019-10-30 journal: periodic and non-periodic fevers doi: 10.1007/978-3-030-19055-2_4 sha: doc_id: 18638 cord_uid: 4pyjhpbk kawasaki disease (kd) is the commonest cause of acquired heart disease in children in the developed world and is increasingly being reported from developing countries. kd has a predilection for the coronary arteries. etiology of this disorder is remains an enigma. diagnosis of kd is essentially clinical with the help of set of clinical criteria. incomplete kd is said to occur when these criteria are not fulfilled. however, incomplete kd should not be considered as a milder form of the disease. 2d-echocardiography remains the imaging modality of choice for evaluation and monitoring of cardiac complications but often needs to be supplemented by ct coronary angiography. intravenous immunoglobulin along with aspirin is the gold standard therapy of treatment for kd. however, there is no consensus on treatment of resistant forms of kd. patients with kd should be on long-term follow-up especially if they have developed coronary artery abnormalities during the acute stage. kd is a complex disorder in which an infectious/environmental agent is believed to trigger the onset of disease in a genetically susceptible host [18] . various susceptibility genes have been identified to have association with kd. these includes inositol 1,4,5-trisphosphate 3-kinase c (itpkc), caspase-3 calcium release-activated calcium modulator 1 (orai1), and cd 40 [19] [20] [21] . knowledge about these susceptibility genes may provide new insights in etiopathogenesis of kd. reports have suggested association of transforming growth factor (tgf)-β variants with development of caas in patients with kd [22] . although etiopathogenesis of kd is not clear, various epidemiological and laboratory studies have shown that an infectious agent triggers a cascade that causes the illness ( fig. 4.2 ). histopathologic studies have emanated from children with kd who have died from unrelated causes [23] . the vasculitic process shows three distinct phases [24] : (a) acute necrotizing arteritis phase: in which there is neutrophilic infiltration of intima and media. (b) subacute/chronic arteritis phase: in which the neutrophilic infiltrate gets replaced by lymphocytes, plasma cells, and macrophages. (c) luminal myofibroblastic phase: in which there is proliferation of smooth muscle cells in the media that can result in luminal narrowing [24, 25] . japan, korea, taiwan: incidence rates of kd-308, 194.7,69.5/100,000 children below 5. incidence of kd is still increasing in these countries europe, north america, australia, new zealand: incidence rates of kd-vary from 9-30/100,000 children below 5. incidence of kd in these regions has pleatued china, india: nationwide data are not available in these countries. city specific incidence rates that have been reported: sichuan (china) 7.1; shenghai (china) 43.1; beijing (china) 55.1; hong kong sar 74 and chandigarh (india) 4.5/100,000 children below 5. latin america: chile has a reported incidence of 7.1/100,000 children below 5. putative genes associated with pathogenesis of kd the etiopathogenesis of kd is closely linked to an infectious process. evidence for this comes from both seasonability and clustering of cases of kd [7, 26] . the presence of febrile exanthemata and cervical lymphadenopathy, uncommon occurrence in babies below 3 months, and the rarity of cases in adults, further lends support to this hypothesis. some of the infectious agents that have been linked to the etiology of kd are parvovirus, epstein-barr virus, staphylococcus aureus, chlamydia, and mycobacteria. it has been hypothesized that the putative infectious trigger sets up a cytokine storm that manifests as kd [23] . some investigators have also proposed a super-antigen theory that triggers an immune response against vascular endothelium [27] . diagnosis of kd is essentially clinical. criteria for diagnosis of kd have been updated from time to time. currently there are two sets of guidelines-american heart association (aha) guidelines (2004 [3] and 2017 [28] ) and kawasaki disease research committee guidelines (japanese guidelines), 2002 (table 4 .1) [29] . aha 2017 guidelines (clinical criteria) for diagnosis of kd are given in table 4 .2. patients who fulfil the criteria are classified as having complete kd (also known as classical or typical kd), while those who do not fulfil criteria are classified as incomplete kd [28] . principal clinical features in kd are reviewed in table 4 .3. the clinical course of kd has three distinct phases: (a) acute febrile phase, (b) subacute phase, and (c) convalescent phase [4] . however in clinical practice, these features often overlap. acute phase: this phase starts with abrupt onset of high grade fever that is characteristically accompanied by significant irritability. it usually lasts for 10-14 days. fever with marked irritability may be the initial clinical presentation of kd, especially in young infants [30] . presence of intermittent or remittent fever is not characteristic of kd. cough can be present in a small subset of patients but nasal catarrh is [29] five of the following six criteria (at least five items of 1-6 should be satisfied for diagnosis of kd. however, patients with 4 items of the principal symptoms can be diagnosed with kd when coronary aneurysm or dilatation is recognized by 2-d echocardiography or coronary angiography) 1. fever persisting ≥5 days (inclusive of cases in whom the fever has subsided before the fifth day in response to therapy) 2. bilateral conjunctival congestion 3. changes of lips and oral cavity 4. polymorphous exanthema 5. changes of peripheral extremities 6. acute non-purulent cervical lymphadenopathy table 4 .2 aha 2017 diagnostic criteria for kd [28] diagnosis of classic kd can be proffered in the presence of fever for at least 5 days associated with at least 4 of the 5 following principal clinical features. in the presence of ≥4 principal clinical features, particularly when redness and swelling of the hands and feet are present, the diagnosis of kd can be made on day 4 of fever also. principal clinical features: 1. changes in lips and oral cavity: erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal mucosae 2. changes in extremities acute: erythema of palms, soles; edema of hands, feet subacute: periungual peeling of fingers and toes in weeks 2 and 3 3. polymorphous exanthema (diffuse maculopapular, urticarial, erythroderma, erythemamultiforme like, not vesicular or bullous) 4. bilateral bulbar conjunctival injection without exudates 5. cervical lymphadenopathy (>1.5 cm diameter), usually unilateral a careful history may reveal that ≥1 principal clinical features were present during the illness but resolved by the time of presentation exclusion of other diseases with similar findings (e.g., scarlet fever, viral infections like measles, adenovirus, enterovirus, stevens-johnson syndrome, toxic shock syndrome, drug hypersensitivity reactions, systemic juvenile idiopathic arthritis) unusual for kd. rash in kd is usually generalized, erythematous, polymorphic ( fig. 4.3b ), but is never vesicular or bullous. cervical lymphadenopathy (≥1.5 cm size) is usually unilateral and is often more commonly seen in the anterior cervical triangle. cervical lymphadenopathy may be mistaken for suppurative lymphadenitis. [28] clinical manifestation characteristics fever is typically high grade, acute onset, unremitting, without any response to antimicrobials and can associated with extreme irritability. extremity changes (acute) in acute phase include erythema of palms and soles that is usually associated with edema over dorsum of hands and feet. diagnosis of kd can be made on day 4 of illness if one of the features is redness and dorsal edema of extremities. extremity changes (subacute) periungual sheet like peeling of skin is a pathognomonic sign of kd that usually appears in the second to third week of illness. diffuse erythematous polymorphous rash usually appears in the first few days of illness and may be seen in >90% patients. bullous, vesicular and petechial lesions are not seen in kd. bilateral nonexudative conjunctival injection with characteristic sparing of limbus is an important and specific clinical sign and often helps in making a clinical diagnosis. it may be seen in >85% patients. changes in lips and oral cavity erythema of lips and oral cavity with vertical lip cracking in a febrile child is an important diagnostic clue and is seen in >95% patients. in kd, there is enlargement of multiple lymph nodes along with retropharyngeal edema while bacterial lymphadenitis is mostly associated with a single lymph node with a central hypoechoic region [28] . however, such differentiation on basis of ultrasound examination requires lot of expertise and that may not be readily available in the usual clinical setting. oral cavity and lip changes include redness of lips with bleeding and vertical cracking, oral mucosa redness and a strawberry tongue ( fig. 4.3d ). oral ulcers are distinctly unusual in kd. conjunctival injection is characteristically nonexudative and with typical sparing of limbus ( fig. 4 .3a). conjunctivitis with discharge is a strong pointer towards an alternative diagnosis. edema of the dorsum of extremities is an early sign and is usually transient (fig. 4 .3e). perianal desquamation is virtually pathognomonic of kd and is a useful clinical sign for diagnosis of the disease during the acute phase ( fig. 4 .3c). arthritis in kd is typically oligoarthritis, involving large joints and resolves without sequelae [31] . erythema at bcg injection site is an important clinical sign during acute stage of kd and more common in infants [32] . hydrops of gall bladder is also an important finding during acute stage. mild pericardial effusion is a common finding on 2dechocardiography (2de). caas are usually not seen during the first week of illness. subacute phase: this stage usually lasts for another 2-3 weeks during which fever usually subsides. periungual peeling is characteristically seen during this stage ( fig. 4 .3f). irritability that is prominent during acute phase subsides completely in this phase. arthritis in kd can also develop in subacute phase. caas most commonly become apparent during this time. an important laboratory manifestation that is seen in the subacute phase is development of thrombocytosis and this in conjunction with periungual desquamation is very suggestive of kd. chronic phase: it lasts for few weeks to months; there are no symptoms during this phase and the inflammation tends to subside. beau's lines presents as horizontal ridging over nails and first manifest at the subsidence of the subacute phase ( fig. 4 .3g). this is the only clinical sign of kd that can be seen for several weeks. measles can present with similar clinical features; however, the presence of a viral prodrome, exudative conjunctivitis and koplik spots will help to differentiate measles from kd. in measles, lymphocytic leucocytosis is usually prominent (unless there is secondary infection) while children with kd have polymorphonuclear leucocytosis. procalcitonin levels are normal in measles but may be elevated in kd. other infectious causes that can mimic kd include viral infections (cytomegalovirus, adenovirus, epstein barr virus, and enterovirus), bacterial infections (bacterial cervical lymphadenitis, scarlet fever, toxic shock syndrome, staphylococcal scalded skin syndrome, and leptospira), and systemic juvenile idiopathic arthritis. absence of eye changes and lip changes, presence of sand paper rash, elevated antistreptolysin o titres, and a brisk response to antimicrobials are pointers towards scarlet fever. presence of exudative conjunctivitis, ulcerative lesions in oral cavity, exudative pharyngitis, generalized lymphadenopathy and significant running nose are certain clinical features that make the diagnosis of kd less likely [28] . the diagnosis of kd is challenging and requires experience. clinical features of kd are nonspecific and overlap with various common childhood disorders especially infections [33] . patients who are not fulfilling clinical criteria completely are labelled as incomplete kd. in these situations, one has to rely largely on clinical assessment supplemented by laboratory parameters. incomplete form of kd is more commonly seen in infants (especially in babies below 6 months). approach for diagnosis of incomplete kd has been simplified in new aha 2017 guidelines [28] . incomplete kd should, by no means, be considered a milder form of kd. a patient can be said to have atypical kd if the clinical manifestations are unusual. these atypical manifestations may include arthritis [31] , nephritis [34] , pneumonia [35] , myositis, central nervous system involvement, uveitis [36] , and retinal vasculitis [37] . common neurological findings include extreme irritability and aseptic meningitis. rare neurological manifestations include transient peripheral facial nerve palsy (mostly unilateral) and profound sensorineural hearing loss. vomiting, diarrhea, and transient hepatitis are common gastrointestinal manifestations [38] . other relatively uncommon findings include jaundice, gall bladder hydrops, and pancreatitis. genitourinary findings include urethritis which usually presents as sterile pyuria [39] . atypical presentations of kd can pose difficult clinical problems for the attending physician. in infancy, and especially in babies below 6 months, kd is often a diagnostic challenge because it may present with incomplete manifestations. kd in this age group may often remain undiagnosed for several days, leading to increased incidence of development of caas. this group of patients also has higher intravenous immunoglobulin (ivig) resistance [28, 30, 40, 41] . sterile pyuria is another clinical presentation of kd in this age group and may mistakenly get treated as a urinary tract infection. the consequent delay in diagnosis can result in serious clinical sequelae [39] . due to these reasons, kd in infants has been given special consideration in new aha guidelines. it has been highlighted that if an infant has fever for more than 7 days without explanation, kd should always be in list of differential diagnosis. according to aha 2017 guidelines kd should be considered as a clinical possibility in the following situations: • babies <6 months who present with fever and extensive irritability. • infants having prolonged fever and unexplained aseptic meningitis. • children presenting with longer duration of fever and -culture-negative hypotensive shock. -cervical adenopathy that is unresponsive to antibiotic therapy. -parapharyngeal or retropharyngeal phlegmon that is unresponsive to antibiotic therapy. kd is uncommon in older children and may often go unrecognized. due to missed or delayed diagnosis, there is higher risk of caas in this age group. it may be difficult to assess caas by 2de in this age group of patients because of limited acoustic window and thick chest wall [42, 43] . myocarditis in kd is said to be very common and may even be universal. it is not often recognized and can, at times, be severe and symptomatic. myocarditis can develop during acute stage and manifest with unexplained tachycardia, hemodynamic compromise, or cardiovascular collapse [44] . approximately 5% patients with kd can present with cardiovascular collapse. this entity is known as kd shock syndrome (kdss). the shock in these patients is multifactorial and may have both cardiogenic and distributive components. the distributive shock may result from cytokine storm leading to uncontrolled inflammation [45] . patients with kdss are usually present to emergency room and intensive care units with shock and may be inappropriately treated for bacterial sepsis and presumed septic shock. diagnosis of kd gets often delayed in these cases and can have devastating consequences. differentiation between kdss and septic shock in the early phase of clinical diagnosis is often challenging. however, 2de should always be performed in patients with fever and shock as presence of caas will suggest kdss. differentiation of kdss and septic shock is critical as management of both diseases is entirely different. presence of conjunctival injection, dorsal edema, perineal desquamation, incomplete response to antimicrobials, and no microbiological evidence for infection are indicators towards kd in these patients. these patients are reported to have increased risk of having ivig resistance, caas, and myocardial dysfunction [28, 46, 47] . it is said that kdss should always be considered in children presenting with fever, cardiovascular collapse and myocardial dysfunction. kdss has been discussed at length in the aha 2017 revised guidelines because of these highlighted facts [28] . infections have been commonly considered as triggers for kd. at the bedside, it is often difficult to differentiate the clinical features of kd from that of viral exanthemata. however, if a child is having typical clinical features of the kd, the diagnosis cannot be excluded even in the presence of a documented infection. adenovirus, coronavirus, dengue virus, enteroviruses, measles virus, respiratory syncytial virus have been reported to trigger the kd in children [23] . toxin-mediated diseases (e.g., staphylococcal and streptococcal infection) have also been also closely associated with the pathogenesis of kd [27] . candida infection has been linked to the causation of kd in mice models and as well as in epidemiological studies carried out on tropospheric wind patterns in japan and hawaii [48] . the acute phase is characterized by a mild normocytic normochromic anemia, polymorphonuclear leucocytosis, raised erythrocyte sedimentation rate (esr), c-reactive protein (crp), and usually a normal platelet count. serum procalcitonin, that is usually thought to be a sensitive and specific marker for bacterial infection, may get elevated in kd as well. thrombocytosis develops during the end of second week or in the third week; however it may even develop earlier [49] . presence of thrombocytopenia during acute stage suggests either macrophage activation syndrome or thrombotic microangiopathy-this is associated with poor prognosis [28] . progressive thrombocytosis has been correlated with development of caas. urine may show sterile pyuria, secondary to urethritis and easily mistaken as urinary tract infection especially during infancy, thereby resulting in delay in diagnosis of kd [39] . it is said that kd is the commonest cause of sterile pyuria in children. diagnosis of kd is essentially clinical and there is no gold standard for confirmation of diagnosis. it is no surprise, therefore, that several biomarkers have been extensively evaluated for their role in diagnosis of this condition. various cytokines (e.g., tumour necrosis factor-α (tnf-α), interleukin 6) have been found to be raised during the acute phase of kd and decrease promptly following ivig administration. in patients with refractory kd or caas levels of tnf-α continue to remain elevated [50] . various microarray based studies have been carried out to identify the genes associated with kd. expression of these genes may be used as a novel diagnostic and prognostic biomarker for kd [51] . n terminal pro-b-type natriuretic peptide (nt-probnp) is a cardiac biomarker that has recently been found to be raised in children with kd during the acute phase. age-based nomograms for pro-bnp are available. these are helpful in differentiation of kd from other febrile illnesses [52] . the values for pro-bnp are comparatively higher in patients who develop caas as compared to patients with normal coronaries [53] . probnp levels also correlate with myocardial dysfunction [45] . cardiac evaluation is an essential component in patients with kd. 2de is an important tool for coronary artery assessment and, evaluation of cardiac structures during acute phase as well as on follow-up. however, diagnosis of kd should never be ruled out on basis of normal 2de examination. the quality of scan obtained by 2de is operator dependent [43] . criteria for definition of caas have been given by aha as well as by the japanese ministry of health. according to the latter coronary involvement in kd is categorized on basis of absolute internal diameter of coronary artery ( [28, 55] . it is mandatory to use body surface area-adjusted 'z' scores for during this period may be mistakenly interpreted as having excluded coronary involvement. 3. while normative data are available only for proximal segment of coronary arteries, there is paucity of literature on data for middle and distal segments of coronary arteries. isolated involvement of distal segments of coronary arteries is uncommon but has been described [56] . 4. it has been suggested that an aneurysm may be better defined as a dilatation that is 1.5 times or more than an adjacent segment. this circumvents the problems associated with z scores. 5. detailed and better evaluation of coronary arteries requires multiple transducer positions, imaging in multiple planes and high frequency transducers. coronary artery diameters refer to the maximal internal luminal diameter. measurements should not be taken at branching points. 6. limitations of 2de include difficulty in visualization of distal coronaries, frequent non-visualization of left circumflex coronary artery, difficulty in commenting on stenosis or thrombosis and limited field of vision in older children because of thick chest walls. another problem is due to artifacts especially while scanning the right coronary artery or left circumflex coronary artery. 7. several nomograms on z scores are available and there may be variations in the measurements. body surface area calculations have to be carried out meticulously and there is no consensus on the ideal method. it cannot be overemphasized that a trivial difference in measurement of weight and height (especially in infants and young children) can significantly impact the calculations of z scores. 8. there are no normative data for "z" scores for left circumflex coronary artery. although 2de has hitherto been considered the imaging modality of choice for coronary artery evaluation, ctca is now increasingly being performed for better delineations of coronary arteries. ctca is a useful modality for better characterization and delineation of coronary arteries dilatations, ectasia and aneurysms especially in the mid-and distal segments. it also provides precise details of aneurysm size, morphology, and thrombus. in the last decade, due to advancements in ct technology and the development of dual-source ct scanners (dsct), it is now possible to obtain high resolution motion-free images at acceptable radiation dose. in the convalescent phase, ctca can be used for delineation of complications such as intra-aneurysmal thrombus, segmental stenosis, and mural calcifications [57] . main aim of therapy in kd is halting of acute phase inflammation and arterial damage. management includes use of ivig, aspirin with or without anticoagulant therapy. ivig is the standard of care for the patients with kd. it should ideally be administered in first 10 days of illness. in the acute stage, ivig (2 g/kg) is given over 10-12 h as a single infusion along with oral aspirin [3, 28] . if diagnosis is made after 10 days, ivig should still be given if fever is persistent, inflammatory parameters are raised or if caas are present. administration of ivig during acute stage has reduced the rate of coronary artery complications to less than 5%. approximately 1-3% patients with kd can have recurrences [58] . aspirin has anti-inflammatory and antiplatelet activity depending on the dose being used. it remains an essential component of management in kd. however, effect of aspirin on development of caas is inconclusive. during the acute phase of illness, aspirin should be administered at high (50-100 mg/kg/day) or moderate (30-50 mg/kg/day) doses 6-8 hourly [59, 60] . anti-inflammatory dose of aspirin is usually continued until 48-72 h after the patient becomes afebrile. after discontinuation of anti-inflammatory dose of aspirin, low-dose aspirin (3-5 mg/kg/day) is started and continued for 6-8 weeks. at this time if there are no caas on 2de, aspirin can be discontinued. for children who develop caas, aspirin may need to be given indefinitely [28] . complications related to caas during the acute phase of kd include thrombotic occlusion of a coronary artery aneurysm and rarely coronary artery rupture leading to sudden cardiac death. coronary artery thrombosis in patients with kd is contributed by acute inflammation, high platelet counts, endothelial dysfunction and stasis of blood flow due to abnormal dilatation. in patients with caas assessment with 2de is mandatory to monitor size of aneurysm and presence of thrombus. patients with large coronary artery aneurysms are at high risk of myocardial infarction especially in the first year after illness. they continue to be at increased life-time risk of developing coronary artery events [28] . risk stratification of coronary artery aneurysm should take into account both current and maximal z score. along with a z score classification the shape, location, number of aneurysms and coronary artery wall abnormalities should also be considered for prognostication and risk stratification [61] . in patients with small aneurysms, low-dose aspirin is adequate for thromboprophylaxis. however, treating physicians can consider addition of another antiplatelet agent (e.g., clopidogrel) in patients with moderate size aneurysms. patients having large or giant aneurysms are at very high risk for coronary artery complications including thrombosis and rupture. these patients should be treated with a combination of antiplatelet and therapeutic anticoagulation therapy. this includes low-dose aspirin along with either low-molecular-weight heparin (lmwh) or oral warfarin. lmwh should be given as 1 mg/kg/dose subcutaneously every 12 h. lmwh may be preferred to warfarin in acute phase because of added effects of anti-inflammatory and remodeling action. transition from lmwh to oral warfarin may be considered in situations where the aneurysm has stopped progressing [28] . majority of patients will respond to first dose of ivig with rapid defervescence of fever and improvement in general well-being. however, approximately 10-20% of patients with kd may go on to develop recrudescent or persistent fever. children who have axillary temperature ≥38.0 °c at 36 h after completion of therapy are said to have resistant or refractory kd [28] . there are multiple factors that have been associated with development of ivig resistance. these include severity of disease and host genetic factors (e.g., polymorphisms in the fcγ receptors). patients having refractory kd are at increased risk of developing caas. various scoring systems have been developed in japan to predict ivig resistance, but the validity of these scores in other countries remains a contentious issue. there are no clear guidelines on management of patients with refractory kd [62] . the aha guidelines recommended use of a repeat dose of ivig (2 g/kg) in these patients. alternatively, the guidelines emphasize the role of intravenous pulse methylprednisolone (30 mg/kg/day, three doses) with tapering oral prednisolone. administration of tapering course of prednisolone for 2-3 weeks with second dose of ivig (2 g/kg) may also be considered in the retreatment of refractory kd patients. infliximab (tnf-α blocker), given as a single dose (5-10 mg/kg) intravenously, is also an important choice in treatment of refractory kd and appears to decrease the chances of developing caas [28] . use of infliximab is associated with prompt reduction of fever. at our centre we prefer to use infliximab as second line therapy [63] . cyclosporine may also be considered as an option in these circumstances. in highly refractory cases, plasma exchange, cytotoxic agents, or other biologicals have been used [28] . there are a few recent reports of successful use of the il-1 receptor antagonist, anakinra, for the treatment of highly refractory kd [64] . long-term follow-up and management of patients with kd is based on risk stratification. children with large caas may need lifelong follow-up. long-term management includes counselling about a healthy lifestyle with balanced diet and exercise to avoid obesity and hypertension. because these patients have already developed a cardiac risk factor (even if there are no obvious caas during acute stage), a second risk factor like obesity, hyperlipidemia, or hypertension must be avoided [28] . uses of statins have also been advocated in these situations. patients having large and giant aneurysms should undergo frequent 2de examinations for monitoring of size and associated complications. these patients may also require ctca at periodic (every 3-5 years) intervals [56] . children with missed and untreated kd can have significant clinical consequences later in life. even though coronary arteries with remodeled aneurysms may become anatomically normal, they continue to remain functionally abnormal. an increasing number of young adults are presenting to cardiologists with myocardial ischemia and infarction-it is not often realized that these could well be late manifestations of kd that has been missed in childhood. these consequences of kd in adulthood are grossly under recognized [65] . there is very little awareness amongst adult cardiologists regarding cardiovascular sequelae of kd and their management. clearly there is a need for an improved evidence base to guide the care and management of adults with coronary artery damage following kd in childhood. whenever a young adult is presenting with myocardial ischemia and there is marked ectasia or proximal coronary artery involvement, possibility of untreated kd in past should be entertained [66] . the aha has published an update on criteria for diagnosis of kd in 2017. while the presence of fever remains an essential criterion and there is no change in the five principal clinical manifestations of the disease, the scientific committee has suggested several amendments. the new guidelines emphasize that some clinical features of kd may subside by the time the patient reaches a clinician. in such situations the clinical findings that have disappeared can also be taken into account for fulfilment of criteria. similarly, the issue of diagnosis in young infants has been addressed at length. the guidelines mention that any infant with unexplained fever lasting for a week or more should be evaluated for underlying kd. this cannot be overemphasized. in the 2017 guidelines, the terms incomplete kd and atypical kd have been used interchangeably. however, these are distinct clinical entities and this fact needs to be kept in mind while evaluating a patient. desquamating groin rash has been included as one of the other clinical findings. it is known that erythema or desquamation of perineal/perianal region occurs earlier than classic periungual peeling and thus may facilitate early consideration of the diagnosis. the aha 2017 guidelines emphasize on the use of z score for assessment of coronary artery size. however, the difficulties involved in calculation of an accurate 'z' score that is reproducible across centres have not been detailed at length. and aha guidelines [28, 29, 54] 1. in the japanese criteria fever is not taken as an essential prerequisite for diagnosis. in other words, a diagnosis of kd can be offered even in absence of fever while using the japanese criteria. 2. definition of coronary artery lesion in japanese ministry of health guidelines is based on absolute dimensions, while aha 2017 guidelines have classified the caas on basis of "z" scores (table 4 .4). 3. refractory kd has been defined as persistence of fever more than 36 h despite treatment as per aha guidelines. however, the cut-off for duration of fever is 24 h in japanese guidelines. diagnosis of kawasaki disease diagnosis, treatment, and long-term management of 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authors: nakra, natasha a.; blumberg, dean a.; herrera-guerra, angel; lakshminrusimha, satyan title: multi-system inflammatory syndrome in children (mis-c) following sars-cov-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management date: 2020-07-01 journal: children (basel) doi: 10.3390/children7070069 sha: doc_id: 314662 cord_uid: nem6dw34 severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection may result in the multisystem inflammatory syndrome in children (mis-c). the clinical presentation of mis-c includes fever, severe illness, and the involvement of two or more organ systems, in combination with laboratory evidence of inflammation and laboratory or epidemiologic evidence of sars-cov-2 infection. some features of mis-c resemble kawasaki disease, toxic shock syndrome, and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. the relationship of mis-c to sars-cov-2 infection suggests that the pathogenesis involves post-infectious immune dysregulation. patients with mis-c should ideally be managed in a pediatric intensive care environment since rapid clinical deterioration may occur. specific immunomodulatory therapy depends on the clinical presentation. the relationship between the immune response to sars-cov-2 vaccines in development and mis-c requires further study. severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection has rapidly spread worldwide since it was first identified in china in late 2019, with subsequent epicenters being recognized in europe and the u.s. previous reports of sars-cov-2 infection indicated that young children were disproportionately spared from infection [1, 2] , although it remains unclear if this is due to a lack of detection because of predominantly asymptomatic or mild disease in this age group. in the latter half of april 2020, a novel syndrome in children and adolescents termed "multisystem inflammatory syndrome in children" (mis-c) with likely relation to sars-cov-2 infection was first described. initial reports surfaced in the uk [3] and italy [4] , followed by new york and other parts of the u.s. preliminary accounts of the features of this syndrome resemble those of known entities such as kawasaki disease (kd), toxic shock syndrome (tss), and secondary hemophagocytic lymphohistiocytosis (shlh)/macrophage activation syndrome (mas). here we review the preliminary (1) an individual aged < 21 years with: (2) clinical criteria: • a minimum 24-h history of subjective or objective fever ≥ 38.0°c and • severe illness necessitating hospitalization and • two or more organ systems affected (i.e., cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, neurological) data regarding the clinical presentation and epidemiologic characteristics of children with mis-c are still limited and evolving daily. in a case series from the uk [3] , italy [4] , france, and data regarding the clinical presentation and epidemiologic characteristics of children with mis-c are still limited and evolving daily. in a case series from the uk [3] , italy [4] , france, and switzerland [6, 7] , the ages of affected children (n = 70) ranged from 2-16 years, and the majority did not have underlying comorbidities. most had fever present for ≥4 days, and common presenting symptoms included gastrointestinal symptoms (59/70 = 84%), including vomiting, abdominal pain, and/or diarrhea; mucocutaneous symptoms reminiscent of kd, including conjunctivitis and rash; and neurologic findings including headache, irritability, and encephalopathy. a few children presented with an acute surgical abdomen and underwent exploratory laparotomy, with intra-operative findings of mesenteric lymphadenitis and peritonitis. several children developed hypotension (52/70 = 74%) requiring admission to pediatric intensive care unit (picu) and inotropic support, and some required non-invasive or invasive mechanical ventilation due to respiratory distress from cardiac dysfunction. a minority of children (11/70 = 16%) were placed on extra-corporeal membrane oxygen (ecmo) support. echocardiography demonstrated depressed cardiac ventricular function in the majority of patients, but they were less commonly reported to have valvular regurgitation, dilated coronary arteries (11/70 = 16%). or frank coronary artery aneurysms (caas) (3/70 = 4%). universally, laboratory testing revealed the significant elevation of inflammatory markers, such as c-reactive protein (crp), erythrocyte sedimentation rate (esr), procalcitonin, and/or ferritin. other common findings included hyponatremia, acute kidney injury, and hypoalbuminemia, and several patients had serous effusions (pleural, pericardial, and peritoneal), suggestive of generalized inflammation. troponin levels were elevated in many patients (57/70, 81%), and pro-b-type natriuretic peptide (probnp) levels were markedly elevated in most (59/65 = 70%), suggesting myocardial damage and heart failure, respectively. hematologic abnormalities reported included neutrophilia, lymphopenia, low to normal platelet levels, elevated d-dimer, and low fibrinogen. thrombotic events were not reported. the majority of affected children were treated with intravenous immune globulin (ivig), and several also received adjunctive high-dose steroids. most responded favorably to therapy with an improvement in vital signs and cardiac dysfunction, and only a few children required additional therapies, such as anakinra (recombinant il-1β antagonist) or a second dose of ivig. one child in the uk cohort was reported to develop a giant caa after discharge from the initial hospitalization. overall mortality has been low, with a single death in the uk cohort (due to a cerebrovascular accident while on ecmo), and three reported deaths in new york city (ny times) [8] . of note, a case report from the u.s. described a six-month infant with positive sars-cov-2 reverse transcriptase polymerase chain reaction (rt-pcr) testing from a nasopharyngeal swab who met the classical criteria for kd without evidence of multisystem involvement [9] . she was treated with ivig and high dose aspirin, as per kd guidelines, and quickly defervesced with the resolution of stigmata of kd. at this time, it is unclear if mis-c with kd features is different from kd. a positive sars-cov-2 test does not necessarily indicate causality and could represent coincident infection [10] . epidemiologic evidence implicates sars-cov-2 as the likely cause of the newly recognized mis-c, although causality has not yet been established ( figure 2 ). the emergence of clusters of cases in locations that have been heavily impacted by covid-19, such as italy, the uk, and new york city, is highly suggestive of a link to infection with sars-cov-2. the case series from bergamo, italy, a region with a high incidence of covid-19 disease, described a 30-fold increase in the monthly incidence of kd cases between 18 february 2020 and 20 april 2020 in comparison to the previous 5 years [4] . on 13 may 2020, the new york state department of health (nysdoh) reported 102 probable cases of mis-c in new york hospitals, following the peak of covid-19 infection in early april [11] . interestingly, the cluster of mis-c cases in these communities lags behind the peak covid-19 incidence among adults by approximately one month. the fact that mis-c was not identified in china and other asian countries affected by covid-19 has led to speculation regarding variations in the virus affecting areas with mis-c cases or an increased susceptibility or genomic variation of these populations, although this is currently conjectural. the majority of published cases have had positive serologic testing for sars-cov-2 (60/69, 87%) and less commonly positive rt-pcr testing from nasopharyngeal testing (23/70, 32%), suggesting that this syndrome may be post-infectious rather than related to acute early infection (stage ifigure 2 ). it is uncertain if broncho-alveolar lavage (bal) sampling would increase the yield of detection in mis-c. in adults with severe respiratory failure from sars-cov-2 infection, who typically experience clinical deterioration about 1 week following illness onset, a dysregulated immune system is thought to drive disease manifestations, as opposed to direct cellular injury from viral infection (stage ii-pulmonary phase). children appear to have less severe pulmonary manifestations compared to adults, possibly due to lower gene expression of the angiotensin converting enzyme (ace)-2 receptor (the target of sars-cov-2) [12, 13] . immune dysregulation in adults with respiratory disease is characterized by lymphopenia (specifically nk cells, cd4 t lymphocytes and b lymphocytes) and sustained production of pro-inflammatory cytokines, such as tumor necrosis factor (tnf)-α and interleukin (il)-6 [14] . this immune dysregulation has been the basis of immunomodulatory therapies for adults with severe sars-cov-2 infection, such as tocilizumab, a humanized monoclonal antibody against the il-6 receptor. in kd, a systemic hyper-inflammatory state is characterized by elevated levels of tnf, il-6, il-1β, il-17, and granulocyte colony stimulating factor (g-csf) [15] . we speculate that mis-c is a delayed immunological phenomenon associated with inflammation (stage iii-hyperinflammation phase) following either symptomatic or asymptomatic covid-19 infection. children 2020, 7, x for peer review 4 of 14 that this syndrome may be post-infectious rather than related to acute early infection (stage ifigure 2 ). it is uncertain if broncho-alveolar lavage (bal) sampling would increase the yield of detection in mis-c. in adults with severe respiratory failure from sars-cov-2 infection, who typically experience clinical deterioration about 1 week following illness onset, a dysregulated immune system is thought to drive disease manifestations, as opposed to direct cellular injury from viral infection (stage iipulmonary phase). children appear to have less severe pulmonary manifestations compared to adults, possibly due to lower gene expression of the angiotensin converting enzyme (ace)-2 receptor (the target of sars-cov-2) [12, 13] . immune dysregulation in adults with respiratory disease is characterized by lymphopenia (specifically nk cells, cd4 t lymphocytes and b lymphocytes) and sustained production of pro-inflammatory cytokines, such as tumor necrosis factor (tnf)-α and interleukin (il)-6 [14] . this immune dysregulation has been the basis of immunomodulatory therapies for adults with severe sars-cov-2 infection, such as tocilizumab, a humanized monoclonal antibody against the il-6 receptor. in kd, a systemic hyper-inflammatory state is characterized by elevated levels of tnf, il-6, il-1β, il-17, and granulocyte colony stimulating factor (g-csf) [15] . we speculate that mis-c is a delayed immunological phenomenon associated with inflammation (stage iii-hyperinflammation phase) following either symptomatic or asymptomatic covid-19 infection. early infection (phase i) with sars-cov-2 is likely to be asymptomatic or mildly symptomatic in children. the pulmonary phase (phase ii) is severe in adults but is mild or absent in many children. the early infection appears to trigger macrophage activation followed by the stimulation of t-helper cells. this in turn leads to cytokine release, the stimulation of macrophages, neutrophils, and monocytes, along with b-cell and plasma cell activation with the production of antibodies leading to a hyperimmune response (stage iii). this immune dysregulation is associated with the inflammatory syndrome in affected children. direct infection with sars-cov-2 is less likely to play a role in mis-c. ace2-angiotensin converting enzyme 2 receptors; tnf-βtumor necrosis factor β; il-interleukins. similarities between patients with mis-c and other well-defined syndromes, including kd, tss, and shlh/mas, allow for hypotheses to be made regarding pathogenesis and may help guide treatment. table 1 compares common clinical and laboratory findings between mis-c, kd, and tss. early infection (phase i) with sars-cov-2 is likely to be asymptomatic or mildly symptomatic in children. the pulmonary phase (phase ii) is severe in adults but is mild or absent in many children. the early infection appears to trigger macrophage activation followed by the stimulation of t-helper cells. this in turn leads to cytokine release, the stimulation of macrophages, neutrophils, and monocytes, along with b-cell and plasma cell activation with the production of antibodies leading to a hyperimmune response (stage iii). this immune dysregulation is associated with the inflammatory syndrome in affected children. direct infection with sars-cov-2 is less likely to play a role in mis-c. ace2-angiotensin converting enzyme 2 receptors; tnf-β-tumor necrosis factor β; il-interleukins. similarities between patients with mis-c and other well-defined syndromes, including kd, tss, and shlh/mas, allow for hypotheses to be made regarding pathogenesis and may help guide treatment. table 1 compares common clinical and laboratory findings between mis-c, kd, and tss. abbreviations: +, generally present; ++, almost always present; −, generally absent; ±, may be present or absent; ↑ increased; ↑↑, highly increased; ↓ decreased; alt, alanine transaminase; pro-bnp, pro-b-type natriuretic peptide; crp, c-reactive protein; id, insufficient data; kd, kawasaki disease; kdss, kawasaki disease shock syndrome; m, months; mis-c, multisystem inflammatory syndrome in children; pt/ptt, prothrombin time and partial thromboplastin time; tss, toxic shock syndrome; wbc, white blood cell count; y, years. kd is an acute medium-vessel vasculitis with a predilection for coronary arteries that occurs more commonly in young children; it is the most common cause of acquired heart disease in childhood in developed countries [16] . the kd defining features include rash, cervical lymph node enlargement, and ocular and oral mucosal changes, although the involvement of other organs, such as the liver, lungs, gastrointestinal tract, the central nervous system, and joints is widely recognized. similar to mis-c, laboratory markers of inflammation, such as crp, are increased. hematologic abnormalities are slightly different, as patients with kd tend to have leukocytosis with neutrophil predominance and thrombocytosis. thrombocytopenia has been described in kd but is rare. the cardiac findings in mis-c also are divergent from kd, as mis-c patients are much more likely to exhibit cardiac dysfunction and hypotension, as opposed to coronary artery abnormalities [17] . despite extensive efforts to identify the triggers for the inflammatory cascade in kd, the etiologic agent remains elusive. however, there is evidence that viral infections may elicit an inflammatory response in genetically predisposed children [18] . a viral trigger seems likely based on the typical occurrence of cases during winter and spring when respiratory viruses are circulating, as well as the young age of affected children, who are susceptible due to a lack of pre-existing immunity. previous studies have attempted to implicate other human coronaviruses as the etiology of kd [19] , but further studies did not confirm this association. the management of children with kd includes the administration of intravenous immune globulin (ivig), treatment with high-dose aspirin, and occasionally the use of other immune-modulating drugs. the mechanism of ivig is unclear, and may include immunomodulatory effects on t regulatory cells [20] . the treatment of children with kd has decreased the risk of caas from 25% to 4% [16] . a subset of children (<5%) with kd will present with shock/hypotension resembling bacterial sepsis. as compared to other children with kd, patients with "kawasaki disease shock syndrome" (kdss) have higher band counts, lower platelet counts, lower hemoglobin levels, and higher c-reactive protein levels [21] . they are also more likely to have coronary artery dilation and abnormalities of cardiac ventricular function [22] . the treatment approach to patients with kd and kdss is similar, although patients with kdss have higher rates of treatment failure with first-line therapies [23] . this subset of kd patients has several similarities to the newly described mis-c. tss is a unique syndrome secondary to the uncontrolled activation of the immune system by "superantigens", proteins that non-selectively stimulate t cells, resulting in massive cytokine release. bacterial species, such as staphylococcus aureus and streptococcus pyogenes, are known to produce exotoxins that can function as superantigens, although viruses can also act as superantigens. interestingly, prior research done on sars-cov-1 indicated that the viral structure included motifs consistent with superantigens [24] . the clinical presentation of toxic shock syndrome includes hypotension, diffuse erythrodermic rash, mucous membrane involvement, and multisystem organ dysfunction (renal, hepatic, hematologic, respiratory, muscular, and neurologic) [25] . typical treatment for tss includes volume resuscitation, treatment with anti-microbial agents directed against the inciting infection, and occasionally the use of ivig for patients with refractory hypotension [26] . the proposed mechanisms of ivig in patients with tss include the neutralization of bacterial superantigens and the downregulation of the overactive immune response. tss can resemble kdss, but patients with tss tend to be older than those with kdss (9 ± 4.6 years vs. 3 ± 3.4 years, respectively) [27] and are more likely to have normal hemoglobin, a lower platelet count, and elevated creatinine compared with kdss patients. patients with kdss are more likely to exhibit coronary artery changes, valvulitis, and impaired cardiac ventricular function on echocardiogram as compared with tss [27] . hemophagocytic lymphohistiocytosis (hlh) is characterized by a robust immune response that is unabated and self-perpetuated. primary hlh is secondary to anomalies in genes that regulate the degranulation of natural killer cells and cytotoxic cd8+ lymphocytes. this results in the inability to eliminate the antigenic stimuli that led to cellular activation, leading to a "cytokine storm" [28, 29] . elevated levels of pro-inflammatory cytokines, such as interferon (ifn)-gamma, il-18, and il-1, subsequently activate other cells of the immune system (i.e., macrophages) leading to organ damage and the characteristic hemophagocytosis of affected organs [29] . hlh is considered secondary when it is triggered by an autoimmune or autoinflammatory condition (referred to as mas in this context), medications, malignancy, or infections. regarding the latter, viral infections are well-known triggers of shlh [30, 31] . kd has also been associated with the development of mas [32] . notably, some patients that are thought to have shlh are found to have mutations seen in primary hlh, so the distinction between primary and secondary hlh may be blurred [33] . although not pathognomonic, the presence of hyperferritinemia (>500 ng/ml) should alert a physician to the possible presence of shlh/mas, especially in the presence of fever [34, 35] . patients with shlh typically have evidence of systemic inflammation with elevated levels of crp, triglycerides, and d-dimer, as well as organ dysfunction, such as coagulopathy, liver failure, cns dysfunction, and cardiac dysfunction. notably, the peripheral white blood cell count, platelet count, and esr tend to be depressed in shlh [29, 34] . mortality is high in untreated shlh. although not designed for infection-related shlh, the criteria for primary hlh (table 2) [36] or mas in systemic juvenile idiopathic arthritis [37] may aid in the diagnosis of shlh. it is important to note that the primary hlh criteria have low sensitivity for mas [38] and this may be true for infection-associated shlh as well. additionally, the absence of hemophagocytosis in a bone marrow aspirate does not rule out the diagnosis. [36] . molecular diagnosis consistent with hlh 2. diagnostic criteria fulfilled by meeting five out of the eight criteria below a. fever b. splenomegaly c. cytopenias affecting two out of three blood lineages in peripheral blood hemoglobin < 90 g/l (in infants < 4 weeks: hemoglobin < 100 g/l) platelets < 100 × 10 9 /l neutrophils < 1.0 × 10 9 /l d. hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides ≥ 3.0 mmol/l (i.e., ≥265 mg/dl) fibrinogen ≤ 1.5 g/l e. hemophagocytosis in bone marrow or spleen or lymph nodes and no malignancy f. low or absent nk cell activity (according to local laboratory reference) g. ferritin ≥ 500 mg/l h. soluble cd25 (i.e., soluble il-2 receptor) > 2400 u/ml abbreviations: dl, deciliter; g, grams; il, interleukin; l, liter; mg, milligrams; ml, milliliter; mmol, millimoles; u, units. patients with mis-c may quickly progress to critical illness and hypotension. therefore, they should be managed in a center with pediatric intensive care capabilities. laboratory evaluation for generalized inflammation, multisystem involvement, and possible infection is appropriate (box 2). particular attention should be paid to the monitoring of cardiac function, respiratory status, neurologic status, and renal function. depending on organ system involvement, the early consultation of specialists from pediatric intensive care, cardiology, rheumatology, infectious disease, immunology, and neurology should be considered. box 2. proposed approach to children presenting with signs concerning for mis-c. consider observation in unit with cardio-respiratory monitoring capabilities 2. laboratory evaluation a. complete blood count with differential b. blood chemistry, including bun and creatinine c. liver function tests (alt, ast, albumin, bilirubin) d. cardiac markers: troponin and pro-bnp e. urinalysis with culture if indicated f. blood gas with lactate g. markers of inflammation: esr, crp, procalcitonin, ferritin, triglycerides, il-6 if available h. coagulation panel: pt, ptt, fibrinogen, d-dimer i. creatinine kinase, lactate dehydrogenase j. blood culture k. serology for sars-cov-2 l. np swab or lower respiratory tract sample for sars-cov-2 by rt-pcr; consider sending from stool if presenting with gi symptoms m. additional studies as indicated: respiratory pathogen panel from np swab or lower respiratory tract, stool studies/cultures, viral blood pcrs or serologies to rule out other causes of myocarditis, genetic testing for hlh, soluble il-2 receptor, nk cell function 3. imaging: a. chest x-ray b. abdominal ultrasound or ct scan if concerning symptoms/physical findings 4. twelve-lead electrocardiogram (ekg) 5. echocardiogram (transthoracic) 6. early consultation of specialists to assist in management, such as intensive care, cardiology, rheumatology, infectious diseases, allergy/immunology, neurology abbreviations: alt, alanine transaminase; ast, aspartate transaminase; pro-bnp, pro-b-type natriuretic peptide; bun, blood urea nitrogen; crp, c-reactive protein; ct, computed tomography; esr, erythrocyte sedimentation rate; gi, gastrointestinal; hlh, hemophagocytic lymphohistiocytosis; il, interleukin; mis-c, multisystem inflammatory syndrome in children; nk, natural killer; np, nasopharyngeal; pt, prothrombin time; ptt, partial thromboplastin time; rt-pcr, reverse transcriptase polymerase chain reaction; sars-cov-2, severe acute respiratory syndrome coronavirus 2. of note, in the absence of a positive test for sars-cov-2 or a positive epidemiological exposure, we suggest the consideration of alternative diagnoses. serology can be repeated 2-4 weeks later, and if results are negative but suspicion remains high, serology can be repeated using a different assay. the testing of household contacts can also reveal evidence of exposure. the goals of treatment for mis-c are to decrease systemic inflammation and restore organ function, in order to decrease mortality and reduce the risk of long-term sequelae, such as the development of caas or persistent cardiac dysfunction. treatment should be dictated by phenotype until new research provides clear guidelines. given the novelty of this syndrome, the following recommendations are based on extrapolation from other syndromes and constitute the opinion of the authors (see table 3 for detailed dosing of medications). all patients meeting the criteria for kd should be treated as per published guidelines. first-line therapy for kd includes treatment with high-dose ivig and aspirin. given the highly favorable results in early case series of children with mis-c who received ivig, we would also recommend the consideration of ivig for patients with mis-c who do not meet kd criteria for possible beneficial immunomodulatory effects, analogous to its use in tss. corticosteroid treatment is a commonly used adjunctive therapy to ivig for treatment of kd. in japan, scoring systems such as the kobayashi score predict a high risk of ivig resistance and have been used to inform decisions about who should receive steroids concomitantly with ivig [41] . this approach has been shown to decrease the risk of coronary abnormalities in high-risk children, and could be helpful in to inform treatment decisions in mis-c [42, 43] . per kd guidelines from the european initiative single hub and access point for paediatric rheumatology in europe (share) [39] , corticosteroids should be considered for children with features of severe kd, defined by fever or persistent inflammation ≥ 48 h after ivig, kobayashi score ≥ 5, features of shlh (i.e., ferritin > 500 ng/ml), shock, age < 1 year, or coronary or peripheral aneurysms at the time of diagnosis. therapy with anakinra may be considered for patients with kd-like disease who are refractory to first-line therapy with ivig (with or without the addition of corticosteroids) [44] . tocilizumab is an il-6 inhibitor that has been used in the setting of refractory kd, although one report demonstrated the rapid development of caas in two out of four patients following therapy, suggesting caution be used with this agent in patients with kd [45] . it is important to note that the evidence for this association is weak and contradicts the favorable results obtained with tocilizumab in the treatment of large cell vasculitis in adults [46] . for the management of mis-c with features of shlh involvement, the consultation of pediatric rheumatology, immunology, or hematology/oncology is highly recommended. for initial treatment, we suggest following the cytokine storm treatment pathway described by halyabar et al. [28, 34] with anakinra and ivig. tocilizumab (il-6 inhibitor) has been studied for the treatment of covid-19 infection in adults in an uncontrolled study [47] . although no conclusions can be made from this study regarding the efficacy of tocilizumab in covid-19 pneumonia, the survival rates reported are encouraging and suggest that tocilizumab is at least safe in severe covid-19 infection. we consider that tocilizumab may also be substituted for anakinra in mis-c with shlh features, especially in the setting of active sars-cov-2 infection. for severe disease, the addition of pulsed corticosteroids and other immunosuppressive agents, such as cyclosporine and tacrolimus, may be considered. if mis-c is truly a post-infectious process, the immunosuppressive effects of therapy would not risk the flare of infection, as the infection is resolved. however, in the case of active sars-cov-2 infection, there is the theoretical possibility that immunomodulatory treatment could worsen the infection. anakinra has been proven to be effective and safe for the treatment of sepsis with features of shlh [48] . regarding the safety of steroids in the setting of active covid-19 infection (sars-cov-2 rt-pcr positive), no conclusions can be made with the currently available evidence; steroids or other immunosuppressive agents may be warranted for particular cases. pulsing with a lower dose of methylprednisolone (10 mg/kg/dose) may be an alternative for severe shlh. for some children with short duration of fever (<4 days) who are not critically ill and do not exhibit multi-system involvement, initial evaluation in the ambulatory setting may be considered. a preliminary laboratory workup, including complete blood count with differential, liver function tests, electrolytes, crp, esr, urinalysis, and sars-cov-2 nasopharyngeal pcr and serology can be helpful to decide whether further evaluation or hospitalization is necessary. evaluation for other causes of fever as appropriate based on symptomatology (i.e., respiratory viruses, streptococcal pharyngitis) should be undertaken. for children with persistent fever or new symptoms, repeat clinical evaluation and laboratory testing should be performed in the ambulatory or emergency department (ed) setting every 24 h. referral to a hospital providing specialty pediatric care should be strongly considered for abnormal laboratory values or changes in clinical status. antiviral therapy with remdesivir, a nucleotide analogue with in vitro activity against sars-cov-2 [49] , may be considered for sars-cov-2 rt-pcr positive patients. it is not likely to be of benefit for patients who are pcr negative, as studies have shown its benefit is greatest when administered early in disease [50] . initial treatment with broad antimicrobials is appropriate, given that many of these patients present with clinical features and laboratory findings consistent with bacterial sepsis. however, we recommend that antimicrobial treatment be discontinued once a patient is recognized to have mis-c and bacterial cultures are negative. elucidating the pathogenesis of mis-c will be critical to inform rational management strategies and possible preemptive measures. more robust clinical data will be useful in determining risk factors for the development of mis-c, as well as prognosis. the follow up of mis-c patients is imperative for determining possible sequelae. immunologic studies involving serial measurements of both cell-mediated and cytokine immune responses will provide insight into pathogenesis. the creation of a registry of mis-c patients may be the most expedient manner to compile this information. genetic studies will be vital to our understanding of why some children with sars-cov-2 infection ultimately develop mis-c. of note, a widespread sars-cov-2 vaccine use could theoretically predispose to mis-c, given that this is likely an immune-mediated phenomenon. the risk of mis-c will depend on the qualities of the immune response achieved, for example, whether the th1 or th2 response is predominant [51] . as an example, initial attempts at a respiratory syncytial virus vaccine found that a formalin-inactivated vaccine candidate resulted in enhanced pulmonary disease after subsequent infection [52] . some deaths were attributed to an intense th2 vaccine response which resulted in profuse pulmonary inflammation and subsequent parenchymal tissue damage. this has implications for vaccine development, especially in the selection of adjuvants to generate the intended immune response [53] . an additional concern related to mis-c and immunization is the effect of mutations in circulating sars-cov-2 strains [54] and whether heterotypic immunologic responses may result in severe immunologic manifestations after subsequent infection, similar to concerns regarding dengue vaccines [55] . the close monitoring of mis-c incidence will be required, as immunization trials are carried out in children. the hope is that a fully effective vaccine will preempt mis-c. based on initial reports from china, it was thought that children have a low incidence of symptomatic infection. however, the increased prevalence of mis-c suggests a delayed hyperimmune response to sars-cov-2 infection. the exact incidence of mis-c following an asymptomatic or mildly symptomatic infection with sars-cov-2 is not known. further studies evaluating the predisposing factors and pathogenesis of mis-c are warranted to appropriately prevent and optimally manage this condition. the authors declare no conflict of interest. cdc covid-19 response team. coronavirus disease 2019 in children-united states children with covid-19 in pediatric emergency departments in italy hyperinflammatory shock in children during covid-19 pandemic an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study cdc health alert network. mulitsystem inflammatory syndrome in children (mis-c) associated with coronavirus disease 2019 (covid-19). available online acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic outbreak of kawasaki disease in children during covid-19 pandemic: a prospective observational study new inflammatory condition in children probably linked to coronavirus, study finds covid-19 and kawasaki disease: novel virus and novel case clinical and virologic characteristics may aid distinction of acute adenovirus disease from kawasaki disease with incidental adenovirus detection health advisory: pediatric multi-system inflammatory syndrome temporally associated with covid-19 interim case definition in new york state covid-19 in newborns and infants-low risk of severe disease: silver lining or dark cloud? nasal gene expression of angiotensin-converting enzyme 2 in children and adults complex immune dysregulation in covid-19 patients with severe respiratory failure decreased levels of 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syndrome: a systematic review and meta-analysis early differentiation of kawasaki disease shock syndrome and toxic shock syndrome in a pediatric intensive care unit on the alert for cytokine storm: immunopathology in covid-19 macrophage activation syndrome in the era of biologic therapy dna viremia is associated with hyperferritinemia in pediatric sepsis hemophagocytic lymphohistiocytosis and infections: an update macrophage activation syndrome in the acute phase of kawasaki disease mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome marked hyperferritinemia does not predict for hlh in the adult population hlh-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a european league against rheumatism/american college of rheumatology/paediatric rheumatology international trials organisation collaborative initiative performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis european consensus-based recommendations for the diagnosis and treatment of kawasaki disease-the share initiative prediction of intravenous immunoglobulin unresponsiveness in patients with kawasaki disease intravenous immunoglobulin plus corticosteroid to prevent coronary artery abnormalities in kawasaki disease: a meta-analysis efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe kawasaki disease (raise study): a randomised, open-label, blinded-endpoints trial usefulness and safety of anakinra in refractory kawasaki disease complicated by coronary artery aneurysm coronary-artery aneurysm in tocilizumab-treated children with kawasaki's disease long-term efficacy and safety of tocilizumab in giant cell arteritis and large vessel vasculitis tocilizumab for cytokine storm syndrome in covid-19 pneumonia: an increased risk for candidemia? interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase iii trial remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro remdesivir in adults with severe covid-19: a randomised, double-blind, placebo-controlled, multicentre trial immunology of vaccination the long road to protect infants against severe rsv lower respiratory tract illness. f1000 res vaccine adjuvants: putting innate immunity to work spike mutation pipeline reveals the emergence of a more transmissible form of sars-cov-2. 2020 dengue vaccine development: global and indian scenarios key: cord-342372-2g9sq36w authors: zhu, frank h.; ang, jocelyn y. title: the clinical diagnosis and management of kawasaki disease: a review and update date: 2016-09-28 journal: curr infect dis rep doi: 10.1007/s11908-016-0538-5 sha: doc_id: 342372 cord_uid: 2g9sq36w kawasaki disease is an acute, self-limited vasculitis of childhood and has become the leading cause of acquired pediatric heart disease in the usa. prompt treatment is essential in reducing cardiac-related morbidity and mortality. the underlying etiology remains unknown. the disease itself may be the characteristic manifestation of a common pathway of immune-mediated vascular inflammation in susceptible hosts. the characteristic clinical features of fever for at least 5 days with bilateral nonpurulent conjunctivitis, rash, changes in lips and oral cavity, changes in peripheral extremities, and cervical lymphadenopathy remain the mainstay of diagnosis. supplementary laboratory criteria can aid in the diagnosis, particularly in cases of incomplete clinical presentation. diagnosis of kawasaki disease can be challenging as the clinical presentation can be mistaken for a variety of other pediatric illnesses. standard of care consists of intravenous immune globulin and aspirin. corticosteroids, infliximab, and cyclosporine a have been used as adjunct therapy for kawasaki disease refractory to initial treatment. there is ongoing research into the use of these agents in the initial therapy of kawasaki disease. kawasaki disease (kd) is an acute self-limited vasculitis which presents with characteristic clinical features first described in 1967 [1] . the high prevalence of coronary artery aneurysm/ectasia and its associated cardiovascular morbidity in untreated children is well characterized [2] . kawasaki disease is now the leading cause of pediatric acquired heart disease in the usa [3] . prompt treatment with high-dose intravenous immune globulin (ivig) reduces the incidence of coronary artery abnormalities from 18 to 4 % [4] . however, significant gaps remain in our understanding of kd. the underlying etiology remains unknown. epidemiological studies have recently attributed the possible source of the etiologic agent of kd to northern china with subsequent spread to japan via tropospheric winds [5•] . the diagnosis of kd remains primarily based upon the characteristic clinical features of ≥5 days of fever, bilateral nonpurulent conjunctivitis, rash, cervical lymphadenopathy, and mucocutaneous changes [6••] . however, diagnostic challenges often arise given the significant overlap in clinical features of kd and other pediatric illnesses. additionally, kd can also present with incomplete clinical features and a number of atypical presentations. yet, accurate diagnosis is integral in prevention of morbidity and mortality of kd as prompt treatment with ivig significantly reduces the incidence of long-term cardiac complications. the most recent epidemiological data describes a divergence in the incidence of kd between the west (north america, australia, europe) and east asia (japan, taiwan, korea). in the west, the current incidence of kd is 4-25/100,000 in children <5 years. in the last decade, the overall incidence in the west has plateaued following an initial increase. by comparison, the incidence of kd in east asian countries has continued to increase and currently report an incidence 10-20 times higher than usa and europe. japan has the highest incidence of kd in children <5 years of any country (265/ 100,000), followed by korea (134/100,000), and taiwan (83/100,000) [7•] . ethnic variation in the incidence of kd suggests genetic susceptibility as a significant factor in the higher prevalence of kd in east asian countries. within the usa, the incidence of kd ranges from 17.5 to 20.8/100,000 in children <5 years [8] . however, the incidence of kd is significantly higher in pacific islanders and african americans. in particular, americans of japanese ancestry in hawaii exhibit a similar incidence of kd to that of the general population of japan (>200/100,000 in children <5 years) [9] . many infectious etiologies for kd have been proposed, although a putative agent has not been isolated. the young age of children affected by kd suggests that kd is triggered by an agent to which the population becomes immune to by late childhood [10] . a variety of bacterial and viral pathogens have been isolated from patients with kd. these include staphylococcus aureus, streptococcus pyogenes, adenovirus, parvovirus b19, human herpes virus 6, rotavirus, human coronavirus, bocavirus, parainfluenza, epstein-barr, dengue, varicella-zoster, measles, and influenza viruses. while intracytoplasmic inclusion bodies found in the bronchial epithelium on autopsy may support a viral etiology [11] , the etiologic importance of the concurrent infectious pathogens seems to be limited. the possibility of a superantigen/bacterial toxin etiology has been postulated due to the similar desquamation found in scarlet fever, toxic shock syndrome, and kd. however, significant supportive data is lacking. paralysis of the adaptive immune system typically seen in superantigen-mediated illness is not seen in kd. additionally, no bacterial toxin has been detected in the peripheral blood of kd patients making such a toxin unlikely to be responsible for the diffuse inflammation found in acute kd [11] . a primary autoimmune etiology is unlikely due to the self-limited and nonrecurring nature of kd. the correlation of the seasonality of kd with tropospheric winds from densely cultivated region of northeastern china to japan suggests a possible windborne pathogen as the underlying etiology of kd [5•] . nevertheless, the clinical features of kd may be the result of a common pathway of immunemediated vascular inflammation after a variety of inciting infections rather than infection with a specific pathogen [12] . the fact that a putative infectious agent has not been isolated despite significant investigation supports this hypothesis. through exposure to a causative trigger(s), systemic inflammation is induced in the host through an incompletely understood cascade [13] . the inflammation primarily targets the medium-sized muscular arteries, most notably the coronary arteries. the initial infiltrate is primarily neutrophilic in the first 2 weeks. this is followed by infiltration of eosinophils and cd8 t cells >2 weeks after disease onset [10] . investigation of coronary arteries with light and transmission electron microscopy has identified three distinct vascular processes: necrotizing arteritis (na), subacute/chronic (sa/c) vasculitis, and luminal myofibroblastic proliferation [14] . the extent and permanence of vascular damage depends upon the scope of involvement of vascular inflammation. mild inflammation and damage generally preserves the internal and external elastic lamina, which may cause mild dilation but allows the arteries to maintain its normal morphology. as the severity of the inflammation increases, the internal and external elastic lamina is destroyed resulting in progressively larger aneurysms. these aneurysms may be fusiform (from mild sa/c vasculitis) or saccular (from severe sa/c vasculitis or na). these aneurysms are at risk for rupture or development of thrombosis. thrombosis may result in ischemia/myocardial infarction or can undergo organization and ultimately recanalization [14] . coronary artery aneurysms have also been previously described to remodel and regress [15] [16] [17] . there is no single diagnostic test or pathognomonic clinical feature of kd. therefore, a thorough history and physical examination for the established clinical diagnostic criteria is essential. the classic clinical criteria for the diagnosis of kd require the presence of ≥5 days of fever and ≥4/5 clinical features (see table 1 ) [6••] . the characteristic clinical features are typically not present all at the same time, and therefore continuous close observation may be necessary to make the diagnosis. the fever of kd is high-spiking, peaking >39-40°c, with a mean duration of 11 days, although it has been reported to last for up to 3-4 weeks in the absence of treatment. upon initiation of treatment, the fever typically resolves within 1-2 days. extremity changes initially present as erythema, induration, and swelling of the hands and/or feet in the acute phase of kd. desquamation of the fingers and toes is typically a late finding, beginning 2-3 weeks after onset of the fever. the polymorphous exanthema of kd may take various forms: maculopapular rash (most common), scarlatiniform rash, erythroderma, erythema-multiforme, or micropustular. bullous/vesicular rashes have not been described. the rash typically presents within the first 5 days of fever as a generalized eruption involving the trunk, extremities, and perineal region. early desquamation may occur in regions of perineum and is a strong indicator of kd. bilateral conjunctival injection in kd affects the bulbar conjunctivae and spares the limbus. the injection is nonpurulent and painless, presenting shortly after onset of fever. mild anterior uveitis may be present on slit lamp examination. oral cavity and lip changes in kd present include generalized erythema of the lips and oropharyngeal mucosa, peeling/cracking/fissuring of the lips, and erythema and prominent fungiform papillae on the tongue, commonly referred to as a "strawberry tongue." strawberry tongue is not unique to kd as it is also associated with streptococcal scarlet fever. cervical lymphadenopathy in kd is usually unilateral, classically presents in the anterior cervical triangle, and diagnostic criteria require ≥1 enlarged lymph node which is ≥1.5 cm in diameter. of the classic clinical features, cervical lymphadenopathy is the least commonly observed. the diagnosis of incomplete kd is made in patients who do not fulfill the classic clinical criteria (see fig. 1 ). incomplete kd is a separate entity from "atypical" kd, which present with symptoms typically not seen in kd. incomplete kd should be considered in children with unexplained fever for ≥5 days in addition to the presence of 2-3 principal clinical features of kd. there is a higher prevalence of "incomplete" presentation in younger children. therefore, incomplete kd should be considered in young children (<12 months old) with unexplained fever for ≥5 days associated with any of the clinical features as kd [6••] . in the evaluation for incomplete kd, the presence of supportive laboratory and echocardiogram findings (see table 1 ) is useful in ultimately confirming the diagnosis. the term "atypical kd" has been used interchangeably with incomplete kd in the past, but should be reserved for cases of kd which present with findings rarely associated with kd. these features include transient unilateral peripheral facial nerve palsy, transient high-frequency sensorineural hearing loss, hepatic enlargement with jaundice, and acalculous gallbladder distention. testicular swelling, pulmonary nodules, pleural effusions, and hemophagocytic syndrome have also been reported but are less common. kawasaki shock syndrome, the presentation of kd disease with systolic hypotension or clinical signs of poor perfusion, has also been described as a rare presentation of kd [18•] . the major cardiac sequelae of kd affect the coronary arterial system. the pericardium, myocardium, endocardium, valves, and coronary arteries may all be affected by the diffuse inflammatory process of kd. this may present as pericarditis, myocarditis, valvulitis, and new valvular regurgitation. a gallop rhythm with innocent flow murmur may also be present, commonly in the setting of anemia and fever of acute kd. poor myocardial function can also result in cardiogenic shock. arrhythmia, prolonged pr interval, and nonspecific st and t wave changes may be present on ekg. supplementary laboratory criteria supporting the diagnosis of kd are listed in table 1 and include hypoalbuminemia, anemia for age, elevation of alanine aminotransferase (alt), thrombocytosis after 7 days, leukocytosis, and sterile pyuria. additional nonspecific laboratory findings are elevated markers of inflammation (erythrocyte sedimentation rate (esr) and c-reactive protein (crp)). approximately 50 % of patients with kd have wbc >15,000/mm 3 . anemia may develop in patients with prolonged duration of active inflammation and is typically present with normal rbc indexes. acute phase reactant elevation (esr/crp) is nearly universally present, although discordant esr/crp can be seen in the acute presentation of kd. thrombocytosis, with platelet counts from 500,000 to >1 million/mm 3 , is a late feature of kd commonly occurring in the second week of the disease and slowly resolving by weeks 4 to 8 in uncomplicated kd. elevation of alt is typically mild to moderate and occur in ≤40 % of cases. hypoalbuminemia (albumin ≤3.0) is associated with more severe and prolonged disease. sterile pyuria is present in approximately one third of patients. sterile pyuria is not found in suprapubic aspiration of urine as underlying urethritis is present in kd. the differential diagnosis of patients presenting with the clinical features of kd is vast. there is considerable overlap in the clinical features of kd with several common pediatric illnesses including but not limited to adenovirus infection, bacterial cervical adenitis, retropharyngeal abscess, systemic onset jra, and toxic shock syndrome. incomplete kd often presents the greatest diagnostic challenge as initial presentation may be consistent with any of the previously mentioned clinical illnesses given the limited clinical manifestations. therefore, it is essential to consider kd in the differential diagnosis of these illnesses. adenovirus infection is one of the most common pediatric infections, comprising 7-8 % of all pediatric respiratory illnesses [19] . the presence of adenovirus can be detected through polymerase chain reaction (pcr) testing of the nasopharynx (np) swab in up to 11 % of healthy children [20] . in patients with kd with subsequent development of coronary artery abnormalities, incidental detection of adenovirus by pcr in np swab has been described. therefore, accurate differentiation between the incidental detection of adenovirus in patients with kd and primary adenoviral disease is essential to avoid the subsequent mortality/morbidity associated with undiagnosed kd. prolonged fever and elevated inflammatory markers are common features of adenovirus infection and kd. the most commonly described clinical feature of kd compared to adenoviral infection reported in a cohort study was conjunctivitis. features of adenovirus conjunctivitis include unilateral onset, prominence of tearing more frequently than purulence, and follicular hyperplasia. additionally, adenovirus often presents with pharyngoconjunctival fever, characterized by nonexudative or exudative pharyngitis in addition to conjunctivitis. extremity changes and unilateral neck swelling were the least common clinical features of kd seen in patients with adenoviral disease [21•] . node-first presentation of kd (nfkd) is the manifestation of kd with fever and cervical adenopathy prior to the presentation of other clinical features of kd. compared to typical kd, the patients of nfkd tend to be older and have higher markers of inflammation. node-first presentation of kd may often be misdiagnosed as bacterial cervical adenitis as fever and cervical adenopathy are characteristic clinical findings in both diseases. laboratory findings to aid in differentiation of these two entities include lower wbc count, hemoglobin, platelet counts, and higher absolute band count, crp, esr, alt in nfkd. additionally, radiographic findings in bacterial cervical adenitis favor a single dominant node or conglomerations and suppuration of lymph nodes. conversely, radiographic findings in nfkd favor multiple discrete nodes [22•] . retropharyngeal edema is a rare presentation of kd, which due to unfamiliarity with the presentation, is often misdiagnosed as retropharyngeal abscess. many of these patients have underwent pharyngeal needle aspiration and antibiotic therapy due to misdiagnosis, delaying treatment for kd and increasing the risk of development of coronary artery abnormalities [23, 24] . the diagnosis of kd with retropharyngeal edema should be considered in patients diagnosed with retropharyngeal abscess subsequently found to have sterile culture results from surgical drainage. there were no significant differences in laboratory findings between these two entities. clinical symptoms classically associated with retropharyngeal abscess such as stridor, neck pain, and dysphagia are less common in the retropharyngeal edema of kd. radiological findings of ring enhancement and mass effect on neck ct were more commonly found in patients with retropharyngeal abscess [25•] . systemic onset juvenile idiopathic arthritis (sojia) is an autoimmune disease characterized by severe inflammation of multiple organ systems. the clinical features of early stage sojia (fever, rash, thrombocytosis, increased markers of inflammation, and arthritis) may resemble kd. coronary artery dilation can be present in sojia, but is less common. arthritis is a feature that may be present in both kd and sojia. it is generally mild and self-limited in kd, as compared to the persistent and severe arthritis of sojia which often requires treatment with immunosuppressive agents for resolution [26] . the rash of sojia is typically intermittent and coincides with fever spikes as compared to the fixed rash of kd. the presence of mucocutaneous findings suggests kd as this finding is absent in sojia. additionally, thrombocytosis is typically a late finding of kd (occurring in the second week of disease) as compared to the early stages of sojia. as ivig is an adjunctive rather than primary modality of therapy for sojia, the diagnosis of sojia should be considered in patients with kd which do not respond to multiple ivig infusions [27] . toxic shock syndrome (tss) is a toxin-mediated disease which presents with clinical features of fever, hypotension, rash, and subsequent desquamation of the skin with multi-organ involvement and may be confused with kd. the most common causative organism is s. aureus. the condition has been misdiagnosed as kd due to similar clinical features of rash and fever. the hypotension of tss can be misattributed to the shock associated with kd. patients presenting with tss are on average older (mean age 113 ± 56 months) than patients with kd (37 ± 41 months) [28•] . other features suggestive of tss include elevated creatinine and labile blood pressures requiring higher vasopressor support and increased fluid resuscitation. features suggestive of kd include anemia, thrombocytosis, and cardiac abnormalities [29] [30] [31] . the use of intravenous immune globulin (ivig) in the acute phase of kd to prevent the development of coronary artery abnormalities is well defined [4, 32, 33] . treatment with ivig within the first 10 days of illness reduces the risk of development of coronary artery abnormalities to approximately 5 % from 25 % [32] . the mechanism of action remains unknown, but the generalized anti-inflammatory effect of ivig likely inhibits progression of kd, ultimately preventing the development of coronary artery abnormalities. the use ivig is recommended for treatment of patients with kd [6••] and has been shown to be cost effective [34] . dosed at 2 gm/kg in a single infusion, ivig should be given as initial treatment for kd. treatment should be instituted within the first 10 days of illness and should still be administered to children after the tenth day of illness should fever persists, or with ongoing systemic inflammation (elevated esr/crp) or the presence of coronary artery abnormalities [6••] . treatment of kd prior to day 5 of illness may be associated with increased need for ivig retreatment [35] . live vaccines, particularly measles and varicella, should be deferred for 11 months after ivig treatment. children at high risk of measles exposure may be vaccinated earlier, but will require re-immunization 11 months after ivig treatment. treatment with ivig is given concurrently with aspirin (see below). during the acute phase of kd, aspirin (asa) is administered at high dosages (80-100 mg/kg/day divided every 6 h). concurrent administration of high-dose asa with ivig during the acute phase of kd seems to provide an additive antiinflammatory effect. high-dose aspirin alone does not lower the frequency of development of coronary abnormalities despite its anti-inflammatory effect [32] . the duration of high-dose aspirin therapy varies with institution. all institutions require resolution of fever for 48-72 h prior to stopping high-dose asa therapy. however, some institutions will treat with high-dose asa until day 14 of illness regardless of fever resolution. once high-dose asa is discontinued, low-dose asa (3-5 mg/kg given daily) is started. low-dose asa is used for its anti-platelet effect to prevent possible complications from coronary artery abnormalities associated with kd. evaluation for coronary abnormalities should be done at least until 6-8 weeks after the onset of kd. low-dose asa is discontinued if there is no evidence of coronary abnormalities and platelet count is normal at that time. should evidence of coronary abnormalities develop or persist, low-dose asa is continued indefinitely. ibuprofen should be avoided while the patient is on asa as it antagonizes the platelet inhibition of asa [36] . children receiving asa therapy are at risk of development of reye syndrome, particularly during active infections with varicella or influenza. reye syndrome has been reported in patients receiving prolonged high-dose asa therapy for kd [37] , although it is unclear whether low-dose asa increased the risk of reye syndrome. children on long-term asa therapy should receive inactivated influenza vaccine. physicians should evaluate patients on asa who are exposed to or develop symptoms of influenza and varicella. approximately 13 % of patients with kd fail to respond to initial treatment with ivig [38] . failure to respond is characterized as persistent fever ≥36-48 h following completion of ivig infusion. the most likely explanation for persistent fever in these patients is failure of initial ivig to abort the disease process of kd. however, kd can be misdiagnosed due to its shared clinical characteristics with a wide variety of common pediatric illnesses. therefore, patients with refractory kd should be assessed for possible misdiagnosis of kd as well (see "diagnostic challenges" section). patients with kd who fail to respond to initial ivig therapy should receive a repeat infusion of ivig at the same dose (2 gm/kg as a single infusion). retreatment at lower doses (1 gm/kg) has been associated with increased risk of developing coronary abnormalities [38] . pulse steroid therapy in patients with kd refractory to two ivig infusions (2 gm/kg infusion followed by 1 gm/kg infusion) has been associated with shorter duration of fever and hospital stay when compared to repeat 1 gm/kg ivig infusion [39] . the use of corticosteroids in patients with kd is currently reserved for children who have received ≥2 infusions of ivig on the basis that effects of steroid therapy on coronary artery abnormalities were uncertain at the time of publication of kd treatment guidelines in 2004. the most commonly used steroid regimen is iv methylprednisolone (ivmp) 30 mg/kg daily for 1-3 days [6••] . further research into the use of corticosteroids in the primary treatment of kd remains ongoing. in 2007, a randomized controlled trial by newburger et al. showed that the addition of one dose of ivmp therapy to initial ivig infusion did not reduce the prevalence of coronary artery abnormalities or total length of hospital stay [40] . in japan, the study on the efficacy of ivig and steroids in patients with severe presentation of kd (raise study), a multicenter, prospective, randomized, open-label, blinded-endpoints trial, showed combination treatment with ivig and prednisolone had significant advantages over ivig alone in the prevention of coronary artery abnormalities with rapid defervescence of fever and normalization of inflammatory markers [41•] . severe kd was determined through a risk score evaluation of five points or higher per kobayashi risk score scale, which predicts a >30 % probably of nonresponsiveness to initial ivig treatment (table 2 ) [42] . there were significant differences in corticosteroid regimen between the two trials. the median start time of therapy in the raise study was 2 days earlier than in the trial by newburger et al. additionally, the steroid dosage of the raise study was iv prednisone 2 mg/kg divided three times a day over 5 days followed by titration to oral prednisolone dosed at 2 mg/kg/day until resolution of fever and improvement in inflammatory markers. the median duration of steroid therapy in the raise study was 21 days. this is a significant increase in total steroid dose as compared to the single dose of 30 mg/kg methylprednisolone in the newburger study. the earlier initiation of ivig and corticosteroid therapy with subsequent increased steroid treatment duration was associated with significantly lower rates of coronary artery abnormalities in the raise study. this may be a result of early suppression of vasculitis that precedes vascular remodeling due to early initiation of corticosteroid therapy. the addition of corticosteroid therapy to the initial treatment regimen of kd is not the standard of care at this time. infliximab (remicaide), a human monoclonal antibody against tumor necrosis factor (tnf)-α, can be used in the treatment of refractory kawasaki disease. during the acute phase of kd, tnf-α is markedly elevated and degree of elevation has been correlated to the development of coronary artery abnormalities [43] . the most commonly used regimen is one infliximab infusion dosed at 5 mg/kg. two retrospective reviews of patients with refractory kd treated with infliximab showed complete resolution of symptoms in majority of patients with refractory kd following administration of infliximab [44, 45] . additionally, a recent pilot study randomized 43 patients with kd refractory to initial ivig infusion to receive either repeat ivig (2 gm/kg) or infliximab (5 mg/kg). treatment with infliximab was associated with shortened duration of fever and lengths of hospitalization and possible reduction in the need for retreatment [46•] . the effects of infliximab on the development of coronary artery abnormalities in kd remain unclear. this study did not show reduction in the development of coronary artery abnormalities. however, regression in both the progression of coronary artery dilation/formation [44] and the resolution of dilated coronary arteries [45] following infliximab infusion have been reported. therefore, infliximab may inhibit progression of coronary artery dilation and injury rather than prevent the formation of coronary artery abnormalities [46• ]. in a phase 3 randomized, double-blind placebo-controlled trial, the addition of infliximab did not reduce treatment resistance of initial therapy but did shorten fever duration, time to normalization of inflammatory markers (crp, esr), and had a larger decrease in the z score of the left anterior descending coronary artery [47•] . currently, there is no indication for the addition of infliximab to the initial treatment regimen of uncomplicated kd. cyclosporin a (csa) is a calcineurin inhibitor, which targets the ca 2+ /nfat signaling pathway. this pathway is associated with immune hyper-reactivity. unresponsiveness to ivig therapy and coronary artery abnormalities in kd patients have been associated with single nucleotide polymorphisms of genes (itpkc, casp3) which downregulate the ca 2+ /nfat signaling pathway. therefore, inhibition of the ca ca 2+ /nfat signaling pathway through csa may be considered in patients with refractory kd. in a retrospective review of 19 patients with refractory kd treated with csa, dosed at 4 mg/kg/day for 14 days, 14/19 patients became afebrile within 5 days. in these patients, significantly lower serum inflammatory cytokines were found [48] . a phase iii multicenter, randomized, open-label, blinded-end point trial to evaluate the efficacy and safety of immunoglobulin plus cyclosporin a in patients with severe kd (kaica trial) is currently ongoing in japan. the trial aims to compare ivig with concurrent csa therapy to ivig therapy alone in patients with severe kd defined as a kobayashi risk score scale >5. the primary endpoint is the frequency of coronary artery abnormalities at 12 week follow up [49•] . the dose of csa in the kaica trial is 5 mg/kg/day with a target blood concentration level of 60-200 ng/ml for a total of 5 days. prevention of thrombosis in patients with kd varies with the extent of the coronary artery abnormality present in the patient. low-dose asa is appropriate for asymptomatic patients with mild to stable disease. however, as the severity of coronary artery enlargement increase, the combination of asa with other antiplatelet agents such as clopidogrel is warranted. additional anticoagulation is necessary with further coronary aneurysm expansion. frequently, warfarin is added to lowdose aspirin for patients with giant aneurysms. low molecular weight heparin has also been used in place of warfarin by some physicians. the efficacy of other anti-inflammatory agents in the treatment of kd is currently being investigated. of particular interest is the efficacy of these new agents in the kd complicated by coronary artery abnormalities. the current treatment regimen of ivig and aspirin is well documented to reduce the incidence of coronary artery abnormalities in kd, but effective agents in the prevention of progression of coronary artery abnormalities are currently under investigation. the il-1 inflammatory pathway is upregulated in kd and involved in coronary artery inflammation. blockade of this pathway in mouse model of kd has been shown to prevent the development of coronary artery abnormalities [50] . anakinra is an il-1 receptor antagonist which has be used in rare cases of refractory kd [51, 52] . the anakid trial, phase i/iia trial of anakinra in kd patients with coronary artery abnormalities, is ongoing in the usa. subjects will receive a 2-6-week course of daily anakinra injections. the study aims to evaluate the safety and tolerability of anakinra to prevent/attenuate coronary artery damage in patients with kd [53•]. the kawakinra trial, a phase iia multicenter trial of anakinra in kd patients who fail to respond to initial ivig therapy (persistent fever up to 48 h after infusion), is currently enrolling in europe (clinicaltrials.gov nct02390596). in addition to their well-documented cholesterol lowering effects, statins likely have anti-inflammatory and anti-oxidant effects. statins have been associated with reduction in inflammatory markers such as crp [54] . the cholesterol and recurrent events (care) trial found a higher risk of recurrent myocardial infarction in patients with normal cholesterol levels who received placebo rather than pravastatin [55] . the anti-inflammatory, anti-oxidant, and endothelial healing properties of statins have been postulated to be beneficial in blocking the progression of coronary artery abnormalities in kd [56• ]. use of pravastatin in a 40-year-old patient with history of kd and giant left coronary artery aneurysm has been shown to have reduction in coronary artery inflammation [57•] . additionally, treatment of 13 children with kd complicated by medium to giant coronary artery aneurysms with pravastatin resulted in improvement in endothelial function measured by flow-mediated dilation and reduction in crp [58•] . currently, there is a phase i/iia dose escalation study of atorvastatin to determine its safety, pharamacokinetics, and activity in children with acute kd and coronary artery abnormalities (clinicaltrials.gov nct01431105). the diagnosis and initial treatment of kd with ivig and aspirin remains unchanged from the 2004 american heart association (aha) treatment guidelines. however, diagnostic challenges exist, particularly in the presentation of incomplete kd, due to overlap of clinical features of kd with other common pediatric illnesses. prompt treatment with ivig and aspirin remains the mainstay of treatment. treatment options human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by the author. a new infantile acute febrile mucocutaneous lymph node syndrome (mlns) prevailing in japan long-term consequences of kawasaki disease. a 10-to 21-year follow-up study of 594 patients nationwide survey of kawasaki disease and acute rheumatic fever the treatment of kawasaki syndrome with intravenous gamma globulin this report provides the most recent epidemiological data which postulates the source of the etiologic agent kawasaki disease diagnosis, treatment, and long-term management of kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis, and kawasaki disease, council on cardiovascular disease in the young this report provides a current and comprehensive summary of the current global epidemiology of kawasaki disease epidemiology of kawasaki disease in asia, europe, and the united states racial/ethnic differences in the incidence of kawasaki syndrome among children in hawaii kawasaki disease kawasaki disease: novel insights into etiology and genetic susceptibility update on etio and immunopathogenesis of kawasaki disease update on kawasaki disease: epidemiology, aetiology and pathogenesis three linked vasculopathic processes characterize kawasaki disease: a light and transmission electron microscopic study active remodeling of the coronary arterial lesions in the late phase of kawasaki disease: immunohistochemical study regression of aneurysms in kawasaki disease: a pathological study regression of coronary aneurysms in patients with kawasaki syndrome this retrospective review compares the main clinical presentation, echocardiogram and laboratory findings as well as treatment options of kawasaki shock syndrome which is a rare presentation of kawasaki disease adenovirus infections in young children epidemiology of viral respiratory tract infections in a prospective cohort of infants and toddlers attending daycare this report provides a summary of the clinical and microbiological characteristics which may aid in the differentiation of incidental adenovirus detection this retrospective review identifies characteristics differentiating the node-first presentation of kawasaki disease from bacterial cervical lymphadenitis and typical kawasaki disease to aid the recognization and kawasaki disease mimicking retropharyngeal abscess kawasaki disease resembling a retropharyngeal abscess-case report and literature review this retrospective casecontrol study identifies the clinical manifestations as well as radiographic findings to aid in the differentiation of kawasaki disease with retropharygeal edema to those with retropharyngeal abscess incomplete kawasaki disease followed by systemic onset juvenile idiopathic arthritis-the diagnostic dilemma systemic onset juvenile idiopathic arthritis with macrophage activation syndrome misdiagnosed as kawasaki disease: case report and literature review this retrospective review identifies characteristics differentiating toxic shock syndrome with kawasaki disease shock syndrome to aid in recognization and treatment of this rare presentation of kawasaki disease recognition of a kawasaki disease shock syndrome tricuspid and mitral regurgitation detected by color flow doppler in the acute phase of kawasaki disease clinical manifestations associated with kawasaki disease shock syndrome in mexican children the prevention of coronary artery aneurysm in kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment high-dose intravenous gammaglobulin for kawasaki disease economic evaluation of intravenous immune globulin therapy for kawasaki syndrome early intravenous gamma-globulin treatment for kawasaki disease: the nationwide surveys in japan cyclooxygenase inhibitors and the antiplatelet effects of aspirin kawasaki disease with reye syndrome: report of one case intravenous gamma-globulin treatment and retreatment in kawasaki disease. us/canadian kawasaki syndrome study group re-treatment for immune globulin-resistant kawasaki disease: a comparative study of additional immune globulin and steroid pulse therapy randomized trial of pulsed corticosteroid therapy for primary treatment of kawasaki disease this multicenter, prospective, randomized, open-label, blinded-endpoints trial, showed combination treatment with ivig and prednisolone had significant advantages over ivig alone in the prevention of coronary artery abnormalities, rapid defervescence of fever and normalization of inflammatory markers prediction of intravenous immunoglobulin unresponsiveness in patients with kawasaki disease serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-gamma in kawasaki disease involved coronary-artery lesions infliximab treatment for refractory kawasaki disease in korean children infliximab treatment for refractory kawasaki syndrome treatment with infliximab in patients with refractory kawasaki disease was associated with shorter duration of fever and hospitalization when compared to second dose of ivig in this randomized this phase 3 randomized, double-blind placebo-controlled trial revealed that the addition of infliximab to the initial treatment regimen of kawasaki disease did not reduce the incidence of refractory kawasaki disease inflammatory cytokine profiles during cyclosporin treatment for immunoglobulin-resistant kawasaki disease study protocol for a phase iii multicentre, randomised, open-label, blinded-end point trial to evaluate the efficacy and safety of immunoglobulin plus cyclosporin a in patients with severe kawasaki disease (kaica trial) interleukin-1beta is crucial for the induction of coronary artery inflammation in a mouse model of kawasaki disease adjunctive therapies for kawasaki disease high dose anakinra for treatment of severe neonatal kawasaki disease: a case report this phase i/iia trial of anakinra in children with kawasaki disease and coronary artery abnormalities aims to evaluate the saftety and tolerability of 2-6 week course of daily anakinra injection to to prevent or attenuate coronary artery damage associated with kawasaki disease long-term effects of pravastatin on plasma concentration of c-reactive protein. the cholesterol and recurrent events (care) investigators inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. cholesterol and recurrent events (care) investigators this editorial review of the role of statins in non-atherosclerotic, acute and chronic vasculitides due to their anti-inflammatory, anti-oxidant, and endothelial repairing properties provides an concise review of the use of statins in the treatment of kawasaki disease this case report documents the use of pravastatin in a 42 year old pt with history of kawasaki disease complicated by giant left coronary artery aneurysm which resulted in reduction in coronary artery inflammation effect of pravastatin on endothelial dysfunction in children with medium to giant coronary aneurysms due to kawasaki disease key: cord-293714-s6ezxi5r authors: principi, nicola; rigante, donato; esposito, susanna title: the role of infection in kawasaki syndrome date: 2013-04-18 journal: j infect doi: 10.1016/j.jinf.2013.04.004 sha: doc_id: 293714 cord_uid: s6ezxi5r objectives: to analyse the evidence suggesting a possible infectious origin of kawasaki syndrome (ks). methods: pubmed was searched for all of the studies published over the last 15 years using the key words “kawasaki syndrome” or “mucocutaneous lymph node syndrome” and “infectious disease” or “genetics” or “vasculitis” or “pathogenesis”. results: various levels of evidence support the hypothesis that ks is a complex disease triggered by an infection due to one or more pathogens. viruses or bacteria may be the primum movens, although no specific infectious agent can be considered definitely etiological. a number of genetic polymorphisms have been identified in subjects with ks, but none of them can currently be considered a real marker of susceptibility. conclusions: various data suggest that ks is intimately related to infectious diseases and that its clinical expression is influenced by predisposing genetic backgrounds, but our knowledge of the infectious agent(s) involved and the genetic characteristics of susceptible children remains only partial. further studies are needed to address the many still open questions concerning the disease. kawasaki syndrome (ks), originally called "mucocutaneous lymph node syndrome" in 1967, 1 is an acute multisystem vasculitis that causes generalised inflammatory cell tissue injury starting in the vascular endothelium and is mainly encountered in children aged less than five years regardless of their ethnicity. 1 the injuries are particularly severe in the coronary arteries, which are frequently affected by dilatations, aneurysms or fistulae, especially in patients who do not receive prompt treatment with intravenous immunoglobulins and anti-inflammatory doses of acetylsalicylic acid. 2 now that rheumatic fever is largely controlled, ks has become the leading cause of acquired heart disease among children in industrialised countries. 3 as no specific diagnostic test is available, ks is identified on the basis of a constellation of non-specific clinical signs. according to the american heart association guidelines, 4 which are shared by most scientific communities throughout the world, a diagnosis requires prolonged fever lasting more than five days and at least four of the following signs: 1) diffuse oral cavity inflammation (including pharyngeal infection), dry fissured lips, and a strawberry tongue); 2) bilateral non-purulent conjunctivitis; 3) heterogeneous skin rashes; 4) angioedema of the extremities (including peripheral erythema, oedema, or induration of the hands or feet); and 5) non-purulent cervical lymphadenopathy exceeding !1.5 cm in diameter. in what are known as "incomplete" cases, one or more of these clinical signs may be absent but a diagnosis can still be made if there is echocardiographic evidence of coronary artery abnormalities. furthermore, a broad range of unusual clinical finding have been reported as defining the "atypical" variant of ks, including aseptic meningitis, peripheral facial nerve palsy, uveitis, gastrointestinal complaints, acalculous gallbladder hydrops, urethritis, testicular swelling, pulmonary nodules, liver impairment with jaundice, and even hemophagocytic syndrome. 5 laboratory investigations (listed in table 1 ) can only support the diagnosis of ks, but they still need to be validated before they can be used in everyday clinical practice. however, although the clinical features of ks are usually recognisable, its underlying immune mechanisms are still being investigated. most experts consider it to be the consequence of an abnormal immunological response evoked by one or more widely distributed infectious agents in genetically susceptible individuals, but it still remains a medical enigma. the main aim of this review is to analyse the available evidence suggesting that ks may have an infectious origin. pubmed was used to search for all of the studies published over the last 15 years using the key words: "kawasaki syndrome" or "mucocutaneous lymph node syndrome" and "infectious disease" or "genetics" or "vasculitis" or "pathogenesis". more than 1300 articles were found, but only those published in english or providing evidence-based data were included in the evaluation. various levels of evidence support the hypothesis that ks is a complex disease initiated by an infection due to one or more pathogens (table 2) . however, no strict and unmistakable correlation between specific infectious agents and the development of the disease has ever been identified. a number of bacterial and viral infectious agents have been sporadically isolated from ks patients. the most frequently implicated bacteria are staphylococcus aureus, 6 streptococcus pyogenes, 7 and atypical pathogens, 8e10 and the viruses associated with ks over recent years are epsteinebarr virus, 11 adenovirus, 12 parvovirus b19, 13 herpesvirus 6, 14 parainfluenza type 3, 15 measles, 16 rotavirus, 17 dengue virus, 18 and human immunodeficiency virus. 13 varicella, 19 2009 h1n1 pandemic influenza 20 and coxsackie b3 virus 21 have also been described in patients with ks, but they were equally found in the blood or body fluids of both patients and healthy subjects. moreover, no relationship was reported between ks and the circulation of the commonest respiratory viruses. 22 the most recent and numerous studies of ks-related viruses have postulated the etiological role of human coronavirus (hcov) nl63 and bocavirus, 23e25 but this has not been confirmed by subsequent studies. in order to evaluate the importance of hcov-nl63 in ks, shimizu et al. established a multi-institutional collaborative research project to test respiratory samples using realtime polymerase chain reaction (rt-pcr), and found that only one out of 48 ks patients (2%) was positive 26 ; dominguez et al. found exactly the same prevalence in nasopharyngeal wash samples from ks patients and healthy controls over a period of seven months 27 ; and lehmann et al. measured the concentrations of igg, igm and iga antibodies against hcov nl63 and oc43 in the blood of children showing the signs and symptoms of ks for 3e10 days and healthy controls, but did not find any difference between the two groups. 28 the data regarding bocavirus (a virus that has recently emerged as a possible cause of respiratory infection) are also unconvincing 29 : although it was identified in the serum, stool and cerebrospinal fluid of some children with ks, no definitive conclusion could be drawn concerning its etiological role. the limited etiological importance of the pathogens so far identified seems to be supported by the studies of benseler et al. 30 and jordan-villegas et al., 31 who found that that concomitant infections in children with ks did not alter the response to treatment with intravenous immunoglobulins, and did not influence the risk of coronary artery involvement or affect overall cardiovascular outcomes. however, the lack of any clear relationship between one or more pathogens and the development of ks does not exclude the possibility that a real infectious disease may be involved, and other factors support this hypothesis. on the other hand, the unsuccessful identification of a specific pathogen to which ks could be ascribed has led some authors to postulate that variants of normal flora in the gut, oral cavity or skin of young children with a genetic defect of proper immune maturation do not induce immune tolerance as self commensals, but rather induce an imbalance of the immune system, leading to a hyperimmune reaction and the manifesting ks. 32 table 1 laboratory findings supporting a diagnosis of kawasaki syndrome. 1. c-reactive protein !3.0 mg/dl 2. erythrocyte sedimentation rate !40 mm/h 3. albumin 3.0 g/dl 4. age-relative anaemia 5. high alanine aminotransferase levels 6. platelet count !450,000/mm 3 in the subacute phase of the disease 7. white blood cell count !15,000/mm 3 8. white blood cells/high-power field !10 in urinalysis histopathological data some histological findings strongly suggest that ks has an infectious origin, although they do not identify the responsible pathogen. the most important is that persistent intracytoplasmic inclusion bodies (iibs) showing amphophilic staining by haematoxylin-eosin and stain for rna have been found in most of the tissues of patients who have died because of ks. 33 as transmission electron microscopy (tem) of bronchial epithelia has revealed virus-like particles associated with the iibs, it was thought that these may be a "footprint" of a viral infection that may persist indefinitely: rowley et al. speculated that the infection associated with the development of ks could be due to a new and ubiquitous rna virus that caused only asymptomatic infection or very mild disease in the general population, but ks in genetically selected subjects. 34 it was thought that the first site of infection was the respiratory tract, with further dissemination through macrophages to all body sites, including the medium-sized arteries (mainly the coronary arteries) that are the most crucial targets in ks. further findings that strongly support an infectious origin of ks are those of orenstein et al., who used light microscopy and tem to study tissue specimens from 32 autopsies, eight heart transplants and an excised coronary aneurysm of patients with ks and identified three different vasculopathic processes: acute self-limited necrotising arteritis (na), subacute/chronic vasculitis, and luminal myofibroplastic proliferation. on the basis of the changes in coronary and non-coronary arteries during the different phases of ks, they considered na the only self-limiting process of the three, and that it was consistent with an acute viral infection. 35 many epidemiological findings regarding ks are consistent with an infectious origin, as they are quite similar to those of various infectious diseases. first of all, there is the occurrence of epidemics because, although cases of ks are diagnosed, there are also sometimes widespread epidemics. in japan, where nationwide epidemiological surveys of ks have been carried out almost every two years since 1970, 36 three large-scale epidemics were recorded in 1979, 1982, and 1986, with incidence rates that were several times higher than those reported in the previous and following year. secondly, as in the case of a number of infectious diseases, 37, 38 ks is more frequent in boys, and the male to female ratio is about 1.6. 39 thirdly (once again as in the case of many infectious diseases), the incidence of ks seems to be closely related to weather conditions, although the predominant season varies from country to country: winter and spring in the united kingdom, australia and the usa, and spring and summer in china. 40e43 pitzer et al., examined seasonal changes in the age and incidence of ks hospitalisations in the usa, and found that periods of high incidence corresponded to a low average age, and vice versa. 40 comparison of the observed pattern with those predicted by a suite of models based on different etiological hypotheses, the ageincidence pattern of ks suggested the involvement of an imperfectly immunising infection and/or a persistently infectious agent. the possible relationship between seasonal variations in the incidence of ks and an infectious aetiology is also supported by data showing that its incidence in the usa inversely correlates with average monthly temperature (r z à0.47; p < 0.001) and positively correlates with the role of infection in ks average monthly precipitation (r z à0.52; p < 0.001). 41 moreover, analyses of the three major ks epidemics in japan, major non-epidemic inter-annual fluctuations of ks cases in japan and san diego, and seasonal variations in the incidence of ks in japan, hawaii and san diego have revealed a consistent pattern linking ks cases to large-scale wind currents originating in central asia and crossing the north pacific. 42 this seems to indicate that the environmental trigger of ks may be wind-borne, and this has led some experts to suggest that efforts to isolate the causative agent should concentrate on the microbiology of aerosols. 43 finally, children in the first months of life only exceptionally develop ks, which supports the hypothesis that most infants are protected by passively acquired specific maternal antibodies against the possible causative agent(s). on the other hand, the very low incidence of ks beyond the fifth year suggests that most children are infected uneventfully by one or more of the infectious agents associated with ks in early life and can then mount a long-lasting, strong and protective immune response. recurrences of ks have been reported in only 1e3% of children, and are best documented in japan. 44 the clinical findings of fever, an erythematous pharynx, conjunctival injection, rash, oedema of the extremities and cervical adenitis in patients with ks, and the clear tendency of these signs to resolve spontaneously even without treatment also support an infectious aetiology. a number of viral diseases have a similar clinical picture. moreover, some of the clinical features of ks, such as mucous membrane erythema and desquamation of the fingers and toes (usually beginning within 2e3 weeks of the onset of fever), overlap those associated with some bacterial diseases that are considered to be a consequence of the superantigen (sa)-mediated activation of t cells leading to the overproduction of cytokines, systemic inflammation and shock. 45e47 the best examples in this regard are toxic shock syndrome (tss) and scarlet fever due to s. aureus, and streptococcal toxic shock syndrome (stss) due to streptococcus pneumoniae. the similarity between these conditions and ks has led to the conclusion that, at least in some cases, ks may follow an infection due to an saproducing pathogen. a number of sas have been identified: the most widespread bacterial pathogens are s. aureus and s. pneumoniae, but yersinia pseudotuberculosis, mycoplasma pneumoniae and mycobacterium tuberculosis have also been associated with sa formation 45 ; among viruses, sas have been found in epstein barr virus, rabies virus and mouse leukaemia virus. 46 sas are a family of potent immunostimulatory proteins whose particular structures and sequences lead to a shared ability to by-pass the mechanism of conventional major histocompatibility complex (mhc)-restricted antigen processing. when an sa is involved, t cell responses are quantitatively and qualitatively different from conventional t cell activation by normal antigens. in particular, sas activate t cells in a manner that depends on the t cell receptor variable domain (vb), and so a large number of t cells can be simultaneously activated. 85 the activation is extremely potent and a number of studies have found that ks is characterised by the marked activation of t cells and monocytes/macrophages, and increased production of il-1b, tnf-a and il-6, which are the same immunological findings as those of tss. 47 although some attempts to demonstrate the presence of sa-producing pathogens in children with ks have led to negative results, 48e51 others have provided data suggesting the direct involvement of sas. leung et al. blindly studied bacterial sas potentially involved in the pathogenesis of ks in cultures of patients in the acute phase and controls, 52 and found sa-producing bacteria in 13 of the 16 patients but in only one of the 15 controls (p < 0.0001). eleven of the 13 toxin-positive cultures from the patients with ks contained toxic shock syndrome toxin (tsst)-1 secreting s. aureus, and the remaining two contained streptococci producing streptococcal pyrogenic exotoxin b (speb) and streptococcal pyrogenic exotoxin c (spec). twelve of the culture-positive patients had toxin-producing s. aureus isolated from pharyngeal or rectal cultures, thus suggesting the gastrointestinal tract as the primary entry site. similar findings of tsst-1-producing s. aureus and spec-producing streptococci in children with acute ks have been recently published. 47 the sa theory may be supported by anecdotal reports of ks patients with guttate psoriasis because it has been suggested that this form of psoriasis is due to toxinmediated t cell activation. 53 furthermore, a number of studies analysing the t lymphocyte receptor repertoire and the titres of antibodies against selected sas have indirectly demonstrated that these proteins may be related to the development of ks. 52,54e56 in addition, suenaga et al. examined five sa genes in the stools of ks patients, febrile controls and healthy children, 57 and found at least one of the genes in 42 specimens from the patients with ks (70%), in 14 from the febrile group (38.9%), and in seven from the healthy group (26.9%). the detection rate between subjects with and without ks was of at least one of the 5 sa genes (p < 0.001), and more than two sa genes were significantly different (p z 0.002), thus suggesting the direct involvement of sas in the development of ks. despite the direct and indirect evidence supporting the hypothesis that ks is an infectious disease, only "susceptible" subjects seem to develop it and genetics seem to play a role in selecting the patients. ks occurs throughout the world, but is significantly more common in some asian countries, such as japan, korea and taiwan. it has been reported that the annual incidence of ks in japan in 2009 and 2010 was respectively 206.2 and 239.6 per 100,000 children aged 0e4 years 58 ; on the contrary, a recent analysis found that the 2009 ks-related hospitalisation rate in the usa was 19 per 100,000 children aged <5 years, 59 and even lower incidence rates have been calculated for a number of european countries. 60e63 theoretically, various factors could explain this large difference. the incidence of ks is rapidly increasing throughout the world, and so surveys carried out at different times may lead to different results. moreover, although ks is significantly more frequent in younger children than in older children, adolescents or adults, its frequency in younger patients also varies. a comparison of the incidence of ks in northern european and japan found that 86.4% of the japanese patients were aged <5 years, but 67.8% of the cases diagnosed in norway, finland, sweden and denmark (p < 0.001). 63 the incidence of ks in different regions may be affected by differences in surveillance methods, clinical diagnostic and treatment practices, physician awareness of ks, and the occurrences of ks clusters or outbreaks. however, a global evaluation of all these factors suggests that they are unlikely to be the only reason for such a striking difference. furthermore, american studies have clearly shown ethnicity-related variations in the incidence of ks: in comparison with white subjects, the incidence is twice as high among asians and pacific islanders, and about 1.5 times higher among black subjects. 64 similarly, its incidence in hawaii (the state with the highest proportion of asians and pacific islanders) is 2.5 times higher than that reported for the continental usa. 65 it has also been reported that the incidence of ks is 6e10 times higher among the siblings of ks patients than in the general population, 66 and that children with ks are more likely to have parents who have had the disease. 67 it has been calculated that the inheritability of ks (i.e. the ratio of the incidence of ks between siblings and the general population) is only slightly less than that of type 1 diabetes and about four times more than that of allergic asthma. 68 all of the above findings strongly suggest that genetic factors play a substantial role in the occurrence of ks, but studies of the genetic characteristics of ks patients have not definitively identified which genetic marker(s) may favour or protect humans from developing of ks, or regulate its clinical severity. several candidate genes, mainly chosen among those related to innate and acquired immunity, cardiovascular function, and vascular remodelling, have been tested in patients with ks (table 3 ). 69e117 results were frequently negative or conflicting, particularly when the studies enrolled a limited number of patients and were carried out in populations with significant racial differences that impact the allele frequency of some of the single nucleotide polymorphisms (snps) analysed in the studies. good example at this regard are the data collected on the role of matrix metalloproteinases (mmps), fc gamma receptors (fcgr) and of cd40 ligand snps in conditioning susceptibility, evolution and outcome of ks. mmps play an important role in processes that degrade extracellular matrices. their activity is controlled by specific inhibitors (timps) and imbalances between mmps and timps are associated with several pathological conditions, including vascular aneurysm. association of increased mmp9/timp2 and mmp3/ timp1 ratios with risk of coronary artery lesions was found in japanese children. 95 on the contrary, no association was found between snp of mmp-3 in the korean population. 96 debated is also the role of cd40l, a transmembrane protein that engages with cd40 and transduces signals related to cell activation and development because a strict association between snps and development and severity of ks was demonstrated in the japanese patients 77 but not in the taiwanese population. 78 however, in some studies more convincing results were found particularly when they could evidence that the same polymorphisms were present in populations with different racial characteristics. onouchi et al. reported that multiple variants in the caspase-3 gene (casp3) that were in linkage disequilibrium conferred susceptibility to ks in both japanese and us subjects of european ancestry. 73 these authors found that a g to a substitution of one commonly associated snp located in the 5 0 untranslated region of casp3 (rs72689236; p z 4.2 â 10 à8 in the japanese and p z 3.7 â 10 à3 in the european americans) abolished binding of nuclear factor of activated t cells to the dna sequence surrounding the snp suggesting that altered casp3 expression in immune effecter cells influences susceptibility to ks. interesting results were also reported by shimizu et al. that investigated genetic variation in 15 genes belonging to the tgf-b pathway in a total of 771 kd subjects of mainly european descent from the united states, the united kingdom, australia, and the netherlands. 101 genetic variants in tgfb2, tgfbr2, and smad3 and their haplotypes were consistently and reproducibly associated with ks susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. a smad3 haplotype associated with ks susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (a/g, rs4776338; p z 0.000022; or, 1.50; 95% ci, 1.25e1.81). pathway analysis using all 15 genes further confirmed the importance of the tgf-b pathway in ks pathogenesis. because similar data regarding susceptibility were reported by kuo et al. 102 it was concluded that genetic polymorphisms in tgfb signalling pathway are strictly associated with the risk of development of ks. however, more reliable results have been obtained using genome-wide association studies (gwas) because genome scanning without a defined hypothesis has the advantage of identifying disease genes even if the functions of these genes are not associated with previous knowledge about the disease's pathophysiology. even in this case, the most important results were those repeatedly reported in different populations. by linkage disequilibrium mapping performed on the region of chromosome 19q13.2, it was found that an snp within the inositol 1, 4, 5-trisphosphonate 3-kinase c (itpkc) gene, a gene that regulates the signal transduction in t lymphocytes and the degree of inflammatory response, was associated with increased susceptibility to ks and with the development of coronary artery in both a japanese and a usa population. 111 further data confirming the relationships between genetics and ks were collected by burgner et al.. 112 these authors conducted a gwas with dutch ks cases and controls and followed up associations signals with a family-based association study of ks families from australia, usa, and uk. they reported that snps in intron 3 of n-acetylated a-acidic dipeptidase-like 2 (naaladl2), a protein possibly involved in immune homeostasis, were associated with ks (p z 1.13 â 10 à6 ) and that mrna expression of the same protein in erythrocytes was significantly lower in the acute phase of ks than in the convalescence period. 107 the presence of a predisposing genetic system favouring the development of ks and regulating its severity was confirmed by the study of kim et al., 113 korean ks patients and 600 healthy controls, and found that 18 genomic regions with one or more sequence variants were associated with ks, and 26 were associated with coronary artery lesions (cals) (p < 1 â 10 à5 ). an snp within the disabled homologue 1 (dab1) gene locus in chromosome 1 (rs527409) was replicated in 266 children with ks and 600 114 the most strongly associated snps detected in the joint analysis corresponded to three novel loci. among kd-associated snps, three were close to the copb2 (coatomer protein complex beta-2 subunit) gene: rs1873668 (p z 9.52 â 10 à5 ), rs4243399 (p z 9.93 â 10 à5 ), and rs16849083 (p z 9.93 â 10 à5 ). moreover, an snp in the intronic region of the erap1 (endoplasmic reticulum amino peptidase 1) gene (rs149481, p z 4.61 â 10 à5 ) and six snps (rs17113284, rs8005468, rs10129255, rs2007467, rs10150241, and rs12590667) clustered in an area containing immunoglobulin heavy chain variable regions genes, with p-values between 2.08 â 10 à5 and 8.93 â 10 à6 , were also identified. because these kd candidates have been implicated in t cell receptor signalling, regulation of proinflammatory cytokines, as well as antibody-mediated immune responses, these findings strongly supported the relationships among genetics, alterations in immune response and development of ks. association of snps within the fcgr gene cluster on chromosome 1 with ks was identified by khor et al. in european and asian populations. 115 in a large study sample (2173 individuals with ks and 9383 controls) including european and asian populations, these authors found that two loci exceeded the formal threshold for genome-wide significance. the first was a functional polymorphism in the igg receptor gene fcgr2a encoding an h131r substitution (rs1801274; p z 7.35 â 10 à11 , or z 1.32), with the a allele (coding for histidine) leading to a high risk of disease. the second was at 19q13 (p z 2.51 â 10 à9 , or z 1.42 for the rs2233152 snp near mia and rab4b; p z 1.68 â 10 à12 , or z 1.52 for rs28493229 in itpkc ), thus confirming the data previously with previous studies. 79 the involvement of the fcgr2a locus may have implications for understanding immune activation in ks pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease. more recently, japanese and taiwanese groups independently reported a significant association between ks and polymorphisms in the intergenic region on chromosome 8p23-p22 between b lymphoid kinase (blk ), a tyrosine kinase involved in b-cell receptor signal transduction and fam167a, a functionally uncharacterized gene. 116, 117 onouchi et al. undertook a gwas involving 428 japanese individuals with ks and 3379 japanese controls genotyped at 473,803 snps. 116 they validated the results in two independent replication panels of 754 cases and 947 controls, and observed significant associations in the fam167a-blk region (rs2254546, p z 8.2 â 10 à21 ). similar results were obtained by lee et al. in 622 individuals with ks and 1107 controls in a han chinese population residing in taiwan, with replication in an independent han chinese sample of 261 cases and 550 controls. 117 they found that polymorphisms at blk gene together with genetic abnormalities at cd40, were associated with ks at genomewide significance (p < 5.5 â 10 à8 ) confirming the role of immune activation and inflammation in the pathogenesis of the syndrome. however, despite these findings, the correlations between genetic markers the risk of developing and severity of ks are far from clear. at the moment the most convincing evidences of a strict correlation between genetic abnormalities and ks regards polymorphisms of itpkc, fcgr, casp3 and tgfb genes. although various data suggest that ks is an infectionrelated clinical syndrome that can only develop in children with predisposing genetic backgrounds, our knowledge of the infectious agent(s) involved and the genetic characteristics of susceptible children is still unsatisfactory. either viruses or bacteria could act as disease, but no specific infectious agent can be considered the definite cause of ks, and so no specific anti-infective therapy can be developed. moreover, although potential genetic determinants have been hypothesised in subjects with ks, none of them can yet be considered real markers of disease susceptibility. consequently, the pathogenesis of ks is only partially known and measures to prevent it remain elusive. further studies are needed to address the many still open questions concerning this still enigmatic disease. a new infantile acute febrile mucocutaneous lymph node syndrome (mlns) prevailing in japan current recommendations for the pharmacological therapy in kawasaki syndrome and management of its cardiovascular complications kawasaki syndrome: an intriguing disease with numerous unsolved dilemmas diagnosis, treatment, and long-term management of kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis, and kawasaki disease, council on cardiovascular disease in the young discrimination between incomplete and atypical kawasaki syndrome versus other febrile diseases in childhood: results from an international registry-based study kawasaki syndrome-like illness associated with infection caused by enterotoxin b-secreting staphylococcus aureus development of serum igm antibodies against superantigens of staphylococcus aureus and streptococcus pyogenes in kawasaki disease lack of association between kawasaki syndrome and infection with parvovirus b19, human herpesvirus 8, tt virus, gb virus c/hepatitis g virus or chlamydia pneumoniae emerging from obscurity: understanding pulmonary and extrapulmonary syndromes, pathogenesis and epidemiology of human mycoplasma pneumonia infections respiratory tract infections by mycoplasma pneumoniae in children: a review of diagnostic and therapeutic measures kawasaki disease with a concomitant primary epstein-barr virus infection adenovirus type 2 isolated from a patient with fatal kawasaki disease kawasaki disease and parvovirus b19 infection in an adult hiv-1-infected patient isolation of human herpesvirus-6 from an infant with kawasaki disease kawasaki disease associated with klebsiella pneumoniae bacteremia and parainfluenza type 3 virus infection kawasaki disease associated with measles virus infection in a monozygotic twin association of rotavirus infection with kawasaki syndrome concomitant dengue hemorrhagic fever with kawasaki disease kawasaki disease associated with chickenpox: report of two sibling cases kawasaki disease coincident with influenza a h1n1/09 infection kawasaki syndrome and concurrent coxsackie-virus b3 infection kawasaki disease in england: ethnicity, deprivation, and respiratory pathogens association between a novel human coronavirus and kawasaki disease detection of human bocavirus in children with kawasaki disease kawasaki disease and human bocavirus e potential association? human coronavirus-nl63 infection is not associated with acute kawasaki disease blinded case-control study of the relationship between human coronavirus nl63 and kawasaki syndrome kawasaki disease lacks association with human coronavirus nl63 and human bocavirus impact of human bocavirus on children and their families infections and kawasaki disease: implications for coronary artery outcome concomitant respiratory viral infections in children with kawasaki disease kawasaki disease may be a hyperimmune reaction of genetically susceptible children to variants of normal environmental flora rna-containing cytoplasmic inclusion bodies in ciliated bronchial epithelium months to years after acute kawasaki disease ultrastructural, immunofluorescence, and rna evidence support the hypothesis of a "new" virus associated with kawasaki disease three linked vasculopathic processes characterize kawasaki disease: a light and transmission electron microscopic study epidemiology of kawasaki disease e a 30-year achievement. tokyo: shindan-to-chiryosha the male predominance in the incidence of infectious diseases in children: a postulated explanation for disparities in the literature genetic susceptibility to infectious diseases kawasaki disease: a brief history modelling seasonal variations in the age and incidence of kawasaki disease to explore possible infectious aetiologies relationship of climate, ethnicity and socioeconomic status to kawasaki disease in san diego county association of kawasaki disease with tropospheric wind patterns infectious disease: blowing in the wind cardiac sequelae of kawasaki disease among recurrent cases superantigen: structureefunction relationships superantigen-induced regulatory t cells in vivo the role of superantigens of group a streptococcus and staphylococcus aureus in kawasaki disease tcr vb family repertoire and t cell activation markers in kawasaki disease characterization of cd4þ t helper cells in patients with kawasaki disease (kd): preferential production of tumor necrosis factoralpha (tnf-a) by vb2_ or vb8_ cd4þ t helper cells the absence of evidence of staphylococcal toxin involvement in the pathogenesis of kawasaki disease serologic evidence that streptococcal superantigens are not involved in the pathogenesis of kawasaki disease prevalence of superantigen-secreting bacteria in patients with kawasaki disease association of psoriasis-like eruption and kawasaki disease analysis of t-cell receptor v-beta 2 in peripheral blood lymphocytes as a diagnostic marker for kawasaki disease selective increase of v beta 2 þ t cells in the small intestinal mucosa in kawasaki disease t cell activation profiles in kawasaki syndrome detection of multiple superantigen genes in stools of patients with kawasaki disease epidemiologic features of kawasaki disease in japan: results of the 2009e2010 nationwide survey epidemiology of kawasaki disease in asia, europe, and the united states rising incidence of kawasaki disease in england: analysis of hospital admission data kawasaki syndrome hospitalizations in ireland increased detection rate of kawasaki disease using new diagnostic algorithm, including early use of echocardiography incidence of kawasaki disease in northern european countries hospitalizations for kawasaki syndrome among children in the united states racial/ethnic differences in the incidence of kawasaki syndrome among children in hawaii kawasaki disease in families kawasaki disease in parents and children the value of isolated populations in genetic studies of allergic disease high incidence of angiotensin i converting enzyme genotype ii in kawasaki disease patients with coronary aneurysm polymorphism of angiotensin-1converting enzyme gene and kawasaki disease insertion/deletion polymorphism of angiotensin converting enzyme gene in kawasaki disease possible synergic effect of angiotensin-i converting enzyme gene insertion/deletion polymorphism and angiotensin-ii type-1 receptor 1166a/c gene polymorphism on ischemic heart disease in patients with kawasaki disease common variants in casp3 confer susceptibility to kawasaki disease genetic variations in the receptor-ligand pair ccr5 and ccl3l1 are important determinants of susceptibility to kawasaki disease the ccr5 (-2135c/t) polymorphism may be associated with the development of kawasaki disease in korean children polymorphisms in chemokine receptor genes and susceptibility to kawasaki disease genetic polymorphisms in the cd40 ligand gene and kawasaki disease inflammatory gene polymorphisms and susceptibility to kawasaki disease and its arterial sequelae polymorphism of fc gamma riia may affect the efficacy of gamma-globulin therapy in kawasaki disease the involvement of fc gamma receptor gene polymorphisms in kawasaki disease association of il-1ra gene polymorphism, but no association of il-1beta and il-4 gene polymorphisms, with kawasaki disease the -590 c/t and 8375 a/g interleukin-4 polymorphisms are not associated with kawasaki disease in taiwanese children interleukin 6 gene promoter polymorphism is not associated with kawasaki disease the il-10 (-627 a/c) promoter polymorphism may be associated with coronary aneurysms and low serum albumin in korean children with kawasaki disease influence of interleukin 18 promoter polymorphisms in susceptibility to kawasaki disease in taiwan inducible and endothelial constitutive nitric oxide synthase gene polymorphisms in kawasaki disease increased frequency of alleles associated with elevated tumor necrosis factor-alpha levels in children with kawasaki disease association of mannose-binding lectin genotype with cardiovascular abnormalities in kawasaki disease polymorphisms in the mannose-binding lectin gene as determinants of age-defined risk of coronary artery lesions in kawasaki disease modulating effects of mannose binding lectin genotype on arterial stiffness in children after kawasaki disease monocyte chemoattractant protein 1 gene regulatory region polymorphism and serum levels of monocyte chemoattractant protein 1 in japanese patients with kawasaki disease polymorphism of transmembrane region of mica gene and kawasaki disease circulating matrix metalloproteinases and their inhibitors in patients with kawasaki disease polymorphism of matrix metalloproteinase-3 promoter gene as a risk factor for coronary artery lesions in kawasaki disease genetic analysis of mmp gene polymorphisms in patients with kawasaki disease association of the matrix metalloproteinase-3 (-439c/g) promoter polymorphism with kawasaki disease in korean children methylenetetrahydrofolate reductase polymorphism in kawasaki disease a polymorphism in plasma platelet-activating factor acetylhydrolase is involved in resistance to immunoglobulin treatment in kawasaki disease polymorphism of slc11a1 (formerly nramp1) gene confers susceptibility to kawasaki disease transforming growth factor-beta signaling pathway in patients with kawasaki disease polymorphisms of transforming growth factor-b signaling pathway and kawasaki disease in the taiwanese population tissue inhibitor of metalloproteinase 2 and coronary artery lesions in kawasaki disease analysis of tumor necrosis factor-alpha production and polymorphisms of the tumor necrosis factor-alpha gene in individuals with a history of kawasaki disease association between levels of tnf-alpha and tnf-alpha promoter -308 a/a polymorphism in children with kawasaki disease tumor necrosis factor-alpha levels and promoter polymorphism in patients with kawasaki disease in korea association of vascular endothelial growth factor (vegf) and vegf receptor gene polymorphisms with coronary artery lesions of kawasaki disease vascular endothelial growth factor gene haplotypes in kawasaki disease association of vascular endothelial growth factor c-634 g polymorphism in taiwanese children with kawasaki disease lack of association of the vascular endothelial growth factor gene polymorphisms with kawasaki disease in taiwanese children itpkc functional polymorphism associated with kawasaki disease susceptibility and formation of coronary artery aneurysms a genome-wide association study identifies novel and functionally related susceptibility loci for kawasaki disease a genome-wide association analysis reveals 1p31 and 2p13.3 as susceptibility loci for kawasaki disease identification of novel susceptibility loci for kawasaki disease in a han chinese population by a genome-wide association study genome-wide association study identifies fcgr2a as a susceptibility locus for kawasaki disease a genome-wide association study identifies three new risk loci for kawasaki disease two new susceptibility loci for kawasaki disease identified through genome-wide association analysis this review was supported by a grant from the italian ministry of health (bando giovani ricercatori 2007). the authors have no potential conflict of interest to declare. key: cord-286607-5i406twr authors: esposito, susanna; polinori, ilaria; rigante, donato title: the gut microbiota-host partnership as a potential driver of kawasaki syndrome date: 2019-04-05 journal: front pediatr doi: 10.3389/fped.2019.00124 sha: doc_id: 286607 cord_uid: 5i406twr kawasaki syndrome (ks) is a necrotizing vasculitis of smalland medium-sized vessels mostly affecting children under 5 years of age; a host of clinical and epidemiological data supports the notion that ks might result from an infectious disease. however, many efforts have failed to identify a potentially universal trigger of ks. the contribution of the intestinal microbial community—called the “microbiota”—to ks has been evaluated by an increasing number of studies, though limited to small cohorts of patients. differences in the microbiota composition were found in children with ks, both its acute and non-acute phase, with abnormal colonization by streptococcus species in the intestinal tract and a wider presence of gram-positive cocci in jejunal biopsies. in particular, a higher number of gram-positive cocci (of the genera streptococcus and staphylococcus), eubacterium, peptostreptococcus, and hsp60-producing gram-negative microbes have been found in the stools of ks children, and their effects on the antigenic repertoire of specific t cells and vβ2 t cell expansion have been assessed. conversely, lactobacilli were lacking in most children with ks compared with other febrile illnesses and healthy controls. all studies available to date have confirmed that an imbalance in the gut microbiota might indirectly interfere with the normal function of innate and adaptive immunity, and that variable microbiota interactions with environmental factors, mainly infectious agents, might selectively drive the development of ks in genetically susceptible children. further investigations of the intestinal microflora in larger cohorts of ks patients will provide clues to disentangle the pathogenesis of this disease and probably indicate disease-modifying agents or more rational ks-specific therapies. the most insidious primary vasculitis in childhood is kawasaki syndrome (ks), an acute multi-systemic illness which predominantly affects children under 5 years of age (1) . currently, this disorder of unknown etiology remains the main cause of acquired heart disease among children living in developed countries, where rheumatic fever has been surpassed (2, 3) . this condition was originally called "mucocutaneous lymph node syndrome" by dr. tomisaku kawasaki, who was its discoverer, and was thought to be a benign children's disease; nowadays, the illness has been described worldwide in children of every ethnicity following the presence of fever persisting (at least) 5 days together with (at least) 4 of the 5 following signs: bilateral conjunctival injection, oropharyngeal inflammation, abnormalities of hands and feet, polymorphous exanthema, and non-purulent cervical lymphadenopathy, usually unilateral (4) . several years after the first description, fatalities occurred among children with ks younger than 2 years living in japan, prompting clinicians to reconsider ks's long-term risks related to systemic and necrotizing effects on the vascular endothelium of small-and medium-sized arteries, which have been acknowledged in all guidelines related to the management of ks (5, 6) . the most relevant sequelae of ks include variable degrees of damage within coronary arteries in combination with angina, myocardial infarction, ischemic cardiomyopathy, and sudden death; these complications should be preventable with a timely treatment of high-dose intravenous immunoglobulin (ivig), which is the recommended therapeutic strategy in ks (7) . higher acute phase reactants and younger age at onset of ks are nodal points in determining, respectively, a failure in the response to ivig and an increased occurrence of coronary artery abnormalities (8) . the prediction of ivig resistance is also crucial in ks patients, as recognizing these high-risk children should consent to start an intensified treatment protocol combined with ivig to prevent coronary injuries (9) . ks incidence varies widely among different ethnic groups; for instance, in the united kingdom it has stabilized and remains low at 2.8 per 100,000 population under the age of 20 years. however, general practitioners should be aware that the condition occurs throughout childhood and across the seasons, and-given the potential cardiovascular sequelae-ks should be considered in all children with persistent fever, even in older children and adolescents (10) . ks is most prominently recognized in japan, korea, and taiwan, reflecting increased genetic susceptibility among asian populations. a recent study reported an incidence of ∼240 per 100,000 children under 4 years of age in japan (11) . there is still much controversy about the etiology of ks, though epidemiologic and clinical data suggest that ks might originate from an abnormal response to undisclosed infectious diseases in genetically susceptible children (12) . there is no agreement whether ks-related infectious agents are of viral, bacterial or fungal origin (13) , and the underlying immune mechanisms behind ks have not been completely highlighted, remaining only partially known. the absence of a proven unambiguous cause of ks has induced the scientific community to pay attention to other environmental hypothetical triggers, and in particular the composition of the resident intestinal flora as a potential contributor to ks has been evaluated by different research groups. the main aim of this review was to analyze the relationship between the microbial community, or the "microbiota, " and the overall impact of bacterial or viral infections in the potential development of ks. scientific papers have been searched from the electronic databases of pubmed until january 2019; the retrieving words were "kawasaki disease, " "kawasaki syndrome, " "microbiota, " and "microbiome"; additional reports were identified and analyzed through the specific references cited in the retrieved papers. only papers published in english and those showing evidence-based data were included in our evaluation. the microbiota, a microbial community of trillions of microorganisms and at least 1,000 different bacterial species, some eukaryotic fungi and viruses, and which covers every surface of the human body, plays a contributory role in many infections, immune-mediated disorders, rheumatologic diseases, and disorders of the nervous system. the microbiome, on the other hand, is the collection of the whole genome sequences of those microorganisms, consisting of more than 5,000,000 genes (14, 15) . in particular, the gut microbiota is strictly linked to the chronological age of each individual and modulates host physiology and metabolism through different mechanisms. each stage of human life is characterized by a specific intestinal microbial composition: the microbiota that initially colonizes the fetus' intestinal tube consists of aerobic organisms such as enterococcus and streptococcus, is then gradually replaced by anaerobes such as bifidobacterium and lactobacillus and finally reaches the adult composition dominated by bacteroides and firmicutes (16, 17) . the fetal microbiota is prone to be conditioned by the type of delivery; the mother's vaginal flora is a relevant source of lactobacillus, prevotella, and bifidobacterium. conversely, a cesarean delivery delays contact with these species, producing a similar-to-skin flora, dominated by staphylococci (18) . the feeding regimens and food supplements also play a role in modifying the resident flora; a greater complexity is normally seen in infants fed with formula, rather than in breastfed babies who have an "adult-like" structured microbiota with a population rich with bifidobacteria, lactobacilli, and bacteroides (18). the infant gut microbiota is variable in composition over time and highly changeable during the first year of life, being influenced by specific bacteria to which a baby happens to be exposed, as shown by the resemblance of infants' stool microbial community with mothers' milk and vaginal samples (19) . thereafter, the infant's intestinal tract progresses toward an extremely dense colonization, ending with a mixture of microbes that is broadly very similar to an adult's intestine. during adulthood, the gut microbiota becomes stable and this intestinal homeostasis remains in equilibrium with the host. food habits influence the composition of the whole intestinal microbiota, as testified by the lower prevalence of bacteroides in those suffering from malnutrition and by different microbiota changes occurring in children with diet-related diseases, such as allergies and obesity (19) . arumugam et al. identified three distinct enterotypes, namely bacteroides, prevotella, and ruminococcus, which reflect many individual alimentary profiles: bacteroides correlates to a highfat or high-protein regimen, whereas prevotella is associated with higher consumption of fibers and simple sugars (20) . more recent data have consented to unify bacteroides and ruminococcus enterotypes due to the large similarity between the two (21) . it is well-established that early events of birth, environmental factors during infancy, sex hormones, diet, body weight, and use of antibiotics can undoubtedly differentiate the composition of the microbiota (22, 23) . there are no ideal culture methods to give us a real overview of the complete intestinal flora, though molecular methods, e.g., dna microarrays with comprehensive coverage of most bacterial taxa represented in the available database of small subunit ribosomal rna gene sequences, should allow the characterization of most taxonomic groups of the intestinal bacteria (24, 25) . the ancient symbiosis between the human gastrointestinal tract and its resident microbiota involves diverse reciprocal interactions between the microbiota itself and the host, with relevant consequences for human health and physiology. the quality of the microbial flora has an impact on the maintenance of health and also on prevention of diseases. indeed, there are numerous roles carried out by the intestinal ecosystem, as the stimulation of angiogenesis, control of host fat storage and protection against other pathogens. in particular, the microbiota influences the formation and progress of regulation of both innate and adaptive immunity in close interaction with the intestinal mucosal immune system. the intestinal mucosa may be considered as an immunological niche as it hosts a complex immune-functional organ comprised by t cell subpopulations, neutrophils, macrophage-dendritic cells, enterocytes (that possess tight intercellular junctions) and their related anti-and pro-inflammatory cytokines as well as several other mediators of inflammation or antimicrobial peptides, defensins, and secretory immunoglobulin a (iga) (26) . the intestinal microbiota may also have direct or indirect effects on the natural course of viral infections, interacting with viral particles and leading to differences in either pathogenicity or anti-viral immune response through recruitment and activation of several t cell subpopulations (18) . a large amount of data has also depicted the relevance of gut microbiota-immune system cross-talk in several diseases, and indeed an "imbalance" of the intestinal flora has been shown in patients with atopic diseases and various noninfectious diseases, including metabolic disorders, chronic inflammatory bowel disease (ibd), irritable bowel syndrome, pancreatic diseases, atherosclerosis, and rheumatoid arthritis (27, 28) . furthermore, the gut microbiota, interacting with pattern recognition receptors (prrs), signaling receptors that can recognize molecular structures of pathogens and activate the cascade of innate immunity, plays a crucial role in maintaining the homeostasis of the innate immunity responses in the gut, and leaks in the intestinal mucosal barrier lead to the translocation of bacterial products into portal circulation which promotes systemic inflammation (29) . in addition, the microbiota can maintain a segregation between intestinal mucosa and bacteria via prrs, though pathogens might usurp innate signals to their advantage (30) . several immunologic, metabolic and nutritional processes are normally controlled by the intestinal microbiota, and changes in the local microbial communities have been linked to chronic low-grade inflammation (31) . alexander et al. demonstrated that the microbiota has specific effects on adaptive immunity, such as the induction of regulatory effector cd4+ cells and production of cytokines and antimicrobial factors, influencing the individual response to various environmental stimuli, as seen in ibd, crohn's disease and ulcerative colitis (32) . in a recent work, schwiertz et al. have shown microbiota changes characterized by decreased numbers of faecalibacterium praunsitzii and increased numbers of escherichia coli in ibd (33) . additionally, in celiac disease de palma et al. have described a difference in the microbiota composition with a reduction of bifidobacterium, clostridium histolyticum, clostridium lituseburense, faecalibacterium prausnitzii, and an abundance of bacteroides and prevotella strains (34) . a significantly higher biodiversity in coeliac children's duodenal mucosa was demonstrated by schippa et al. who also highlighted that the possible pathophysiological role of such microbial differences needs further characterization (35) . in addition, many immune phenomena were shown to deteriorate under the effect of changes in the microbiota, as revealed by the correlation among intestinal bacterial overgrowth, increased permeability, and development of non-alcoholic steatohepatitis (36) . much interest has also been paid to the role of the microbiome in the development of "sterile" inflammation, and recent studies have proved that either depletion of the microbiota or changes in the diet and in the gut microbiome might lead to the improvement of inflammasome-mediated manifestations of autoinflammatory disorders, which are caused by dysregulation of specific components of innate immunity (37) . these diseases can be subdivided into monogenic and multifactorial disorders, with the former being caused by mutations of genes involved in the regulation of the innate immune system and the latter by a combination of genetic background and environmental factors (38) (39) (40) . given the evidence for the role of the intestinal microbiota in the inflammatory state of ibd, atopic diseases and numerous non-infectious diseases, it has been speculated that intestinal microbial agents might also play a trigger role in the development of other inflammatory disorders which do not have a clearly defined etiology, such as ks. the etiology of ks remains obscure, although clinical and epidemiological features suggest a primary infectious cause. indeed, a self-limited and generally nonrecurring illness that manifests itself by fever, rash, mucositis, conjunctival injection, and cervical adenopathy fits well with an infection. more precisely, clinical features of ks resemble some peculiar infectious diseases, such as streptococcal infections, staphylococcal toxic shock syndrome, and atypical measles (12, 13) . additionally, age distribution, winter-spring seasonality, high rates of ks in siblings, and occurrence of community outbreaks are suggestive of a transmissible childhood disease, though many efforts with conventional bacterial and viral cultures and serological methods as well as animal inoculation studies have failed to identify a final unique infectious agent of ks (41) . reported non-infectious factors associated with ks include carpet shampoo, preexisting eczema, environmental pollution, and house dust mites (42) . the higher incidence of ks in asian populations, presence of familial clustering, and elevated risk of recurrence vs. the risk of a first episode in ks-naïve children are all strong evidence of a genetic contribution to ks susceptibility, probably in association with an infectious trigger (43, 44) . however, ks does not appear easily transmittable and does not respond to any antibiotics: these characteristics should contradict a primitively infectious pathogenesis of the illness. the most current theory about the pathogenesis of ks is that the disease results from an exaggerated immune response toward environmental stimuli occurring in a genetically susceptible child (13) . the prominent role played by the immune system in ks is confirmed by the high number of studies revealing the activation of neutrophils and multiple immune cells with overproduction of pro-inflammatory cytokines, including tumor necrosis factor (tnf)-α (45, 46) . manlhiot et al. have very recently proposed a new pathogenetic model of ks in which the disease risk is determined by concurrent interacting processes: genetic susceptibility, habitual exposure to allergens, atmospheric biological particles, and infectious agents (47) . a study exploring the immune responses during the acute phase of ks showed increased levels of lipopolysaccharide (lps) bound to the surfaces of circulating neutrophils via cd14 receptor and found markedly increased levels of the soluble cd14 in the plasma (48) . furthermore, chen et al. (49) demonstrated that nlrp3 inflammasome activation is associated with the development of coronary arteritis in a mouse model of ks, and that infusion of visfatin, a major injurious adipokine, can activate nlrp3 inflammasome and increase interleukin (il)-1 production, leading to enhanced endothelial dysfunction. these novel molecular mechanisms of vasculitis mediated by inflammasome activation open more specifically the road to innate immunity pathways in the interpretation of ks (49, 50) . unchallengeable proof that an infection is the starting point of ks is not available. different epidemiologic studies have supported this hypothesis, based on documented infections by various microorganisms in many cases of ks. further clues are the occurrence of ks in epidemics, higher incidence during spring and winter and early age at which the disease might be acquired, that is 6 months to 5 years (5). striking perturbations of many immune pathways occur during the acute phase of ks, which determines a multi-cytokine cascade in the vascular endothelium with focal disruption of small-and mediumsized vessels. however, the exact key steps leading to coronary arteritis are still far from being clarified, though endothelial cell activation; prolonged start-up of neutrophils, cd68 + monocyte/macrophages and cd8 + lymphocytes; production of oxygen intermediates and lysosomal enzymes; and oligoclonal iga response by plasma cells all appear to be involved (45, 46, (51) (52) (53) . the contribution of viruses to ks has been suggested by ultrastructural studies which found cytoplasmic inclusion bodies containing rna of viral origin in the bronchial epithelia (54) as well as by studies revealing the detection of intracytoplasmic inclusion bodies containing viral proteins and nucleic acid aggregates (55, 56) . recent investigations have supported the hypothesis that immune responses in ks are oligoclonal rather than polyclonal (as found typically in superantigen-driven responses), and that iga plasma cells play a crucial role. indeed, higher levels of iga have been found in the vasculature of patients with previous ks, indicating an antigen-driven response against an etiologic agent which might have a respiratory or gastrointestinal portal of entry (57) . about half of all ks patients might have one or more respiratory viruses detected by polymerase chain reaction, without any particular predominance, but a positive respiratory viral test or presence of respiratory symptoms at the time of presentation should not be used to exclude the diagnosis of ks (58) . other studies have investigated a potential relationship of ks with coronaviruses, though without finding definite proof of cause and effect (59, 60) . many viruses have been suggested to be implicated in the pathogenesis of ks, such as adenovirus, parvovirus b19, rotavirus, h1n1 influenza virus, epstein-barr virus, herpesvirus 6, coxsackie b3 virus, parainfluenza virus type 3, measles virus, dengue virus, human immunodeficiency virus, and varicella-zoster virus, but no significant differences emerged from case-controlled studies (61) (62) (63) (64) (65) (66) (67) (68) (69) . one of the most difficult infections that are harder to distinguish from ks is caused by adenovirus, due to its frequent incidental detection in ks patients and frequent laboratory finding of increased inflammatory markers (70) . in particular, adenovirus has been detected in 8.8 and 25% of cases with complete and incomplete ks, respectively, by jaggi et al. (71) . there are reports that have emphasized the possible relationship of cytomegalovirus (in one child from turkey) and human bocavirus 1 (in a french cohort of 32 patients) with ks through serologic tests and molecular techniques, but this link might be only casual and misleading (72, 73) . regarding the bacterial origin of ks, it is debated if the infectious agents might be conventional bacteria or bacteria with superantigen activity. superantigens (sags) are the most powerful t cell mitogens ever discovered, with potent immunostimulatory actions that simultaneously activate the major histocompatibility complex class ii molecules and t cell receptors, leading to massive activation of various immune cells. matsubara et al. conducted a case-control study with a serological approach based on enzyme-linked immunosorbent assay and measured serum antibodies against staphylococcal enterotoxins, including tsst-1, and streptococcal pyrogenic exotoxin (spe), such as spe-a. they showed that ks patients had significant elevation of igm antibodies against one or more of five sags throughout the first to the fourth disease week (76) . in a further paper the same authors analyzed the studies regarding the role of sags produced by staphylococcus aureus and streptococcus pyogenes in the pathogenesis of ks, finding numerous sags implicated, which brought the total number of the known staphylococcal sags to over 20 and streptococcal sags to 12 (77) . the most recent work that analyzed the relationship between sags and ks examined different sag derived from streptococcus pyogenes in the stools of patients with ks. stool specimens were obtained from 36 patients with ks during the acute phase and 26 age-matched healthy children. the authors examined genes related to five sags-spe-a, spe-c, spe-g, spe-j, and tsst-1using polymerase chain reaction; throat and stool cultures were assessed to evaluate the presence of streptococcus pyogenes and staphylococcus aureus in ks patients. they reported that at least one of the sag-related genes was detected more frequently in the stools of children with ks (78). furthermore, among 358 patients with ks, 54 developed concurrent pneumonia and 12 of these (22.2%) had high titers of anti-mycoplasma pneumoniae antibody (>1:640), suggesting a potential role of mycoplasma pneumoniae in ks and the importance of anti-mycoplasma treatment (79) . another study has reported a possible role of fungal infections in the development of ks in japan, san diego, and the island of hawaii through an active role of tropospheric wind patterns leaving from central asia, in which toxins of candida species are aerosolized (80) . in addition, due to the observation that candida albicans-derived substances, such as candida albicans watersoluble fraction (caws), induce a coronary arteritis in mice similar to that observed in ks, sato et al. evaluated the role of a free-β-glucan diet on caws-induced vasculitis and found that quality of diet might affect the progression of systemic vasculitis (81) . caws should act as a pathogen-associated molecular pattern in mice and activate lectin pathway of complement by binding to mannose-binding lectin and inducing an acute inflammatory reaction in the vascular system (82, 83) . there are three main reasons that led us to postulate a role of the microbiota in ks. the first is the unsatisfactory microbiological data that limited the association between infections and ks and a lack of evidence of any clear relationship between one or more pathogens with this illness. second, the most frequent bacteria or viruses associated with ks have a higher prevalence in the overall pediatric population, but only a limited number of children will develop the disease. third, the association of genetic predisposition and environmental factors in the pathogenetic process of ks makes ks itself similar to other multifactorial diseases. currently, the majority of data has found that the composition of the gut microbiota in ks patients differs from healthy subjects. lee et al. have postulated that the immune system should lose tolerance toward a part of the resident intestinal flora and that environmental factors, i.e., a western lifestyle or improved public hygiene systems, could transform the commensal flora into a pathogen one, as observed in different gastrointestinal disorders (84) . a recent study about the resident flora and ks was focused on throat flora. horita et al. (85) assumed that throat flora could be a reservoir of microorganisms triggering ks and, following this hypothesis, they investigated throat microorganisms of ks patients for their content and individual sag activity. in particular, they collected throat swabs at the start of ivig infusion in 21 ks patients and compared them with non-ks controls (displaying other febrile illnesses). the results showed no difference in the throat flora between ks and febrile controls even in the mean mitogenic activity of bacteria isolated (85) . the gastrointestinal tract could be one of the primary sites of entry of bacterial toxins in children with ks, and a perturbation in the intestinal microbiota has been linked to the disease's pathophysiology in another study by yamashiro et al. (86) who investigated the microflora of the small intestine in 15 japanese patients with ks. the range of bacterial species isolated from jejunal biopsies was characterized by a wider variety of gram-positive cocci in the acute phase of ks. notably, 5 kinds of streptococci (streptococcus salivarius, streptococcus mitis, streptococcus oralis, streptococcus sangius, and gemella haemolysans) and 2 kinds of staphylococci (staphylococcus capitis and staphylococcus hyicus) were isolated only from ks patients, suggesting that some antigens inducing a delayed-type hypersensitivity reaction in the mucosa might inundate the body by breaching the barrier of the small intestinal mucosa of ks patients (86) . in fact, nagata et al. (87) investigated cell surface phenotypes of mononuclear cells and enterocytes in the jejunal mucosa of 16 japanese patients with ks and in 10 patients with diarrhea due to cow's milk protein intolerance. both hla-dr+cd3+ and dr+cd4+ cells were significantly increased, and cd8+ cells significantly reduced in the lamina propria of ks patients during the acute phase compared with patients with cow's milk protein intolerance. these cell patterns returned to normal in the convalescent phase of ks. the authors concluded that a delayed-type hypersensitivity reaction was indeed present in the small intestinal mucosa of ks patients (87) . due to the fact that the gastrointestinal tract is the largest interface between microbial factors and their host, containing the largest proportion of bacteria and the largest amount of lymphoid tissue in the body, it was hypothesized by eladawy et al. that the intestinal milieu could be altered in children with ks, and indeed ks patients have a higher incidence of gastrointestinal symptoms and complications (88) . specifically, takeshita et al. (89) evaluated 20 patients with ks, 20 patients with acute febrile diseases and 20 healthy children, finding that the incidence of lactobacilli isolated from ks patients (2/20, 10%) was significantly lower (p < 0.001) than in the other cohorts. moreover, no significant differences in the presence of staphylococcus, streptococcus, enterococcus, enterobacteriaceae, bifidobacterium, clostridium, veillonella, or bacteroides were found among the three groups. conversely, the presence of eubacterium and peptostreptococcus was significantly higher in ks patients than in patients with other febrile diseases (p < 0.01 and p < 0.05, respectively), though no significant differences were observed between ks patients and healthy children (89) . this observation confirmed that the majority of lactobacillus species are anti-inflammatory and beneficial for health, particularly during the first years of life, due to their action in protecting against colitis, reducing pro-inflammatory cytokines such as tnf-α, il-1, or il-6, and increasing the subsets of regulatory t cells (90) . in fact, several studies have largely described the specific action of lactobacilli in maintaining the epithelial homeostasis of the gut and their striking anti-inflammatory potential (91, 92) . nagata et al. (93) also studied the role of the gut microbiota in ks pathogenesis via sags and heat shock proteins (hsps) produced by gut bacteria: the authors evaluated sags and hsps released by microorganisms isolated from the jejunal mucosa of 19 children with ks compared with 15 age-matched healthy controls, identifying 13 strains of gram-negative microbes from patients with ks, which produced a large amount of hsp60, having the power to induce an over-secretion of proinflammatory cytokines. they also identified 18 strains of grampositive cocci with sag properties which induced the expansion of vβ2 t cells in vitro (93) . this microbiological analysis disclosed different causative bacteria with a final common pathway of immune activation, which might contribute to the final development of ks. in order to evaluate the differential microbiota composition of ks patients, kinumaki et al. (94) performed a metagenomic analysis using non-culture-based methods on feces. their study included 28 ks patients (15 males and 13 females, aged 1-114 months, with a median age of 25 months); the time of admission to the study was defined as the acute phase, while 4-6 months after the onset of ks was considered as the nonacute phase. the authors collected a total of 56 samples−28 samples each for both acute and non-acute phases. it was demonstrated that the genera ruminococcus, roseburia, and faecalibacterium were mostly predominant during the nonacute phase, while a higher presence of streptococcus spp., including streptococcus pneumoniae, pseudopneumoniae, mitis, oralis, gordonii, and sanguinis, was detected in the fecal samples during the acute phase (94) . this novel interpretation of a disease can be shared by other conditions, as liver cirrhosis and sjögren syndrome, in which major changes of gut microbiota with higher proportions of streptococcus spp. have been demonstrated (95, 96) . these findings taken as a whole suggest that many other immune-mediated disorders are likely to be connected to an abnormal bacterial colonization of the intestinal tract, with a main role for streptococcus spp., and that changes in the gut microflora composition might promote systemic and extra-intestinal inflammation. therefore, all presented studies confirm the concept that an imbalance in the gut microbiota might directly or indirectly interfere with the normal functions of the immune system, and that the interaction with other environmental factors, mainly infectious agents, might lead to the final development of ks. table 1 shows the characteristics of the microbiota in children with ks, as emerging by the most relevant studies dedicated to this issue. as no etiologic agent has ever been accused of being directly involved in the etiology of ks, basic research evaluating the pathogenic mechanisms of this disease will probably provide better therapies and probably consent to identify the most vulnerable hosts and protect them. a potential relationship between eubiosis and the protean functions of immunity has been contemplated by different studies, and conversely a relationship should exist between dysbiosis and immunity dysfunction shown by various diseases (97) . it is strengthened that heterogeneity and abnormalities in the intestinal microflora composition may trigger or contribute to the development of specific diseases, and an increasing amount of research and microbiologic observations have led to a role of the intestinal microbiota for ks to be postulated. while we are becoming convinced that a role of the microbiota is likely, we do not know exactly the basic mechanism of how the microbiota should act. the principal obstacle of today's medical literature is to understand if the microbiota modification during ks can cause the disease or if it is a mark and a consequence of the disease itself, and if modulating the microbiota/microbiome might represent a future target of therapy in ks. this raises the hypothesis of targeting intestinal microflora in order to restore eubiosis through the rational use of antibiotics, xenobiotics, probiotics and nutrients. while multicenter trials and registries may allow us to improve the general outcome of ks, further in-depth analysis in larger cohorts of affected children will probably unravel the tangled pathogenesis of this mysterious disorder and find new targets for identifying disease-modifying agents or more specific therapies. se, ip, and dr contributed to all stages of the preparation of this manuscript, including conception and writing. all authors approved the final submitted version of the manuscript. viral infections associated with kawasaki disease epidemiology, clinical presentation, and outcomes of kawasaki disease among hospitalized children in an inner city hospital before and after publication of the american academy of pediatrics/american heart association 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induced by c. albicans water-soluble mannoprotein-beta-glucan complex (caws) induction of coronary arteritis with administration of caws (candida albicans water-soluble fraction) depending on mouse strains kawasaki disease may be a hyperimmune reaction of genetically susceptible children to variants of normal environmental flora the throat flora and its mitogenic activity in patients with kawasaki disease microbiologic studies on the small intestine in kawasaki disease immunohistochemical studies on small intestinal mucosa in kawasakidisease kawasaki disease and the pediatric gastroenterologist: a diagnostic challenge characteristic role of intestinal microflora in kawasaki disease the starting lineup: key microbial players in intestinal immunity and homeostasis anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by nod2-mediated recognition of a specific peptidoglycan-derived muropeptide anti-inflammatory effect of lactobacillus casei on shigellainfected human intestinal epithelial cells heat shock proteins and superantigenic properties of bacteria from the gastrointestinal tract of patients with kawasaki disease characterization of the gut microbiota of kawasaki disease patients by metagenomic analysis altered mucosal microbiome diversity and disease severity in sjögren syndrome alterations of the human gut microbiome in liver cirrhosis eubiosis and dysbiosis: the two sides of the microbiota key: cord-261058-yu2qw02l authors: burgner, david; harnden, anthony title: kawasaki disease: what is the epidemiology telling us about the etiology? date: 2005-06-03 journal: int j infect dis doi: 10.1016/j.ijid.2005.03.002 sha: doc_id: 261058 cord_uid: yu2qw02l kawasaki disease (kd) is an important and common inflammatory vasculitis of early childhood with a striking predilection for the coronary arteries. it is the predominant cause of paediatric acquired heart disease in developed countries. despite 40 years of research, the aetiology of kd remains unknown and consequently there is no diagnostic test and treatment is non-specific and sub-optimal. the consensus is that kd is due to one or more widely distributed infectious agent(s), which evoke an abnormal immunological response in genetically susceptible individuals. the epidemiology of kd has been extensively investigated in many populations and provides much of the supporting evidence for the consensus regarding etiology. these epidemiological data are reviewed here, in the context of the etiopathogenesis. it is suggested that these data provide additional clues regarding the cause of kd and may account for some of the continuing controversies in the field. kawasaki disease; vasculitis; genetics; epidemiology; inflammation summary kawasaki disease (kd) is an important and common inflammatory vasculitis of early childhood with a striking predilection for the coronary arteries. it is the predominant cause of paediatric acquired heart disease in developed countries. despite 40 years of research, the aetiology of kd remains unknown and consequently there is no diagnostic test and treatment is non-specific and sub-optimal. the consensus is that kd is due to one or more widely distributed infectious agent(s), which evoke an abnormal immunological response in genetically susceptible individuals. the epidemiology of kd has been extensively investigated in many populations and provides much of the supporting evidence for the consensus regarding etiology. these epidemiological data are reviewed here, in the context of the etiopathogenesis. it is suggested that these data provide additional clues regarding the cause of kd and may account for some of the continuing controversies in the field. # 2005 international society for infectious diseases. published by elsevier ltd. all rights reserved. no predefined order and some may even be absent on presentation. in many children the clinical presentation is striking and kd patients are often misdiagnosed with severe sepsis. however, kd can have similar clinical features to other common childhood illnesses, such as measles, rubella and scarlet fever. these children may present a diagnostic challenge 6 and the lack of a specific diagnostic test may delay treatment and thus worsen prognosis. 7 moreover, to confuse the clinical picture further, there is increasing concern that the diagnostic criteria are too narrow. 'atypical' or 'incomplete' kd is a description used for children presenting with the characteristic fever but fewer than four classical signs. a better descriptive term is 'incomplete kd' because these children do not demonstrate atypical signs, just fewer of them. cervical lymphadenopathy is the least commonly observed of the diagnostic criteria, occurring in about three quarters of usually older children, whilst prolonged fever and peripheral desquamation have been reported as the commonest diagnostic features. incomplete kd may be poorly recognised and occurs more often in infants. 8 children presenting with incomplete kd are at higher risk of developing coronary artery lesions both because of their young age and their potential for not receiving timely immunoglobulin treatment. 8 interestingly, as many as 10% of the children reported in the original report of the syndrome 2 would not fulfil the current case definition. 3 the clinical diagnostic criteria need refinement to increase their positive predictive value and recent guidelines have been developed in an attempt to increase the sensitivity of the clinical diagnosis. 5 it is unclear how these will perform in clinical practice. although these guidelines are intended only as a clinical tool, they are likely to have an impact on the reported epidemiology of kd. kawasaki disease is clearly not the benign childhood exanthem initially proposed 1,2 and has significant long-term implications. kawasaki disease is the most common cause of paediatric acquired heart disease in the world. 3 coronary artery lesions (predominantly aneurysms) occur in up to 30% of untreated and 5-10% of treated children; 1, 9, 10 the poor outcome despite adequate treatment reflects an incomplete understanding of the etiopathogenesis. acute mortality in kd is increased significantly, with deaths predominantly occurring from myocardial infarction following occlusion of giant coronary aneurysms. 11, 12 overall, myocardial infarction occurs in 2% of those with coronary artery lesions. 13 lifelong medical therapy, coronary artery grafting and even heart transplantation may be required. 1 crucially, in children without coronary artery lesions who die of other causes, the coronary arteries are almost invariably markedly abnormal, with striking pro-atherosclerotic changes. 14, 15 abnormal in vivo function in non-coronary arteries 16 suggests that cardiovascular damage post-kd is both pervasive and persistent, even in the absence of acute coronary artery lesions. thus, there is intense speculation that kd is pro-atherosclerotic, but definitive long-term data are lacking. regressed coronary artery lesions result in abnormal coronary artery function 17 and histological changes that are pro-atherosclerotic. 15, 18 the similarities between kd and adult cardiovascular pathology suggest that kd may be a useful paradigm for investigating the etiopathogenesis of atherosclerosis. 19 does kawasaki disease represent an extreme phenotype of a more pervasive phenomenon? it is possible that kd is not a distinct entity, but the more clinically obvious end of a spectrum of pathogenic processes. kd may therefore reflect an extreme clinical phenotype where childhood infections predispose to subsequent endothelial damage and cardiovascular pathology. thus in genetically susceptible children, acute infections such as those causing fever and rash, may result in unrecognised damage to the cardiovascular system that later manifests itself as adult cardiovascular disease. adult atherosclerotic disease (like kd) has not been reliably associated with a single infectious etiology, but correlates with overall infectious burden. 20 furthermore, acute childhood infections are accompanied by pro-atherosclerotic phenomena and subsequent thickening of the arterial intima. 21 understanding the etiopathogenesis of kd may therefore identify common gene-environment interactions that are involved in adult cardiovascular disease. why is it important to understand the etiology and pathogenesis of kawasaki disease? the timely diagnosis of kd is essential in maximising the prevention of overt coronary damage; treatment beyond ten days of onset is associated with a worse outcome and an increased incidence of coronary abnormalities. 22, 23 the lack of a specific diagnostic test and the limited clinical utility of the current clinical diagnostic criteria mean that the diagnosis is often delayed, even in populations where the condition is well recognised. 24 the currently accepted best treatment (intravenous immunoglobulin and aspirin (table 2) 6 fails to prevent coronary artery abnormalities (identifiable by imaging) in up to 10% of cases. 25 specific diagnostic test(s) and rational interventions could be readily developed if the etiopathogenesis of kd was fully understood. moreover, preventative treatments such as vaccines would be justified in populations with the highest kd incidence, where kd affects 1-2% of all children, such as korea and japan. 3 the consensus view is that kd results from a widely distributed infectious agent (or possibly agents) that causes the clinical syndrome in genetically susceptible children. much of the supporting data for this viewpoint is provided by epidemiological studies in a variety of populations. kd is described in all ethnic groups, but the incidence varies dramatically (see below). the homogeneity of the clinical phenotype and epidemiology suggest that kd arises from common disease processes, although the antigenic trigger(s) and/or the genetic determinants may differ between populations. kawasaki disease shows a striking age distribution reminiscent of other childhood infections. over 80% of cases occur between the ages of six months and four years, 26 although the condition occurs rarely both earlier 27 and later 28 in life. the low incidence of kd in both the first six months suggests that most infants are protected by passively acquired maternal antibody against the causative agent(s). a transient immunological immaturity may also account for the low incidence in the first few months postnatally. 29 the low incidence of kd beyond mid-childhood suggest a ubiquitous antigen(s) that most children encounter uneventfully in early childhood and to which they mount an appropriate and protective immune response. kawasaki disease is more common in boys (male:female ratio 1.6:1) 1 a feature observed in many infectious diseases 30, 31 and also in coronary atherosclerosis, where sex differences in immune responses are suggested to mediate susceptibility. 32 seasonal variation in kd incidence is well recognised, but the predominant season varies in different countries. in the uk, 33 australia 24 and the usa 34,35 kd is most common in winter and spring. in china, spring and summer predominate 36 and in korea kd incidence is highest in summer months. 37 in japan, which reports the highest kd incidence, table 2 treatment of kawasaki disease (for detailed discussion of the treatment of kawasaki disease see references 5,6,97 ). at a dose of 2 g/kg given as a single infusion over 10-12 hours (unless cardiac status necessitates infusing the dose more slowly or in divided doses). failure to respond to this initial ivig dose is usually treated with a second dose (usually 2 g/kg as a single infusion). failure to respond to the second ivig dose is often treated with intravenous methylprednisolone under expert supervision the dose of aspirin is controversial and its utility has never been proven in a randomised controlled trial. it remains, however, part of the standard management of kd. generally 'high dose' aspirin (50-100 mg/kg/day in divided doses) is given acutely until the fever defervesces, when 'low dose' aspirin (2-5 mg/kg/day) is given until an echocardiogram at six weeks after the kd diagnosis is normal. if the six week echocardiogram is abnormal, aspirin is usually continued under cardiological supervision anti-cytokine therapies and other interventions are generally unproven but have occasionally been used. for a review see newburger and fullton 5 the seasonal variation is less marked. 38 one possible explanation for these divergent data is that season is a marker for weather conditions that have a more direct role in determining the incidence. in the us, kd incidence clearly correlates negatively with average ambient temperature and positively with average rainfall in the preceding month. 39 studies are underway investigating similar parameters in the uk. it is unknown whether the meteorological conditions themselves predispose to kd, or, more plausibly, if they alter the epidemiology of etiological agents. the lack of consistent seasonal associations in different countries raises the possibility that various etiological agents may be involved in the etiology of kd. geographical clustering of kd cases and epidemics have been reported from a number of countries, 40-44 although they have been much less frequently reported in the past decade, possibly suggesting a changing epidemiology. in japan, which has provided the most comprehensive epidemiological data, epidemics of kd have been described with a clear epicentre and documented geographical spread across the whole nation within six months. 42 these epidemiological data clearly indicate an infectious etiology for kd. the clinical features of the disease are also characteristic of a severe acute childhood infection. it seems likely that the causative agents are widely distributed and are also highly immunogenic, at least in most children, as more than one episode of kd is rare. recurrent kd is reported in 1-3% of children, 45 although it appears less common in caucasians. 46 it may reflect a specific immunological deficiency in these children or exposure to more than one causative agent. 3 various environmental causes of kd have been repeatedly suggested (table 3) , but none has been consistently replicated. however, the possibility of environmental factors influencing etiology, possibly by modulating infection risk, remains a possibility. the search for a single unifying microbiological cause has been unrelenting but, to date, fruitless. standard microbiological techniques, molecular methods and serological investigations have so far failed to identify an etiological agent. molecular techniques fail to detect circulating conserved microbial sequences in kd, 47 indicating that the antigenic stimulus may arise from a distant site (e.g. colonising pathogens in the nasopharynx) and/or may represent host-derived factor(s) that induce or promote the pro-inflammatory cascade. the list of discarded and/or unproven etiological agents in kd is long (table 3) . a recent report of an association between the presence of genetic material from a novel coronavirus and kawasaki disease in a handful of cases 48 remains unproven and may reflect an epiphenomenon; the putative etiological agent is a relatively common viral pathogen in young children and it is unclear how long the dna persists. the lack of a unifying etiological agent despite a significant research effort suggests that kd can follow exposure to more than one infectious agent, or that a novel infectious agent is involved. alternatively the clinical phenotype may reflect a stereotyped response in a genetically-susceptible host to one of a variety of infectious agents. much of the continuing debate in the literature concerns whether kd is caused by a superantigen 49 or a conventional antigen. 50 kd shares many clinical features with superantigen-mediated diseases (for example, rash, conjunctivitis and skin peeling) and kd has occasionally been reported concurrently in children with toxic-shock syndrome, which is caused by superantigens. 51 however, unequivocal epidemiological and laboratory support for a role for superantigens in kd is lacking. in one small study, maternal antibodies against toxic shock syndrome toxin-1 appeared protective against early-onset kd. 52 however, the carriage rates of superantigen-producing bacteria by children with kd are not consistently increased, 53, 54 although these data may reflect the involvement of as yet unidentified 188 d. burgner, a. harnden superantigens, with more than one superantigen capable of causing kd. superantigens bind to the vb region of the t-cell receptor and clonal expansion of vb2-expressing t-cells has been reported in some studies of kd, 55 but again the finding is inconsistent. 56 other studies have reported oligoclonal igaproducing plasma cells infiltrating bronchial and intestinal tissues in fatal kd, 57 which suggests the involvement of a conventional antigen. much of the controversy and inconsistency surrounding the nature of the infectious trigger in kd might reflect multiple etiological agents resulting in the same clinical phenotype. it is possible, for example, that a viral upper respiratory tract infection may alter local immunity and allow elaboration of superantigens by colonising bacteria in the nasopharynx. certainly the epidemiology of kd, with rapid changes in incidence, seasonal variation and the relationship between incidence and weather conditions is more redolent of acute viral infections 58,59 than bacterial colonisation, which alters more slowly. 60 in meningococcal disease, influenza infection acts in an analogous way, and meningococcal epidemics often follow influenza outbreaks. 61, 62 this hypothesis could be addressed through large detailed prospective epidemiological studies. another possibility is that either pathogen or host factors modulate the behaviour of an antigen, so that it behaves both as a conventional antigen and as a superantigen. heat shock proteins are increased in acute inflammatory conditions, including kd 63 and cross-reactivity with certain heat shock proteins is thought to be responsible for the inflammation of the bcg scar in kd. 64 heat shock proteins have been reported to alter the behaviour of superantigens, so that the immune system recognises them as conventional antigens 65 and also can greatly up-regulate pro-inflammatory responses to conventional antigens. 66 the possibility of endogenous stimuli that profoundly suppress or enhance antigenic effects has not previously been considered in kd, but might account for much of the controversy surrounding the roles of conventional or superantigens. whatever the etiological trigger(s) for kd, there is clear evidence that host genetic determinants play a major role in both susceptibility and probably outcome in kd. genetic studies of kd are therefore likely to be highly informative about etiology and pathogenesis. although kd is reported in all ethnic groups, the variation in incidence of kd between (and to a lesser extent within) countries is striking. the annual incidence varies from approximately three (per 100,000 children <5 years of age) in south america, to four in australia, 24 eight in the uk, 33 4-15 in the us, 1 20-30 in china 36 and hong kong 67 50 in taiwan, 68 90 in korea 37 and >130 in japan 69 the reported incidence is probably underestimated in many countries as atypical cases are not included. australian data (burgner et al., unpublished) suggest an incidence 50% higher than that recorded through active surveillance. 24 in a number of countries the incidence of kd appears to be increasing. 33, 68, 69 whilst this may be partly attributable to increased awareness, the increasing incidence is reported in countries where the disease has been widely recognised for several years and where a standard case definition is employed and may therefore reflect changing epidemiology. the incidence of kd is therefore greatest in north-east asians, especially in koreans and japanese. it is estimated that 1-2% of all hospitalised korean children have kd (park yw, personal communication) and that kd affects one in 150 japanese children. 3 this indicates genetic factors may be central in determining susceptibility, especially as the incidence rate remains high in those migrating to lower incidence countries. for example, the incidence of kd in japanese americans in hawaii (135/100,000 <5 years) is identical to the highest rates reported from japanese living in japan. 67 the incidence rate in siblings of affected children is 10-15 fold higher than the population incidence in japan. 70 the ratio of sibling to population incidence is termed the 'heritability' or 'l s '. sibling rates outside japan are unknown, but reports from caucasians support this trend 71 and sibling rates in korea 37 (burgner, unpublished observations) also support this high heritability. this figure is slightly less than the heritability for insulin-dependent diabetes (l s 15) and 4 times higher than that of asthma, 72 suggesting a striking genetic predisposition to develop the disease in a minority of children across different ethnic groups. in addition, the incidence of previous kd in parents of japanese children with kd is significantly increased and these families are much more likely to have other affected children and children with recurrent disease. 73 taken together, these epidemiological data provide convincing evidence for a major role for host genetics in kd susceptibility. whilst there are concerns that cardiovascular damage may be pervasive in kd, overt coronary artery lesions only develop in a minority of children. in acute kd all arms of the innate and adaptive immune response are activated, but lymphocytes, macrophages and neutrophils are central. 74 the extent and kinetics of host inflammation strongly correlates with the risk of coronary damage. the duration of fever prior to treatment, 75-77 the maximal erythrocyte sedimentation rate, 78 the extent of pro-inflammatory cytokine production 79, 80 and the degree of neutrophil activation 81 have all been shown to be risk factors for coronary damage. the extent of the host inflammatory response is partly genetically determined. 82 genetic factors are therefore likely to be important in determining outcome in kd and genetic studies may identify key pathogenic mediators and ultimately guide the development of new interventions. kawasaki disease is likely to be a genetically 'complex disease', with contributions from a number of genetic loci to susceptibility and outcome. associations between genetic variants at candidate loci and kd susceptibility and outcome may be extremely informative about the role of specific mediators in etiopathogenesis, allowing investigation of hypotheses suggested by the clinical data, but untestable by conventional clinical or laboratory studies. the consensus view supports the concept of a genetically-susceptible host in kd 6, 83 and there is growing realisation that immunogenetic studies may reveal much about the disease and improve diagnosis, treatment and prognosis. immunogenetic data suggest a number of plausible associations. many studies focus on putative downstream outcome determinants and suggest a role for mediators of innate inflammation, 84 endothelial activation 85 and cardiovascular homeostasis. 86 studies of susceptibility determinants are more limited. there are associations with class i regions of the human leucocyte antigen (hla) in japanese, 87 with different alleles associated in caucasians. 88 however, these hla studies are largely historical and further work using modern hla typing techniques are warranted. unfortunately, genetic studies of kd have often been undermined by methodological problems 89 that dog many such studies of human complex disease. thus some of the reported associations are likely to be false positive results. in particular, the studies often lack statistical power, employ multiple uncorrected statistical comparisons and many do not replicate findings in an independent population. 87, 88, [90] [91] [92] case-control methodology in a multi-ethnic disease may yield spurious disease associations (type i errors) due to population admixture, 93 unless this is actively identified. 94 inadequate marker density in candidate loci, where the functional variants are unknown, may increase type ii errors. 89 kawasaki disease is a fascinating and important paediatric illness, which presents a significant diagnostic challenge. it is the most common cause of heart disease acquired in childhood and an important paradigm for understanding the determinants of adult cardiovascular pathology. the epidemiology is well characterised and clearly supports the view that the disease results from an inappropriate immunological response to one or more infectious triggers in genetically-susceptible individuals. the search for the microbial etiology has been disappointing and unsuccessful and all that remains of over three decades of such studies is a 'long list of discarded pathogens'. 3 understanding the genetic determinants of susceptibility to kd and those involved in mediating coronary artery damage may be a more profitable approach. the methodological issues that have undermined genetic analyses can be largely overcome by international collaborative studies that employ standardised phenotypic definitions and large sample sizes derived from different ethnic groups. the use of familybased genetic association analyses 95 circumvents the problems of population stratification and the use of trans-racial mapping (i.e. investigating genetic determinants in different ethnic groups) 96 may prove important to defining the critical genetic determinants, particularly in regions of high linkage disequilibrium. newer molecular techniques, particularly gene expression profiling and proteomics may identify novel molecular 'fingerprints' that differentiate kd from other febrile and inflammatory illnesses. 3 the mystery of kd may ultimately be solved by looking within the host. kawasaki disease: a brief history acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children (japanese) kawasaki syndrome kawasaki disease characterized by erythema and induration at the bacillus calmette-guerin and purified protein derivative inoculation sites kawasaki disease kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research effects of gamma-globulin on the cardiac sequelae of kawasaki disease incomplete (atypical) kawasaki disease fate of coronary aneurysms in kawasaki disease: serial coronary angiography and long-term followup study cardiovascular involvement in kawasaki disease: evaluation and natural history mortality among patients with a history of kawasaki disease: the third look. the kawasaki disease follow-up group clinical spectrum of kawasaki disease in infants younger than 6 months of age long-term consequences of kawasaki disease. a 10-to 21-year follow-up study of 594 patients with special reference to the heart and coronary arterial lesions pathological study of postcoronary arteritis in adolescents and young adults: with reference to the relationship between sequelae of kawasaki disease and atherosclerosis endothelial dysfunction late after kawasaki disease long term consequences of regressed coronary aneurysms after kawasaki disease: vascular wall morphology and function noninvasive assessment of the early progression of atherosclerosis in adolescents with kawasaki disease and coronary artery lesions kawasaki disease-from a mystery to a paradigm impact of infectious burden on extent and long-term prognosis of atherosclerosis acute infections in children are accompanied by oxidative modification of ldl and decrease of hdl cholesterol, and are followed by thickening of carotid intima-media a single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute kawasaki syndrome the treatment of kawasaki syndrome with intravenous gamma globulin kawasaki disease in australia, 1993-95 immunoglobulin failure and retreatment in 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results of 12 nationwide epidemiological incidence surveys of kawasaki disease in japan relationship of climate, ethnicity and socioeconomic status to kawasaki disease in san diego county possible ''outbreak'' of kawasaki disease in victoria temporal and geographical clustering of kawasaki disease in japan nationwide epidemic of kawasaki disease in japan during winter of 1985-86 epidemiologic study of kawasaki disease in korea an epidemic of kawasaki syndrome in hawaii cardiac sequelae of kawasaki disease among recurrent cases recurrent kawasaki disease search for highly conserved viral and bacterial nucleic acid sequences corresponding to an etiologic agent of kawasaki disease association between a novel human coronavirus and kawasaki disease superantigens: microbial agents that corrupt immunity superantigens, conventional antigens and the etiology of kawasaki syndrome kawasaki disease and toxic shock syndrome --at last the etiology is clear? maternal antibody against toxic shock syndrome toxin-1 may protect infants younger than 6 months of age from developing kawasaki syndrome prevalence of superantigen-secreting bacteria in patients with kawasaki disease chips with everything: dna microarrays in infectious diseases evidence for a superantigen mediated process in kawasaki disease characterization of the t-cell receptor v-beta repertoire in kawasaki disease detection of antigen in bronchial epithelium and macrophages in acute kawasaki disease by use of synthetic antibody seasonal trends of viral respiratory tract infections in the tropics epidemiology of respiratory viral infection among paediatric inpatients over a six-year period in north-east england the nasopharyngeal bacterial flora in infancy: effects of age, gender, season, viral upper respiratory tract infection and sleeping position outbreak of meningococcal disease after an influenza b epidemic at a hellenic air force recruit training center influenza a and meningococcal disease increased expression of human 63-kd heat shock protein gene in kawasaki disease determined by quantitative reverse transcription-polymerase chain reaction t cells recognize an immunodominant epitope of heat shock protein 65 in kawasaki disease a toxic shock syndrome toxin-1 peptide that shows homology to amino acids 180-193 of mycobacterial heat shock protein 65 is presented as conventional antigen human heat shock protein 60 induces maturation of dendritic cells versus a th1-promoting phenotype summary and abstracts of the seventh international kawasaki disease symposium surveillance of kawasaki disease in taiwan and review of the literature physical and psychosocial health in children who have had kawasaki disease kawasaki disease in families kawasaki disease in siblings the value of isolated populations in genetic studies of allergic diseases kawasaki disease in parents and children kawasaki syndrome kawasaki disease: review of risk factors for coronary aneurysms coronary risks after high-dose gamma-globulin in children with kawasaki disease clinical relevance of the risk factors for coronary artery inflammation in kawasaki disease coronary artery involvement in kawasaki syndrome in manhattan cytokines predict coronary aneurysm formation in kawasaki disease patients raised serum interleukin 15 levels in kawasaki disease urinary neopterin as a predictive marker of coronary artery abnormalities in kawasaki syndrome genetic influence on cytokine production and fatal meningococcal disease kawasaki disease: the mystery continues increased frequency of alleles associated with elevated tumor necrosis factor-alpha levels in children with kawasaki disease high incidence of angiotensin i converting enzyme genotype ii in kawasaki disease patients with coronary aneurysm methylenetetrahydrofolate reductase polymorphism in kawasaki disease hla antigens in kawasaki disease hla antigens in mucocutaneous lymph node syndrome in new england problems of reporting genetic associations with complex outcomes the hla class ii region and susceptibility to kawasaki disease polymorphism of transmembrane region of mica gene and kawasaki disease polymorphism of slc11a1 (formerly nramp1) gene confers susceptibility to kawasaki disease mapping disease genes: family-based association studies control of confounding of genetic associations in stratified populations the tdt and other family-based tests for linkage disequilibrium and association identification of susceptibility loci for insulindependent diabetes mellitus by trans-racial gene mapping the diagnosis and management of kawasaki disease adenovirus infection in patients with kawasaki disease could a herpesvirus be the cause of kawasaki disease? mycoplasma infection and kawasaki disease probable role of streptococcus pyogenes in kawasaki disease serologic evidence that streptococcal superantigens are not involved in the pathogenesis of kawasaki disease variant streptococcus sanguis as an etiological agent of kawasaki disease toxic shock syndrome toxin-secreting staphylococcus aureus in kawasaki syndrome the absence of evidence of staphylococcal toxin involvement in the pathogenesis of kawasaki disease variant strain of propionibacterium acnes: a clue to the etiology of kawasaki disease pathogenicity of propionibacterium acnes isolated from kawasaki disease patients-cytopathogenic protein (cpp) isolated from p. acnes culture filtrates and measurement of the antibody against cpp positive ehrlichia canis serology in kawasaki disease ehrlichia chaffeensis and rochalimaea antibodies in kawasaki disease rickettsia-like bodies and splenitis in kawasaki disease failure to confirm the rickettsial etiology of mcls (kawasaki disease) epstein-barr virus genome-positive tubulointerstitial nephritis associated with kawasaki disease-like coronary aneurysms kawasaki disease, epstein-barr virus and coronary artery aneurysms kawasaki disease and epstein-barr virus the etiology of kawasaki disease: retrovirus? polymerase activity in lymphocyte culture supernatants from patients with kawasaki disease virus-like particles with reverse transcriptase activity associated with kawasaki disease a measles virus isolate from a child with kawasaki disease: sequence comparison with contemporaneous isolates from 'classical' cases isolation of measles virus from child with kawasaki disease demonstration of chlamydia pneumoniae in cardiovascular tissues from children with kawasaki disease is there an association between kawasaki disease and chlamydia pneumoniae failure to demonstrate chlamydia pneumoniae in cardiovascular tissue from children with kawasaki disease is kawasaki disease a variant of q fever? kawasaki disease in european adult associated with serological response to coxiella burneti role of house dust mites in kawasaki disease urine mercury levels in kawasaki disease rug shampoo and kawasaki disease association of rug shampooing and kawasaki disease clinical and epidemiologic characteristics of patients referred for evaluation of possible kawasaki disease. united states multicenter kawasaki disease study group the authors' kawasaki key: cord-269170-9f460xbq authors: kaneko, kazunari; akagawa, shohei; akagawa, yuko; kimata, takahisa; tsuji, shoji title: our evolving understanding of kawasaki disease pathogenesis: role of the gut microbiota date: 2020-07-24 journal: front immunol doi: 10.3389/fimmu.2020.01616 sha: doc_id: 269170 cord_uid: 9f460xbq kawasaki disease (kd) was first described by dr. tomisaku kawasaki in 1967. the etiology of kd has been studied comprehensively but remains largely unknown. the disease seems to result from the interplay of genetic and environmental susceptibility factors with infectious triggers, followed by a subsequent abnormal immune response characterized by increased levels of inflammatory cytokines and chemokines during the acute phase. evidence has mounted to suggest that an imbalance between t helper 17 cells (th17s) and regulatory t cells (tregs) is associated with aberrant immune responses in kd. recent advances in culture-independent techniques for detection and identification of intestinal commensal bacteria enabled the discovery that th17 and treg differentiation are regulated by short chain fatty acids (scfas), in particular butyrate, produced by the gut microbiota. this finding provided a mechanistic link between dysbiosis, defined as changes in the composition of the gut microbiota, and various inflammatory diseases. on this basis, we propose that dysbiosis, with reduced production of scfas leading to imbalances of th17s/tregs, could be involved in the etiology of kd. a pilot study supported this hypothesis, as only fecal concentrations of butyrate were significantly reduced in kd patients among scfas. this evolving perspective prompted us to undertake metagenomic analyses of bacterial dna from the feces of kd patients who were antibiotic-naïve at diagnosis. simultaneous measurements of th17s/tregs in peripheral blood and scfa concentrations in feces would provide valuable information regarding the association between dysbiosis and dysregulated immune responses in kd. kawasaki disease (kd), named after dr. tomisaku kawasaki deceased june 5th, 2020, mainly affects young children between the ages of 6 months and 4 years (1). kd is characterized by persistent fever, bilateral conjunctival congestion, changes of the lips and oral cavity, polymorphous exanthema, changes of peripheral extremities, and acute non-purulent cervical lymphadenopathy (2, 3) . although kd was originally reported to be self-limiting and benign (4) , it is now recognized as a systemic vasculitis with a specific predilection for forming coronary artery lesions. these develop in up to 25% of children with kd who are not treated with intravenous immunoglobulin (5) . coronary artery lesions associated with kd are the most common causes of pediatric heart disease in developed countries. the incidence of kd in the japanese population continues to increase and reached 330 cases per 100,000 children aged ≤4 years per year in 2015 (6) . despite extensive ongoing research into the etiology of kd, the underlying mechanisms of this enigmatic vasculitis are not fully understood (3, 7) . the current paradigm of kd pathogenesis is that the disease results from a pathologically amplified immune response against infectious agent(s) in a genetically and environmentally susceptible child (3) . this paradigm is based on the following observations. first, there is clinical overlap between kd and infectious diseases such as adenovirus and streptococcosis. second, seasonal clustering of kd in the winter and spring mimics that of several viral diseases (8) . third, temporal clusters of epidemics have been reported in japan, the us, canada, and finland (9) . moreover, an outbreak in japan began in tokyo and spread throughout the country over a period of 6 months (10). finally, low incidence in the first 3 months of life suggests at least partial protection from trans-placental antibodies (11) . the low incidence of kd in schoolchildren indicates a potential role of common antigen(s) that most children encounter uneventfully in early childhood and against which they mount an appropriate and protective immune response (12) . however, efforts to find a single unifying microbiological cause of kd have been, to date, unsuccessful. standard microbiological techniques, molecular methods and serological investigations have all failed to identify an etiological agent. it has long been held that infection by one or more widely distributed microorganism(s) might elicit dysregulated immune responses in genetically susceptible children resulting in kd. candidate pathogens include epstein-barr virus (13, 14) , human herpes virus (15), human immunodeficiency virus (16) , human adenovirus (17) (29) , and candida spp. (30) . candida albicans (c. albicans) has recently drawn attention, as administration of caws (water-soluble extracellular polysaccharide from culture supernatants of c. albicans) induces coronary arteritis similar to kd in mice (31) . several reports suggested that c. albicans plays an important role as an infectious trigger of kd (30, 32, 33) . considering the recent pandemic of coronavirus disease 2019 (covid-19), potential links between kd and covid-19 are also deserving of mention (34) (35) (36) (37) . clusters of children presenting with kd-like symptoms have been documented in the uk, us, france, and italy, and some of them were confirmed to have covid-19. it appears that hyperinflammation associated with covid-19 could act as primer for kd development in individuals having genetically or environmentally determined predisposition. however, the specific mechanism is not yet defined (34) . the higher incidence of kd in asian countries suggests a genetic predisposition for acquiring the disease (9) . increased risk in family members of kd patients in japanese populations (38) also hint at genetically determined susceptibility. recent advances have been made in identifying disease-susceptibility genes from genome-wide association studies. candidate genes contributing to kd susceptibility include b-lymphoid kinase (blk) (39) epidemiologic studies have extensively searched for environmental factors that may explain variation and seasonality in kd incidence. surveys from the us and japan have demonstrated that higher precipitation and lower temperatures were associated with higher incidence of kd (45, 46) . an investigation of the role of the early social environment in kd susceptibility in a japanese population found that higher household income, smaller family size, and urbanization were associated with increased kd incidence (47) . this study, however, did not find a significant association between absence of infectious exposures during early life and kd. the prominent role played by the immune system in kd has been confirmed by many studies demonstrating activation of neutrophils and other immune cells as well as overproduction of inflammatory cytokines and chemokines such as tumor necrosis factor-α, interleukin (il)-1, il-2, il-6, and il-8, and monocyte chemotactic protein-1 (3). levels of inflammatory cytokines and chemokines are reported to be elevated during the acute phase of kd. however, the mechanisms responsible for abnormal immune responses and overexpression of inflammatory cytokines remain unclear. several lines of evidence have revealed decreased numbers of regulatory t cells (tregs) and imbalances between t helper 17 cells (th17s) and tregs in acute kd (48) (49) (50) . jia et al. elegantly demonstrated that th17 proportions and cytokine (il-17, il-6, and il-23) levels were significantly increased, while treg proportions and expression of treg transcription factors (e.g., foxp3) were significantly decreased in patients with acute kd (49) . they concluded that th17 expansion and treg depletion were characteristic of acute kd. furthermore, recent studies suggested that treatment efficacy was associated with decreased th17 proportions and increased treg proportions, with both returning closer to a normal range (48, 51) . thus, th17/treg imbalances may contribute to exaggerated immune responses in kd patients. growing evidence suggests that disturbances within intestinal communities of commensal bacteria may lead to illness through aberrant immune system development. while the study of gut microbiology related to human health has a centennial history, recent technological advances have enabled us to explore this field in a more sophisticated manner. current approaches rely primarily on culture-independent methods such as amplification of conserved regions of the 16s rrna gene present in all bacteria (52) . studies using these techniques have demonstrated that an adult humans harbor 100 trillion gut bacteria comprising more than 1,000 different species and approximately 160 species per person per fecal sample (53) . development of the gut microbiota, defined as its colonization by microorganisms, might begin not at birth but in utero. however, the existence of viable bacteria in the womb was recently questioned (54) (55) (56) . the maternal microbiota provides the first microbial inoculum, and from birth, microbial diversity increases and converges toward an adultlike microbiome within the first 3-5 years of life (53) . the composition of the microbiota in childhood depends on various factors including sanitation, mode of delivery, maturity at birth, infant diet, antibiotic use during infancy, immunizations, and environmental factors such as geography or diet (52, 53, 57, 58) . ethnic and genetic factors may also give rise to dysbiosis (59, 60) . the factors that can alter the microbiome are being studied as potential drivers of changing trends in non-communicable diseases. dysbiosis, defined as changes in the composition of the gut microbiota, may be associated with several clinical conditions including obesity and metabolic diseases (61), cancer (62), autoimmune diseases (63), allergy (64), chronic inflammatory bowel diseases (65, 66) , chronic kidney diseases (67) , and autisticspectrum disorders (68) . we also found that dysbiosis was present in children with idiopathic nephrotic syndrome (69) . although research on the mechanism(s) through which dysbiosis impairs human health has just begun, regulation of the gut immune system by microbiota is believed to be involved. experiments with germ-free animals (deficient in commensal microbiota including gut microbiota) have demonstrated that microbial colonization promotes anatomical development of the intestinal epithelium, increases epithelial cell turnover rates, and initiates the maturation of gut-associated lymphoid tissue (70) . both tregs and th17s have received much attention in terms of their role in the gut immune system and its regulation by microbiota (71) . tregs were originally identified as cd4-positive, cd25-positive and foxp3-positive t cells that exerted inhibitory control over immune responses (72) , maintained tolerance to self-antigens, and prevented autoimmune disease (73) . there are several immunosuppressive mechanisms mediated by tregs, including secretion of immunosuppressive cytokines such as il-10 and tgf-β, functional modification or killing of antigenpresenting cells, and cell contact-dependent suppression via cytotoxic t-lymphocyte-associated protein 4 (72) . tregs mainly arise from naïve t cell precursors following stimulation by short chain fatty acids (scfas) such as acetate, propionate or butyrate produced by the gut microbiota (74, 75) . previous studies demonstrated that members of the genus clostridium were potent inducers of treg differentiation through butyrate production (76, 77) and that reduced luminal concentrations of scfas resulted in impaired development of intestinal tregs in germ-free mice (74, 76) . in these mice, reconstitution with commensal bacteria or administration of scfas, especially butyrate, restored treg frequency (76) , supporting the role of bacterial metabolites in treg development. therefore, it has been proposed that a decrease in the relative abundance of butyrateproducing microbes may disrupt mucosal immune homeostasis (78) . the gut microbiota also plays a crucial role in the induction of effector t cell responses in the intestine. th17s are a subtype of cd4-positive t cells specialized for mounting immune responses against fungi and some extracellular bacteria. in addition to il-17a, th17s produce il-17f, il-21, il-22, and il-26 (79) . because il-17 is a potent proinflammatory cytokine that amplifies ongoing inflammation, aberrant regulation of th17s contributes to development of inflammatory and autoimmune disorders. in germ-free mice, the number of th17s was markedly decreased. however, the th17 compartment was restored by reconstitution with conventional microbiota (80), thus indicating a crucial role for gut microbes in th17 development. among commensal bacteria, segmented filamentous bacteria (sfb) are one of the most potent inducers of th17s. colonization of mice by sfb causes abundant accumulation of th17s in the small intestine via enhanced production of serum amyloid a (81, 82) . the existence of human commensal bacteria equivalent to sfb in rodents is probable because mixtures of bacterial strains isolated from fecal samples ulcerative colitis patients could induce th17 development (81) . the gut, the largest interface between microbial factors and the host, contains the largest proportion of bacteria and the largest amount of lymphoid tissue in the body. thus, it was hypothesized that the intestinal environment might be reshaped in patients with kd. indeed, kd patients frequently exhibit gastrointestinal symptoms and complications (83) . the contribution of the gut microbiota to kd has been evaluated in limited numbers of small cohorts using culture-based methods. several studies have been performed to identify the causative microbial agent(s) of kd at disease onset. takeshita et al. showed that the gut microbiomes of kd patients were distinguished by a lack of lactobacilli during the acute phase (84), while nagata et al. isolated both hsp60-producing gram-negative bacteria and gram-positive cocci capable of inducing vβ2 t cell expansion from kd patients (85) . these results indicated that distinctive gut microbes might be involved in the pathophysiology of kd. however, because these studies of the microbiomes of kd patients were carried out using culture-based methods, microorganisms that cannot be cultured, which constitute more than half of the human gut microbiome, would have been overlooked. unlike culture methods, metagenomic analyses can reveal the composition of the intestinal microbiota irrespective of the ability to culture microbes. kinumaki of a metagenomic analysis of feces using culture-independent methods (86) . they collected 28 paired fecal samples from children with kd during the acute and non-acute phases and demonstrated that streptococcus spp., including s. pneumoniae, s. pseudopneumoniae, s. mitis, s. oralis, s. gordonii, and s. sanguinis, were more abundant during the acute phase while the genera ruminococcus, roseburia and faecalibacterium were less abundant. unfortunately, more than half of subjects were treated empirically with antibiotics during the early phase of kd when the fecal samples were collected because clinical and laboratory findings often do not fulfill the diagnostic criteria of kd (2), but are instead suggestive of bacterial infections (87) . as antibiotic administration rapidly perturbs the gut microbiota (88), these results may reflect the effects of antibiotic therapy on the gut microbiota and not dysbiosis associated with kd. here, we would like to focus on a novel viewpoint on the role of the gut microbiota in kd: dysbiosis, defined as changes in the composition of the gut microbiota and caused by various prenatal and postnatal factors that are not necessarily infectious agent(s), might contribute to genetically and environmentally determined predilection for kd. this perspective is illustrated in figure 1 and can be explained as follows: [1] various factors during the in utero and postnatal period drive dysbiosis in young children; [2] dysbiosis results in reduced intestinal production of scfas including butyrate; [3] reduced levels of scfas in the gut cause an imbalance of th17s/tregs; and [4] individuals with th17/treg imbalances develop hypercytokinemia triggered by ubiquitous infectious agents(s), followed by kd (figure 1) . recent observations revealed that viral respiratory infections may alter microbial growth in the gut leading to dysbiosis (89) . in addition, the gut microbiota has been shown to play an important role in regulating the generation of virus-specific cd4-positive and cd8-positive t cells and antibody responses following influenza virus infection (90) . therefore, we hypothesize that young children with dysbiosis are prone to a vicious cycle of hypercytokinemia following infection by viruses. this paradigm for the pathogenesis of kd contrasts with previous hypotheses, which focused on specific microorganisms, toxins, or pathogen-associated molecular patterns (91) (92) (93) . as butyrate has been reported to limit th17 differentiation and promote treg development (94) (95) (96) , we hypothesize that kd-associated dysbiosis might be characterized by lower abundance of butyrate-producing bacteria. interestingly, the genera roseburia and faecalibacterium, which were reported to be less abundant in patients with acute kd by kinumaki et al. (86) , are butyrate-producing bacteria (97, 98) . furthermore, the strong association between kd and allergic diseases (99) (100) (101) in which dysbiosis plays an important role (102) also supports this perspective. recent observations of a potential association between previous antibiotic therapy and development of kd also supports our hypothesis (103) . in this study, the median interval between the final dose of antibiotics and the onset of kd was 2.5 months, which was insufficient time for restoration of the gut microbiota and complete resolution of dysbiosis caused by antibiotic use (104) . to confirm our hypothesis, further investigations involving metagenomic analysis of bacterial dna from the feces of a larger number of antibiotic-naïve patients with kd is clearly needed. it would be worthwhile to compare the proportions of specific microbial species such as butyrate-producing bacteria. simultaneous analysis of th17/treg ratios in peripheral blood and measurement of fecal butyrate concentrations, reflecting the intestinal production of scfas, would also be helpful. we have just begun a project to test our hypothesis with approval from our institutional ethics committee (approval no. 2015127) and parental informed consent. fecal samples will be collected not only from kd patients and healthy children but also from controls with viral infections. this will allow us to specifically characterize dysbiosis in kd because recent observations suggested that viral infection itself may cause dysbiosis (89) . the results of our pilot study of four acute kd patients (median age 1.1 years, range 0.8-2.1 years; 3 boys and 1 girl) and four healthy children (median age 2.1 years, range 1.2-3.7 years, 3 boys and 1 girl) supports our perspective as fecal butyrate concentrations were significantly lower in kd patients (p < 0.05, mann-whitney u test). in contrast, fecal concentrations of acetate, lactate, and propionate did not differ between kd patients and healthy children (figure 2) . the kd patients studied had a median body mass index of 14.7 (range: 13.0-18.1), median maximal body temperatures of 39.0 • c (range: 38.0-39.7 • c), and median maximal c-reactive protein levels of 41 mg/l (range: 20-57 mg/l). all kd patients presented with typical clinical features and fulfilled the diagnostic criteria (2). none reported diarrhea or constipation and none received antibiotics. fecal samples were provided before intravenous immunoglobulin administration. no cases were complicated by coronary artery lesions. what factors perturb the gut microbiota and cause dysbiosis in young children? as shown in figure 1 , both prenatal and postnatal conditions affect the establishment of the intestinal microbiota in infancy. factors that influence the initial colonization of the gut by microbes include maternal factors such as the maternal gut microbiota, vaginal infection or periodontitis as well as postnatal factors such as cesarean delivery, formula feeding, excessive antibiotic use, host genetics, and the environment (105). interestingly, formula feeding (106) and social environment factors such as higher household income, smaller family size, and urbanization were associated with both increased risk of dysbiosis and increased kd incidence (47) . in addition, the peak age of kd onset ranging from 6 months to 4 years corresponds to the critical period for establishment of the gut microbiota during the first 1,000 days of life (107) . we believe that dysbiosis underlies kd and could contribute to genetically and environmentally determined predilections for kd. therefore, kd might be included in the growing list of dysbiosis-associated conditions. if our perspective is confirmed, it would be valuable to investigate whether supplying probiotics starting at birth could reduce the risk of kd in infancy. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. the studies involving human participants were reviewed and approved by ethics committee of kansai medical university. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. all authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. diagnosis, treatment, and long-term management of kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis, and kawasaki disease, council on cardiovascular disease in the young diagnosis of kawasaki disease kawasaki disease: an evolving paradigm acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children kawasaki syndrome nationwide epidemiologic survey of kawasaki disease in japan a framework for understanding kawasaki disease pathogenesis seasonality of kawasaki disease: a global perspective epidemiology of kawasaki disease in asia, 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population-based study in taiwan atopic diathesis in patients with kawasaki disease the role of gut microbiota in atopic asthma and allergy, implications in the understanding of disease pathogenesis previous antibiotic use and the development of kawasaki disease: a matched-pair casecontrol study the pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16s rrna sequencing the microbiome in early life: implications for health outcomes breastfeeding and risk of kawasaki disease: a nationwide longitudinal survey in japan shaping microbiota during the first 1000 days of life we thank edanz group (https://en-author-services.edanzgroup. com/) for editing a draft of this manuscript. 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 kaneko, akagawa, akagawa, kimata and tsuji. this is an openaccess 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-301160-7ik3iszp authors: lee, kyung-yil; rhim, jung-woo; kang, jin-han title: kawasaki disease: laboratory findings and an immunopathogenesis on the premise of a "protein homeostasis system" date: 2012-03-01 journal: yonsei med j doi: 10.3349/ymj.2012.53.2.262 sha: doc_id: 301160 cord_uid: 7ik3iszp kawasaki disease (kd) is a self-limited systemic inflammatory illness, and coronary artery lesions (cals) are a major complication determining the prognosis of the disease. epidemiologic studies in asian children suggest that the etiologic agent(s) of kd may be associated with environmental changes. laboratory findings are useful for the diagnosis of incomplete kd, and they can guide the next-step in treatment of initial intravenous immunoglobulin non-responders. cals seem to develop in the early stages of the disease before a peak in inflammation. therefore early treatment, before the peak in inflammation, is mandatory to reduce the risk of cal progression and severity of cals. the immunopathogenesis of kd is more likely that of acute rheumatic fever than scarlet fever. a hypothetical pathogenesis of kd is proposed under the premise of a "protein homeostasis system"; where innate and adaptive immune cells control pathogenic proteins that are toxic to host cells at a molecular level. after an infection of unknown kd pathogen(s), the pathogenic proteins produced from an unknown focus, spread and bind to endothelial cells of coronary arteries as main target cells. to control the action of pathogenic proteins and/or substances from the injured cells, immune cells are activated. initially, non-specific t cells and non-specific antibodies are involved in this reaction, while hyperactivated immune cells produce various cytokines, leading to a cytokine imbalance associated with further endothelial cell injury. after the emergence of specific t cells and specific antibodies against the pathogenic proteins, tissue injury ceases and a repair reaction begins with the immune cells. kawasaki disease (kd) is a self-limiting systemic inflammatory disease that occurs predominantly in children younger than 5 years of age. 1 clinical manifestations of kd include prolonged fever (1-2 weeks, mean 10-11 days), conjunctival injection, oral lesions, polymorphous skin rashes, extremity changes, and cervical lymphadenopathy, all of which comprise diagnostic criteria. in addition, arthritis, eters; thus, laboratory findings are helpful for diagnosing incomplete kd and evaluating patients for early prediction of ivig non-responsiveness. although some score systems for early detection of ivig non-responders with a higher risk of cals have been developed, 17, 18 further studies are needed for the early detection and proper treatment of initial ivig non-responders. in this article, a brief review of the epidemiologic, clinical and laboratory characteristics of kd, as well as the policy of our institution for initial ivig non-responders according to the changes in laboratory findings after ivig infusion are introduced. we also propose a new concept for the immunopathogenesis for kd under the premise of a "protein homeostasis system" of the host. since kd was first seen in the early 1960's in japan, 1 kd has been recognized worldwide. epidemiological studies in far east asian countries including japan, korea, taiwan and china have revealed that kd is a new disease with similar epidemiologic patterns in these countries; after the initial appearance of kd, the incidence of kd showed a gradual increase for a decade up to a nationwide occurrence (becoming an endemic disease), and then kd occurred everywhere with relatively constant but slowly growing rates. [19] [20] [21] the appearance and subsequent incidence of kd may be associated with the time of industrialization and westernization of these countries. 13 therefore, it could be postulated that in the past, kd (infantile polyarteritis nodosa) might have appeared in western countries around the beginning of the 20th century. throughout the past decade, kd has appeared in rapidly modernizing countries, including india, where kd is more prevalent in modernized cities of economically higher income. 22 environmental factors such as improved public hygiene or westernized lifestyles may be associated with the emergence and establishment of kd. in south korea, although yearly incidence rates show no remarkable spatial (geographical) and temporal (seasonal) differences, 19 recently, clinical features of kd seem to be changing to milder phenotypes with greater numbers of incomplete kd cases. 23 in children of other ethnicities, it was also reported that the clinical features of a disease in an outbreak seem to differ from previous outbreaks. 24, 25 these findings suggest that the etiology of kd may not be due to a single agent and raise aseptic meningitis, anterior uveitis, gall bladder hydrops, urethritis and lung involvement can be seen. 2 some more severely affected patients show cardiac complications, particularly coronary artery lesions (cals) such as aneurysms and ectasias, which develop in approximately one quarter of untreated children and 5-10% of intravenous immunoglobulin (ivig) treated children. 3, 4 these diverse systemic inflammations (mainly vasculitis) may be caused by inflammatory mediators with circulating immune cells (neutrophils, lymphocytes, natural killer cells and monocytes), and there may be various immune cell infiltrations in all affected pathologic lesions from affected lymph nodes to skin rashes. particularly, a larger number of t cells (more cd8 cells than cd4 cells), large mononuclear cells, macrophages and plasma cells, with a smaller number of neutrophils, are observed in various organ tissues of fatal cases of acute kd. [5] [6] [7] [8] in addition, peripheral blood analysis of acute kd patients showed t lymphocytopenia with depressed cd8 t cells, increased activated cd4 t cells and depressed cd4+cd25+ regulatory t cells. [9] [10] [11] these findings suggest that the majority of circulating t cells move to the pathologic lesions of various tissues in acute kd. therefore, circulating immune cells, especially t cells, control the inflammation of the majority of the affected regions of kd patients without sequelae, but they also may be involved in the progression of the disease, such as in the case of cals. epidemiological and clinical data suggest that kd is an immunological reaction to infectious triggers occurring in genetically susceptible children. although studies have provided hypothetical explanations for the pathogenesis of kd, the etiologic agents, the immunopathogenesis of the vasculitis, and the mechanism that underlies the predilection for coronary artery involvement in kd are largely unknown. 2, [11] [12] [13] [14] [15] [16] laboratory parameters are used for the diagnosis and evaluation of conditions of patients for any inflammatory disease. as for laboratory findings in kd, many inflammatory indices change throughout the disease process; elevated levels of c-reactive protein (crp), erythrocyte sedimentation rate (esr), leukocyte count with neutrophilia (lymphopenia), platelet count, alanine aminotransferase (alt), aspartate aminotransferase (ast) and other inflammation associated enzymes, as well as decreased levels of lymphocytes, albumin, hemoglobin, sodium, potassium and total cholesterol including high density lipoprotein cholesterol (hdl-cholesterol) have been detected. 2 the severity of inflammation in kd is reflected by inflammatory param-have been implicated. 15, 36 recently as a more precise genetic tool, a genome-wide linkage analysis and follow-up association study (genome-wide associated study) for the potential loci and genes of susceptibility to kd have also been performed in several countries. [37] [38] [39] [40] the results of the genetic studies may have some limitations resulting from small sample size, failure to replicate results in subsequent studies, and lack of precise phenotype of kd patients based on cal outcomes and response to ivig therapy. 36, 41 in japan, onouchi, et al. 37, 42 reported that the itpkc gene which is a negative regulator of t-cell activation was associated with kd susceptibility and an increased risk of cals. although the association of the itpkc gene in replication studies of other populations is controversial, 39, 40, 43 this finding suggests a relevant clue for the genetic study of kd in which immune reaction of t cells may have a crucial role in the immunopathogenesis of the disease. recently, the international kawasaki disease genetics consortium has been organized and has identified many candidate genes potentially related to inflammation, apoptosis and cardiovascular pathology. 38, 41 although susceptibility to kd is polygenic, further studies are necessary to determine relationships between the candidate genes and functional consequences that lead to kd or cals. the etiology of kd still remains unknown, despite great efforts to identify the cause for nearly a half a century. the epidemiological characteristics of kd are so unique that it is difficult to find a similar model among acute infectious disease, including newly introduced infectious diseases such as retrovirus infections (acquired immunodeficiency syndrome) or conventional infectious diseases. although many putative bacterial agents including superantigen producing bacteria, viral agents such as epstein-barr virus, retroviruses and coronaviruses, and other agents have been suggested, there was no proven single agent for kd. [44] [45] [46] [47] [48] [49] [50] given the epidemiological and clinical characteristics of kd, we previously postulated that etiologic agents were variants of normal flora produced by environmental changes. 13 the microscopic structures and genomic materials between a pathogen and its related flora are nearly identical except for tiny genetic variations, and some pathogens can change to normal flora after infection in a host. it has been reported that the intestinal microflora in infants are different according to ethnic groups and environments. 51, 52 therefore, environment factors and possibly genetic factors can affect the distribution of microflora and induce the variants of normal flora. the possibility of changing epidemiological and clinical features, including treatment response highlighting the need for enhanced surveillance. kd has an age predilection for children from 6 months of age to 5 years of age, with a peak incidence in children between 6 and 24 months old. this trait has not changed since the emergence of kd and is reflected in all ethnic groups. this disposition suggests that the maturing immune system in early childhood is involved in the pathogenesis of kd. 13 in general, acute infectious diseases affect children of all ages, although the phenotypes of some infectious diseases are age-dependent. in viral infections such as hepatitis a virus, coronavirus (sars) and influenza virus as well as in mycoplasma infections, younger children (<5 years of age) show less severe clinical symptoms and signs, compared to older children (>5 years of age) and adults. [26] [27] [28] [29] on the contrary, in bacterial infections such as staphylococcal pneumonia and tuberculosis as well as in parasitic infections such as malaria, younger children have a more severe clinical course. 30, 31 in kd, older children had prolonged fever and a higher incidence of cals compared to younger children. 32, 33 in addition, there are early childhood immune-mediated hematologic disorders, showing a similar age restriction as that of kd, including transient erythroblastopenia of childhood, autoimmune neutropenia of infancy, childhood immune thrombocytopenic purpura, and transient hypogammaglobulinemia of infancy. these disorders may be associated with infectious insults and have a self-limited clinical nature improving before 5 years of age. these findings suggest that the age of around 5 years old in childhood is the turning point of immune maturation of the host. kd may be regarded as among these disease categories, reflecting immunologic immaturity during early childhood, although kd has an acute immune disturbance. kd also has a predilection for certain ethnic groups. asian children, particularly those of japanese, korean and chinese ethnicity have the highest incidence of >10-15 times greater than caucasians, although kd has been reported in all ethnic groups. [19] [20] [21] 34 the incidence for japanese-americans living in hawaii is similar to the incidence for japanese living in japan, supporting a genetic predisposition for kd. 35 with the development of the study of human genetics and genomics, molecular genetics has become an area of interest for the study of kd. many genetic studies in different countries have evaluated variants in candidate kd genes, and a number of variants, including inositol 1,4,5 triphosphate 3-kinase (itpkc) and caspase-3, risk of cals. for example, a severely affected patient who is persistently febrile for a week, showing constant low levels of platelet with high levels of ast and alt in followup examination, may still not have reached the peak stage of inflammation, suggesting a higher possibility of more severe cals. laboratory findings are now mandatory for diagnosis of incomplete kd. 2 patients who do not fulfill conventional diagnostic criteria have been diagnosed as having incomplete kd, with <4 of the principal clinical features of kd. the severity of systemic inflammation in kd varies, resulting in different clinical phenotypes and changes of laboratory parameters among the affected children. a large number of patients have a mild clinical course with shortened fever duration and no cals, but some severely affected patients show prolonged fever duration of up to 2-3 weeks, multiple coronary artery aneurysms and even death. laboratory findings reflect the severity of systemic inflammation in kd, with concurrent increase or decrease of laboratory values. to understand the natural course of kd and the changes of laboratory indices during the febrile period is very important for the diagnosis, proper treatment and evaluation of kd patients. kd is a self-limiting disease. the total duration of fever in the era of non-ivigs is 1-2 weeks (mean 10-11 days), regardless of treatment with aspirin or corticosteroids. 1, 53, 54 therefore, a patient who is expected to have a total fever duration of 11 days reaches a peak in inflammatory processes at the sixth day after fever onset, if the periods of ascent to and regression from the peak are similar (fig. 1) . we previously evaluated the inflammatory indices in kd patients according to the fever duration at presentation. indeed, the levels of white blood cells (wbc) and neutrophil counts and crp levels were highest, while the albumin and hdl-cholesterol levels were lowest, at the sixth day, and these indices showed a bell-shaped or u-shaped distribution trend based on these values at the sixth day (the peak) ( fig. 2 ). 55 these findings suggest that the inflammatory processes of kd progress to a peak, then regress to a convalescent stage during the febrile period. it also suggests that in cases of cals, the immune cells involved in tissue destruction (endothelial damage) have a predominant role in the early stages and the immune cells involved in tissue repair have a predominant role in the late stages of kd, and the results are reflected by laboratory findings. the transaminases (ast and alt) appear to be higher in the early days, and markedly decrease after the peak stage of kd. total cholesterol level may be the lowest in the early days and tends to increase along with the natural course of inflammation. platelet count is well known to increase in convalescent stages of kd. however, platelet count may begin to increase at the peak stage of kd, suggesting involvement in tissue repair (fig. 2) . these findings may be useful for evaluation of the severity of patients who have the highest cals, and were treated with ivig. 2, 57, 58 however, now ivig is recommended for all kd patients. ivig has a potent anti-inflammatory effect on kd although its mode of action is unknown. it has been reported that approximately 10-15% of kd patients are ivig non-responders. 17, 18, 25, [59] [60] [61] [62] [63] early detection of ivig non-responsiveness through laboratory values is a reasonable and simple method for the evaluation of severity of kd and for the selection of severely affected patients who need early intensive treatment. for this purpose, there have been a number of previous reports of putative predictive variables of ivig non-responders. laboratory markers including crp, neutrophil differential including bands, albumin, sodium, hemoglobin, platelets, lactic dehydrogenase (ldh), total bilirubin, î³-gtp, alt, and ast have been reported to differ significantly between ivig non-responders and responders before ivig infusion. 17, 18, 25, [59] [60] [61] [62] [63] these different laboratory predictors with the score systems for ivig non-responsiveness, 17, 18 and the earlier harada score system for risk of cals may have a limitation resulting from confounding factors; difference of sample size, 64 the intensity of inflammation in individuals, the age of patients, 32 the stage of inflammation response at presentation as shown in fig. 1 , 55 and possibly ethnicity. 25, 65 some studies suggest that earlier ivig treatment, particularly before day 5 of illness is associated with an increased risk of nonresponse to ivig. 17, 18, 25, 63 it is plausible that ivig non-responders might have more severe inflammation and more florid clinical symptoms and signs, and consequently they may be diagnosed and treated earlier. 18 because of the limitations of early prediction for ivig non-responders, some study groups have tried early aggressive treatment for prevention of cals with ivig (2 g/kg), aspirin, and methylprednisolone (30 mg/kg) or infliximab. however the results of these studies are controversial. 41, 56, 66, 67 this treatment policy also has some obstacles such as overtreatment of patients with mild clinical course; 85-90% of the patients respond to initial ivig treatment (2 g/kg). furthermore it was reported that ~80% of the patients responded to a medium-dose of ivig (1 g/kg), 68 although high doses of ivig are more effective in preventing cals. 69 thus, early detection of the severely affected patients among all kd patients and prompt further treatment of these patients is necessary because cals develop and progress before the peak stage of the disease. ivig down-regulates nearly all inflammatory laboratory parameters except esr including total wbc and neutrophil count, crp, ast, alt, cpk and ldh in ivig responders. ivig increases esr artificially through interference because incomplete kd is more common in young infants than in older children, 2,32,33 clinicians must make every effort for accurate diagnosis and timely treatment of these young patients. the american heart association provided an algorism for diagnosis of incomplete kd in 2004. patients with fever lasting longer than 5 days with 2 or 3 of the diagnostic signs of kd should be evaluated for systemic inflammation daily if possible. initially crp (>3 mg/dl) and esr (>40 mm/h) levels and complementary laboratory findings including albumin <3.0 g/dl, anemia for age, elevation of alt, platelets after 7 days >450000/mm 3 , wbc count >15000/mm 3 , and urine >10 wbc/high-power field, should be reviewed. patients who fulfill more than 3 of these complementary indices can be treated with ivig as having incomplete kd followed by echocardiography. although laboratory findings in kd are non-diagnostic, they may prove useful in the diagnosis of incomplete kawasaki disease. 2 it is reported that ~25% of untreated patients and ~5% of ivig treated patients are affected with cals. 3,4 therefore, we were able to determine an imaginary line for the threshold of cals during the natural course of systemic inflammation in kd, and we assumed that ivig could lower the peak point of the inflammation curve (fig. 1) . cals begin at the point where the threshold line and the curve of inflammation intersect, and more severely affected patients reach the threshold line earlier before the peak stage of inflammation (arrows in fig. 1 ). early and extensive treatment with ivig (2 g/kg) and methylprednisolone pulse therapy (30 mg/kg) may not prevent cals development in some severely affected patients, 56 and small cals can progress to huge giant aneurysms after defervescence induced by various treatments. these findings suggest that the severity of cals is determined in the early period, before the peak stage of kd. therefore, early ivig treatment before the peak stage is mandatory to reduce the risk of cals and the progression of cals. higher severity of systemic inflammation in kd is reflected by prolonged fever duration, a higher incidence of cals, a higher or lower laboratory values, and a higher rate of ivig non-responsiveness. in the initial periods of ivig treatment in japan and korea, the score system (harada score) for evaluation of the severity of kd (a risk of cals) was used to decide on ivig treatment; wbc count >12000/mm 3 , platelet count <350000/mm 3 , crp >3+, hematocrit <35%, albumin <3.5 g/dl, age <1 year of age, and male sex. 57 kd patients who fulfill â�¥4 of the 7 criteria were regarded as having severe inflammation with higher risk of (initial 2 g/kg, and the second-dose, 1 or 2 g/kg) and intravenous methylprednisolone pulse therapy (10-30 mg/kg, for 3 days). the dose of the second ivig infusion (1 or 2 g/ kg) was assessed on a case-by-case basis. in general, the patients who failed to respond but whose wbc with neutrophil and crp decreased following the initial ivig treatment received a further dose of 1 g/kg, whereas those whose wbc count and/or crp remained unchanged or increased after the initial ivig treatment received a second ivig dose of 2 g/kg. those unresponsive to the second dose of ivig received intravenous pulsed methylprednisolone (10-30 mg/kg, for 3 days), and the dose was also determined by wbc and crp levels within 24 h after the second-dose ivig infusion. we have experienced no patients who remained febrile after termination of this treatment schedule among more than 500 kd patients. we were able to induce defervescence within 12 days from the beginning of the illness in a majority of the ivig non-responders (~10% of total kd patients), and only three patients were discovered to have giant aneurysms (>8 mm in diameter) after defervesccence. 58, 75 since the change of laboratory indices after ivig therapy appears within 2 hrs after termination of ivig infusion 71 and the majority of ivig responders defervesce within 24 hrs of ivig treatment (2 g/kg), it may be possible to make a decision on commencing the next-step in treatment of ivig non-responders, earlier than 24 h. with this, further studies in other populations should aim to optimize treatment of ivig non-responders in kd. for ivig non-responders, re-infusion of ivig (2 g/kg), methylprednisolone pulse therapy (30 mg/kg, for 3 days), infliximab (anti-tnf-î± antibodies), and more powerful immune-modulators such as cyclophosphamide or methotrexate, and plasmapheresis have been tried. [78] [79] [80] [81] [82] it is believed that severely affected kd patients destined to prolonged fever cannot avoid cals in the early stage of this self-limited disease, although these treatments can induce defervescence. for understanding the pathogenesis of kd, a brief review of resembling diseases may be helpful. among bacterial infections, scarlet fever/acute rheumatic fever (arf) may be a representative disease resembling kd. clinical manifestations of scarlet fever, etiologic agents of which are mainly the group a beta-hemolytic streptococci (gas), are fever, with fibrinogen levels. 70 in addition, ivig has a systemic protein modulation effect in vivo; all proteins including albumin, transferrin, apolipoprotein a1, and pro-inflammatory cytokine (tnf-î± and il-6) levels were transiently decreased, but the levels of immunoglobulins (iga and igm), electrolytes (sodium, potassium, chloride, calcium and phosphorus) and serum osmolarity were not changed by ivig infusion. [70] [71] [72] therefore, the beneficial effect of ivig on kd may, in part, be associated with the control of the proteins which are involved in inflammation in various tissues of the host, although ivig has multiple modes of action for immune modulation. 11, 73 on the other hand, ivig non-responders generally have persistently elevated inflammatory parameters, such as neutrophil counts and crp and lower levels of albumin after ivig infusion. 59, 74 we recently observed that ivig non-responders have sustained abnormal laboratory parameters following ivig (within 24 hrs) as well as prior to ivig compared to ivig responders; the cut-off values of >13000/î¼l for total wbc count, >51% for neutrophil differential and <7.2 g/dl for total protein had reasonable sensitivity (91%, 91% and 64%, respectively) and specificity (89%, 76% and 78%, respectively) as independent characteristics of non-response to ivig. 75 in addition, the kinetics of some inflammatory parameters following ivig differed markedly between responders and non-responders. among them, wbc count and crp in non-responders increased or remained unchanged following initial ivig infusion (2 g/kg), in contrast to the marked decline in these parameters in responders. thus, clinicians can use these parameters easily and rapidly for the evaluation of the severity of inflammation in kd. the definition of ivig non-responsiveness and the treatment modality for initial ivig non-responders are not clearly determined among the study groups. many study groups have observed the patients for 36-48 h after termination of ivig infusion to see whether or not the patients showed defervescence and improvement of clinical signs. the non-responders also consisted of patients with a different severity of inflammation. it was reported that 20-50% of initial ivig non-responders also did not respond to a second dose of ivig. 76, 77 for these severely affected patients, rapid treatment may lead to a better outcome, because of the possibility of rapid progression of cals in the early stage of the disease. in our hospital, we defined ivig nonresponders as patients with persistent fever (â�¥38.0â°c) over 24 hrs after termination of ivig infusion. our treatment modality for ivig non-responders is the 2-dose ivig infusion sis of kd is closer to that of arf than scarlet fever. in addition, the causes of death in both acute kd and arf are extensive carditis or complications from distorted cardiac vessels or cardiac valves. there are also rare incidences of a sepsis-like syndrome with multiple organ failure and the fulminating clinical course, which are shown in severely affected patients of gas infections or any acute infectious diseases, including viral infections. the laboratory findings in both diseases have revealed increased leukocytes, and crp and esr values, indicating systemic inflammation with activated immune cells. the characteristic clinical manifestations and pathologic findings in various tissues in scarlet fever, arf and kd may depend on different inflammatory mediators (proteins) and corresponding immune cells. pathogens or sole pathogen-associated structural substances have not been identified in the pathologic lesions of kd or arf (coronary artery, endocardium, and cardiac valve). 86, 87 even in acute gas infections, bacteria are not found in the affected tissues of toxic shock syndrome or necrotizing fasciitis. 85 thus, toxic substances and circulating immune cells may be involved in the tissue injuries from these conditions. there are many enigmas as to the pathogenesis of kd. particularly, as to what the etiologic substance of the systemic inflammation and tissue injury is, how initial inflammation begins, and why only some patients are affected with different clinical severities, as in the case of arf and apsgn after initial gas infections, are of concern. to solve these puzzles, we propose a new hypothesis based on the premise of a "protein homeostasis system" in the host. mammals, including humans, have evolved through genes which code for proteins. all living activities from embryonic development to the aging process are strictly controlled by a variety of proteins at the molecular level. the numbers and kinds of genes (kinds of proteins) that are activated differ according to the different organ tissue cells and timing of their activation. an organ specific cell produces its own specific proteins. also, some proteins are produced only during the embryonic stage while some proteins are produce in later stages of the life cycle of mammals. for example, in genetic diseases such as neurofibromatosis or rare genetic prion diseases including fatal familial insomnia, the expression or progression of these diseases appears after 2-5 decades of age. 88 the pathogenesis of these genetic diseases may be associated with transformed proteins, including prions, which may be toxic to nerve cells, and the toxic proteins should be controlled for avoidance of the disease in vivo. on the other hand, mammals have also strawberry tongue, cervical lymphadenopathy, skin rashes and desquamation of skins after defervescence, mimicking those of kd. although some patients with gas infection complain of severe clinical phenotypes including streptococcal toxic shock syndrome and necrotizing fasciitis, scarlet fever is a self-limited disease, with a mean historical fever duration of 6 days without antibiotic treatment. 83 if enough doses of gas are inoculated to every individual, nearly all individuals who do not have antibodies to toxins would be affected with scarlet fever. the immunopathogenesis of severe gas infections such as streptococcal toxic shock syndrome and necrotizing fasciitis remains unknown. it is suggested that the streptococcal superantigens, including pyrogenic exotoxins, stimulate an intense proliferation and activation of the immune cells (t cells and macrophages), resulting in the production of large quantities of cytokines. the cytokine imbalance of a local environment may be responsible for tissue injuries and many of the clinical manifestations of severe, invasive gas infections. 84, 85 as nonsuppurative complications, arf and acute poststreptococcal glomerulonephritis (apsgn) are well-documented after gas infections. 83 arf is an acute febrile disease characterized with prolonged fever, carditis, arthritis, skin rash (erythema marginata) and chorea. 86,87 arf occurs 2-4 wks after the primary gbs infections of the pharynx. the majority of gas infected patients recover uneventfully, and only some patients who have genetic susceptibility may be affected with arf, similar to kd. although arf is a disease of which the etiologic agent has been proven, the immunopathogenesis of the disease remains unsolved with speculation as to an immunemediated disease triggered by infectious insults. one hypothesis suggests that bacterial exotoxins or superantigens may be involved in the cardiac tissue injury through the direct toxic effect on target tissues or through activated cytokines. others suggest that autoimmune reaction of immune cells that are sensitized to bacterial antigens may attack the target cells that may share epitopes with bacterial antigens ("molecular mimicry"). 86, 87 the clinical manifestations of arf can appear without symptomatic gas infections (pharyngitis) in a third of patients. 86 antibiotic treatment of scarlet fever rapidly improves clinical symptoms and signs of the disease, but shows no effect in arf and kd. there may, however, be sites (foci) in which the substances provoking inflammation in arf or kd as well as in scarlet fever are produced and released to systemic circulation. at this point, we can deduce that the immunopathogene-ies, via cytokine production, using t cell receptors (tcr) or via their effect on cell-bound proteins. macrophages may play the most crucial role in the immune/repair system of the host. also, they synchronize the communications between innate immune cells and adaptive immune cells in inflammatory reactions, and between immune cells and regenerating tissue cells in repair reactions, via a complex of cytokine (protein) networks. although the immune system of the mammals have been divided into the separate categories of innate immune system and adaptive immune system, the two immune systems work together against any internal or external insults in vivo. it is now accepted that the mediators (proteins) from innate immune reactions affect adaptive immune reactions. 91, 92 in infections of various pathogens, pathogen recognition receptors including toll-like receptors (tlrs) and intracellular sensors which recognize components of pathogens (pathogen-associated molecular pattern) of infected cells and macrophages, induce the production of anti-agent proteins (in case of viruses and interferons) and other proteins including pro-inflammatory cytokines. these proteins may affect the function of adaptive immune reactions such as control of expression of co-stimulatory receptors or activation of specific immune cells. 91, 92 b cells (plasma cells) can produce antibodies for any proteins which are recognized by b cell receptors (bcrs). theoretically, gene recombination of bcr genes can match all internal or external proteins. however, b cells cannot induce antibodies against small foreign proteins and a majority of self serum proteins. similarly, tcrs of t cells also comprise recombination of variable tcr genes, matching nearly all peptides (proteins) that are constructed with 12-27 amino acids. despite the more crucial role of t cells than b cells on host defense against invading pathogens (t cell deficiency is more severe compared to b cell deficiency), the role of tcrs is nearly unevaluated except for antigen presentation between t cells and apcs compared to b cell function. lots of small peptides may exist in inflammatory lesions; however, the metabolism and role of these proteins remain to be evaluated. indeed, small peptide hormones such as gonadotrophin releasing hormone (gnrh, decapeptide), vasopressin (9 peptide) and oxytocin (9 peptide) exist in vivo, and they have crucial roles on systemic hormonal homeostasis. 93 furthermore in the nucleus of the cells, replication of dna for cell proliferation and small microsomal rnas, which regulate gene expression, may also be controlled by proteins, including dna polymerases and nucleases, suggesting complex mechanisms of protein homeostasis at a cell level. 94 struggled with external insults in nature. the compositions of various pathogens and animal toxins, such as snake venom and insect venom are mainly proteins of various sizes, shapes and lethal doses. these toxic proteins may have their own affinity to different organ-tissue cells and bind to the receptors on the cells of the host. this toxic protein-receptor binding may induce direct cell injury and/or may produce new proteins through signal transduction pathways in the affected cells. the substances (proteins) from injured cells can be released to systemic circulation and signal other immune cells. now, it is believed that substances from injured cells of a specific organ tissue can induce an immune reaction and subsequently be toxic to other organ cells or their own tissue cells, if released to the systemic circulation. 89, 90 matzniger proposed an interesting hypothesis for this basic immunological concept, the danger model. herein, antigen presenting cells (apcs) can be activated by danger/alarm signals (initiators of inflammation) from the injured cells that are caused by pathogens, toxins, mechanical damage, and so forth. the intracellular contents from necrotically died cells could potentially be a danger signal when released, but not that of healthy cells or by cells undergoing physiological deaths (apoptosis). 89 complete recovery from a systemic infectious disease may be defined as the state in which not only etiologic agents and inflammatory mediators from pathogens but also the substances produced during immune reactions including cytokines and the debris from the injured cells have been completely removed by immune cells, if those substances could be toxic to other tissue cells. we define these toxic proteins as "pathogenic proteins", classifying external pathogenic proteins as those which are of the pathogen origin and internal pathogenic proteins as those which are of host origin, including prions. a strict protein control system controls the balance of proteins and removes the pathogenic proteins at a molecular level in humans. serum proteins including albumin, immunoglobulins and various hormones are maintained at constant levels in a steady (healthy) state by unknown protein control systems, and we have named these systems as "protein homeostasis systems". here, we postulated that the immune system of the host is one of the protein homeostasis systems in vivo. the main function of immune cells at a molecular level is to control of a variety of proteins by recognition of size. innate immune cells (neutrophils and phagocytic monocytes) control larger proteins (microbes and injured cells as a whole), b cells control proteins via antibody production, and t cells control small proteins which cannot induce antibod-corresponding immune cells, including macrophages and t cells, may also be involved in the pathogenesis of keloids. 96 t cells can be activated by various stimuli such as mitogens and monoclonal antibodies for various receptors on t cells in vitro, thus the mechanisms of t cells activation in vivo may be different in various pathologic conditions. although helper t cells can be divided into functional subtypes such as th1, th2, th17 and regulatory t (treg) cells according to the cytokines produced from the t cells, it is expected that more t cells subtypes, which produce different cytokines, may exist in different pathogenic lesions in vivo. 97 therefore, the functions of t cells are more diverse and complex than we have previously known. returning to the immunopathogenesis of kd, it is postulated that systemic inflammation of kd is caused by pathogenic proteins which are associated with an immune reaction of an unknown initial infection. in this infection, a majority of the patients may be asymptomatic. the toxic substances produced during the immune reaction against the initial infection may be removed in a majority of the patients, but some patients who have a genetic defect for this feedback process may lead to foci for which the pathogenic proteins are produced and released into systemic circulation. although the foci producing pathogenic proteins responsible for kd or arf are unknown, the secondary lymphoid organs around the initial infection sites (tonsils, lymph nodes or payer's patches) are primary candidates (fig. 3a) . the pathogenic superantigens are virulent polypeptides (proteins) that are produced by a variety of infectious organisms including gram positive streptococci and staphylococci. superantigens can induce activation of many t-cell clones which have specific vî² chains. however, in any human disease including kd, clinical implications of polyclonal activation of t cells have not been clearly explained. 95 t cells together with other immune cells appear in nearly all pathologic lesions in early stages, before specific t-cells and specific antibodies appear, of infectious diseases, rheumatic disorders including kd and arf, malignancies as tumor infiltration lymphocytes, tissue rejection, and in the repair processes of tissue injury (keloids). for example, in mantoux skin tests for diagnosis of tuberculosis, skin tissue injury (positive result) is induced by proteins (purified protein derivatives) and corresponding immune cells, mainly t cells, which were previously sensitized to the proteins from tuberculosis bacilli or mycobacterium bovis bacillus calmette-guã©rin (bcg). positive skin reactions can be abolished in states of depressed t cell function or an exhausted number of t cells in cases of corticosteroid treatment, systemic viral infections such as measles, and severe tuberculosis infections. 30 furthermore, a clean skin injuries such as scar revision in plastic surgery, in which there are no foreign proteins or pathogens, on occasion result in hypertrophic scars or keloids in genetically susceptible patients. the substances (proteins) from injured skin cells and immune cells start to control these substances, and clinical symptoms and signs begin to appear. the pathogenic proteins bind to receptors of endothelial cells of coronary arteries, and this process induces cell injury and /or other protein production from endothelial cells (b). immune cells recruit to the lesions to control the action of the proteins including pathogenic proteins. initially, non-specific t cells and nonspecific antibodies are involved in this reaction, while hyperactivated immune cells produce various inflammatory cytokines and counterinflammatory cytokines, leading to a cytokine imbalance associated with further endothelial cell injury (c). after emergence of specific t cell clones and specific antibodies for pathogenic proteins, tissue injury ceases and a repair reaction begins with the immune cells (d). kd, kawasaki disease. immune cells stances including antibodies may be different from kd. we previously used this hypothesis to explain the immunopathogenesis of acute lung injury in mycoplasma pneumoniae (m. pneumoniae) and influenza virus infections. 98, 99 for the 2009 h1n1 influenza virus infection, the severity of pneumonia was correlated with lymphocyte counts at presentation, and early immune-modulators (corticosteroids or ivig) induced dramatic recovery of severe pneumonic consolidations within a day. 99, 100 therefore, it is also acceptable as a new concept that small pathogenic proteins are produced during immune reactions in acute systemic infections (influenza virus or m. pneumoniae), not by viruses or mycoplasmas themselves, and can induce cytopathic effects on lung tissues by hyperactivated immune cells, especially t cells. 99 in these infections, like strong natural toxins, extremely small amounts of pathogenic proteins that have affinity to lung tissues can induce severe lung injury leading to death by amplification of a maladjusted immune reaction. along with studies for etiologic agents of kd, some investigators have proposed the immunopathogenesis of kd. recently the study group of yeung 15 presented an interesting model for the pathogenesis of kd using a mouse model of kd. they created experimental mice which were able to develop coronary arteritis in response to intraperitoneal injections of lactobacillus casei cell wall extract (lcwe). this murine model of kd is similar to human kd including the aspect of massive activation of immune cells, disease susceptibility in the young and a similar pathology of coronary arteritis, although replication of the disease is not perfect. they observed that immune cells began to appear in cardiac tissue at day 3 after lcwe injection, and then more immune cells, mainly t cells, infiltrated around the arteries and peaked at day 28. also, disruption of the intima and media as well as aneurysm formation were observed at day 42. 15, 101 they postulated that t cells have a crucial role in the pathogenesis of kd. a superantigen in lcwe activates massive t-cell clones, and t-cells survive from apoptosis by a co-stimulatory signal on coronary endothelial cells as transformed antigen presentation cells. tlr2 on endothelial cells and a corresponding ligand in lcwe may in part intensify co-stimulation expression on the cells. activated t cells continued to produce cytokines including tnf-î± and ifn-î³, causing a cytokine imbalance in local lesions, that may be responsible for vessel wall injuries. it may be true that t cells have crucial roles in animal kd and in human kd, since adaptive immune deficiency mice (recombination activating gene1 knockout mice) and tcr proteins in kd have affinity mainly to endothelial cells of coronary arteries, and bind to the receptors on endothelial cells. this process is directly toxic to the endothelial cells and/or produces new proteins including inflammatory mediators through signal transduction pathways to the nucleus. these mediators from the affected cells are a signal for the recruitment of immune cells (fig. 3b) . to control the pathogenic proteins and/or the new proteins from the injured cells, immune cells, especially t cells for small proteins, are recruited and activated. because there is a time-gap for the appearance of specific immune cell clones (specific t cells and b cells) in an immune reaction, this reaction may be conducted by non-specific t cells and non-specific antibodies initially, until the specific t cell clones and specific antibodies that can efficiently control pathogenic proteins are produced. the activated immune cells during this immune reaction (in the process of protein control) produce various inflammatory cytokines and counter-inflammatory cytokines, and a cytokine imbalance may be associated with the endothelial cell injury in kd. the substances from the injured cells recruit more immune cells with more cytokine production. some cytokines such as tnf-î± induce other proteins including matrix metalloproteinase (mmp) 9, which is toxic to neighboring cells, and aggravate tissue injuries (fig. 3c) . other substances released from the initial focus and/or the substances released from the injured lesions and cytokines spread via systemic circulation and induce the initial clinical manifestations of kd, including fever and other diagnostic clinical signs, and other rare manifestations of kd. the substances inducing extra-coronary manifestations including skin rashes and arthritis in kd are controlled by immune cells, and they may not contain the pathogenic proteins which induce a signal to tissue injury. after the emergence of specific t cell clones and specific antibodies for pathogenic proteins, inflammation ceases and a repair reaction begins with the immune cells and regenerating cells (fig. 3d) . briefly, the genetic determination of kd susceptibility may depend on a defect in the immune cells to detect and remove pathogenic proteins from initial infections. also, severity of the disease may depend on the amount of pathogenic proteins with corresponding hyperactivity of immune cells and the time-period for emergence of specific immune cells against pathogenic proteins. the immunopathogenesis of arf or other immune-mediated disease could be explained similarly by this hypothesis. accordingly, pathogenic proteins, affected target cells, the subset of corresponding immune cells and the kinds of cytokines and other sub-rameters may help shorten the fever duration of the severely affected patients. a hypothetical pathogenesis of kd is proposed using the premise of a "protein homeostasis system" of the host. hyperactive immune cells, especially t cells, with excessive cytokines may be responsible for tissue injury as well as for tissue reconstruction according to this hypothesis. further developed tools including bioinformatics of candidate genes and proteomics may be needed for establishing more detailed explanations on the pathogenesis as well as developing diagnostic tests and improved treatments for the prevention of kd. î±-chain deficiency mice cannot produce vasculitis. 15, 102 we previously described similar phenomena in m. pneumoniae and influenza virus infections. in these infections, t cell deficiency mice or t cells depressed mice had less severe pneumonia with prolonged survival time and little pathologic findings compared to control mice. 98, 99 recently, rowley and shulman 16 proposed a model on the pathogenesis of kd. the agent of kd may be a ubiquitous infectious agent, most probably a single virus or a group of closely related viruses that lead to kd only in a small subset of genetically susceptible children. the initial infection site of the agent may exist in the respiratory tract including ciliated bronchial epithelium, and both innate and adaptive immune responses ensue including b lymphocytes switching to iga lymphocytes. the kd agents in circulating macrophages reach and infect endothelial cells of the coronary artery as main target cells via systemic circulation. immune cells, including previously primed cd8 t cells and iga b cells in initial lymphoid tissues, are re-recruited to infected target tissues and contribute to the inflammatory response within the tissues. differentiated iga b plasma cells produce antigen-specific antibodies, and cd8 t cells attack infected cells by cytotoxic mechanisms. the products from infected cells and immune cells including mmps result in destruction of collagen and elastin fibers, and form an aneurysm. the immune response is ultimately successful in controlling the pathogen, particularly if ivig is given, because ivig may have antibodies to kd agents and have a role in antibody dependent cellular cytotoxicity to infected cells. 16 kd is the most common cause of acquired heart disease in children in developed countries. although the etiology of kd remains unknown, the epidemiological and clinical characteristics of kd suggest that etiologic agent(s) are associated with environmental changes of improved public hygiene and/or industrialization. as a self-limiting systemic disease, the clinical course of kd shows progression and regression of the inflammation intensity reflected in laboratory findings. cals in kd may occur in the early stages of systemic inflammation. although there are no consensus recommendations for the treatment of initial ivig non-responders, intensive treatment as soon as possible is mandatory for prevention and progression of cals. short-term follow-up (within 24 h) examination of some of the inflammatory paacute febrile mucocutaneous 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genetics of prion disease the danger model: a renewed sense of self the danger model in deciphering autoimmunity pathogen recognition and inflammatory signaling in innate immune defenses pathogen recognition by the innate immune system gonadotropin-releasing hormone (gnrh) and its natural analogues: a review micro rnas: tiny sequences with enormous potential superantigens in dermatology the authors thank drs. ji-whan han, june-sung lee, jae-wook lee, and david bergner for critical review of the manuscript, dr. hyun-ju shin for assistance with the figures. key: cord-333145-a20dlaxn authors: johnson, todd a.; mashimo, yoichi; wu, jer-yuarn; yoon, dankyu; hata, akira; kubo, michiaki; takahashi, atsushi; tsunoda, tatsuhiko; ozaki, kouichi; tanaka, toshihiro; ito, kaoru; suzuki, hiroyuki; hamada, hiromichi; kobayashi, tohru; hara, toshiro; chen, chien-hsiun; lee, yi-ching; liu, yi-min; chang, li-ching; chang, chun-ping; hong, young-mi; jang, gi-young; yun, sin-weon; yu, jeong-jin; lee, kyung-yil; kim, jae-jung; park, taesung; lee, jong-keuk; chen, yuan-tsong; onouchi, yoshihiro title: association of an ighv3-66 gene variant with kawasaki disease date: 2020-10-26 journal: j hum genet doi: 10.1038/s10038-020-00864-z sha: doc_id: 333145 cord_uid: a20dlaxn in a meta-analysis of three gwas for susceptibility to kawasaki disease (kd) conducted in japan, korea, and taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated snv in the immunoglobulin heavy variable gene (ighv) cluster in 14q33.32 was identified (rs4774175; or = 1.20, p = 6.0 × 10(−9)). investigation of nonsynonymous snvs of the ighv cluster in 9335 japanese subjects identified the c allele of rs6423677, located in ighv3-66, as the most significant reproducible association (or = 1.25, p = 6.8 × 10(−10) in 3603 cases and 5731 controls). we observed highly skewed allelic usage of ighv3-66, wherein the rs6423677 a allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both kd patients and healthy adults. association of the high-expression allele with kd strongly indicates some active roles of b-cells or endogenous immunoglobulins in the disease pathogenesis. considering that significant association of snvs in the ighv region with disease susceptibility was previously known only for rheumatic heart disease (rhd), a complication of acute rheumatic fever (arf), these observations suggest that common b-cell related mechanisms may mediate the symptomology of kd and arf as well as rhd. kawasaki disease (kd) is an acute systemic vasculitis syndrome characterized by high fever, bilateral conjunctivitis, polymorphous skin rash, reddening of lips and oral cavity, changes in extremities and nonsuppurative cervical lymphadenopathy [1] and predominantly affects infants and children younger than 5 years [2] . in many cases, kd is self-limiting. however, it causes coronary artery complications such as dilatations and aneurysms (coronary artery lesions; cals) in 20-25% of untreated patients [3] . replacing acute rheumatic fever (arf), kd is now the leading cause of acquired heart diseases of children in developed countries [4] . most kd patients are treated with high dose intravenous immunoglobulin (ivig) infusion combined with oral aspirin, which was established in the 1980s and 1990s and has become a standard treatment that is effective at resolving inflammation and reducing cals [5] [6] [7] . however, the mechanism of ivig action on kd has not been revealed, and 10-15% of kd patients do not respond to the treatment and have a higher risk for cal. recently a series of genome-wide association studies (gwas) revealed several definitive kd susceptibility loci [8] [9] [10] . however, these genetic factors can explain only a part of the etiology. also, the reason for the high incidence among east asian children [11] , which is up to 20-fold higher than those in western countries and is a crucial epidemiologic feature of kd, has not yet been explained. it might be attributed in part to lack of statistical power in the previous gwas analyses that were carried out using modest sample-sizes, and therefore, many common genetic factors with relatively low penetrance may have gone undetected. in this study, to identify novel susceptibility loci for kd, we conducted a meta-analysis of gwas from japan, korea, and taiwan, the three countries with the highest incidence of kd in the world. in this study, susceptibility loci for kd were screened and verified in a two-stage association analysis (fig. 1) . stage 1 was a whole-genome meta-analysis of results from gwas conducted in japan [9] , taiwan [10] , and korea [12] involving 6362 individuals. we carried out follow-up association studies using three case-control panels comprised of 1418 kd patients and 1700 controls (japanese), 473 kd patients and 484 controls (korean) and 261 kd patients and 567 controls (taiwanese) independent from the subjects in the gwas and performed meta-analyses with the stage 1 results (stage 2). loci for the follow-up studies were selected based on their predicted potential to achieve impute2 & minimac softwares 1000genomes east asian 572 haplotypes p values less than 5.0 × 10 −8 in the meta-analyses, with the prediction made by iterative simulations of follow-up studies with virtual case and control cohorts (detailed below). to further validate the associations of rs4774175 and rs6423677 in 14q32.33, an additional 1758 kd cases and 653 controls collected in japan were used. the number of kd cases and controls, as well as platforms in the three previous gwas and follow-up studies in japan, korea, and taiwan are summarized in supplementary table 1 . [13]) as reference using pre-phasing with shapeit v1 (ref. [14] ) and imputation with impute2 and minimac softwares [15, 16] . imputed genotype data were analyzed by each study center in a case-control logistic regression analysis, and the output was merged in the r statistics environment (url: https://www.r-project.org/) and filtered for variants that were polymorphic in both cases and controls (maf cases ≥0.01 and maf controls ≥0.01) and had info ≥0.4 in all three studies' dataset; there were 6,265,045 snvs in the final filtered dataset. a fixed-effects meta-analysis of the three data sets' beta-coefficients and standard errors was performed using the r package metafor (https://cran. r-project.org/package=metafor). each chromosome's snvs were filtered for those with a meta-analysis p < 0.01 and then labelled based on linkage disequilibrium to regional "top snvs". briefly, snvs with p < 1 × 10 −4 were sorted by p value, the top snv identified, and any snvs within ±5 mb that had r 2 > 0.1 to that top snv assigned to its region; data on a chromosome was processed as such until no snvs with p < 1 × 10 −4 were remaining. each top snv region was labelled based on chromosome and minimum and maximum positions of the linked snvs. based on that process, each region label would be unique, but regions could overlap with each other. calculation of r 2 was performed using the ld function in the r bioconductor snpstats package using east asian genotype data from the 1000 genomes phase 1 version 3 release. for simplicity, we will refer to the regions of nominally linked snvs described above as "loci". to perform the stage 2 follow-up study efficiently, loci that had a high potential of achieving p values less than 5.0 × 10 −8 in a meta-analysis of stage 1 and 2 results were selected by p value simulation as follows. for each locus, we first selected any nominally associated snvs (p < 0.001) identified in the stage 1 analysis, and for each snv created a virtual set of 100,000 case genotypes and a virtual set of 100,000 control genotypes for each of the three stage 1 case-control panels. each virtual set was generated based on the genotype frequencies observed in that panel's stage 1 cases or controls at a particular snv, and each of those virtual sets was then re-sampled in r to randomize their order. each virtual case and control set was then sampled 100 times to create 100 virtual case-control cohorts; the numbers of cases and controls sampled from the virtual genotype sets were the case-control counts that were expected in the three collaborators' follow-up studies (riken in japan: n cases = 1300, n controls = 1300; academia sinica in taiwan: n cases = 500, n controls = 2000; asan medical center, university of ulsan in korea: n cases = 412, n controls = 600). for each iteration, associations of the candidate snvs were evaluated in a meta-analysis of the virtual cohorts and the three gwas data sets. for each candidate snv, the frequency of observing p values of 5.0 × 10 −8 or smaller in 100 iterations of the simulated meta-analysis was scored as the simulation score. loci with at least one snv having simulation scores of 0.8 or higher were considered to be promising, and for de novo genotyping, a representative snv was selected for which assays were designable across the different platforms employed in each research center (invader in japan, sequenom massarray or taqman in taiwan and veracode goldengate genotyping kit or taqman in korea, respectively) (supplementary table 1 ). nonsynonymous snvs in ighv genes were genotyped basically by the invader assay. primers and the probes were carefully designed in order to ensure specificity of the assay. we refrained from using multiplex pcr to avoid both expected and unexpected nonspecific amplification of dna fragments of high sequence homology which will allow cross reaction between amplicons and probes for different loci. sequences of the primers and probes for 18 nonsynonymous snvs in ighv genes and rs4774175, as well as representative genotyping results of rs6423677, are provided in supplementary tables 2 and 3 and supplementary fig. 1 , respectively. next-generation sequencing (ngs) of ighv repertoires two milliliters of venous blood was drawn from patients who were admitted to the hospitals for kd at four time points including (1) acute phase before receiving ivig (3-8 illness days), (2) 48 h after the patients became afebrile (8-18 illness days), (3) the first follow-up visit to the pediatric clinic after discharge (17-50 days after the disease onset), and (4) the second follow-up visit to the pediatric clinic after discharge (3-4 months after the disease onset). blood samples were collected into vacutainer cpt cell preparation tube (bd) and mononuclear cells were separated according to the manufacturer's instruction. total rna from the mononuclear cells was extracted by using the rneasy mini kit (qiagen). 1.0 μg of rna was reverse transcribed with primescript (takara) and the mixed oligonucleotides of random hexamer and oligo-dt primers. isotype-specific libraries for ngs were prepared as follows. mixed forward primers covering the framework region 1 of 7 subgroups of ighv genes (v1-v7) [17] and reverse primers specific to each ighc gene for igm, igd, igg, and iga (including a partial illumina adapter sequence in the 5′ ends of both primers) were designed for the 1st round pcr. sequences of the primers are provided in supplementary table 4 . 6-base barcode sequence and the full illumina adapter sequence were added at 5′ and 3′ ends of the immunoglobulin amplicons in the 2nd round pcr. the barcode sequences were used to distinguish the patients and the sampling time points. the libraries were sequenced with miseq reagent kit v3 (600-cycle) (illumina). forward and reverse sequence reads were merged by using flash software [18] . sequences unmerged due to insufficient overlapping length were excluded from subsequent analyses. merged sequence reads were classified into isotypes and subclasses based on primer sequences by using blast software (https://blast.ncbi.nlm.nih.gov/blast. cgi), and then quality filtering and removing the primer sequence were performed by using the fastx-toolkit (http://hannonlab.cshl.edu/fastx_toolkit/index.html). immunoglobulin repertoires were determined by migmap-1.0.2 software (https://github.com/mikessh/migmap). sequence reads that terminated prematurely or had a complementarity determining region (cdr) 3 that was non-canonical (i.e., lacking consensus amino acids at both ends or not fully mapped) were excluded from subsequent analyses. clonotypes were defined by combinations of ighv, igh diversity (ighd), and igh joining (ighj) gene alleles. correlation trend between the proportions of the igh clonotypes using ighv3-66 and the c allele counts at rs6423677 was evaluated by the jonckheere-terpstra test using r package pmcmr (https://cran.rproject.org/package=pmcmr). change of each clonotype proportion from baseline (the 1st sampling point) was calculated by subtracting the baseline proportion from those at 2nd, 3rd, and 4th points. the diversity of cdr3 clonotypes was evaluated by the inverse simpson's index using the r package vegan (https://cran.r-project.org/pa ckage=vegan). in the stage 1 analysis, a meta-analysis of three gwas data sets, genome-wide level associations were seen in known susceptibility loci such as fam167a-blk (rs2736340; p = 1.23 × 10 −16 ), itpkc (rs28493229; p = 3.07 × 10 −9 ), casp3 (rs2720377; p = 2.66 × 10 −9 ) and cd40 (rs1883832; p = 1.76 × 10 −8 ). four top snvs in hla class iii~class ii regions (rs2844485, rs73729123, rs7739458, and rs146650659) and rs13330932 in the 16q24.1 region also showed significant associations (supplementary table 5 , supplementary fig. 2) . from a standard test for inflation, the genomic control inflation factor λ gc = 1.0216 ( supplementary fig. 2 ). in a simulation of meta-analyses, a "simulation score" was calculated for each nominally associated snv (p ≤ 0.001; see methods). forty-nine loci were identified with one or more snvs expected to satisfy a p value threshold of 5.0 × 10 −8 with simulation score of 0.8 or higher (supplementary table 6 ). from every locus, we selected representative snvs for genotyping in replication sample panels and then performed a meta-analysis with data from the three gwas. for one particular snv locus (rs181511609) that satisfied the criteria, a genotyping assay could not be designed due to the complexity of the surrounding sequence. as a result, 12 out of 48 examined loci showed significant associations ( table 1, supplementary table 7 ). these included four previously known susceptibility gene loci such as casp3, fam167a-blk, itpkc, and cd40, seven on chromosome 6p21 (nc_000006.11: 25.5-32.78 mb) and one in the immunoglobulin heavy variable gene (ighv) region on chromosome 14q32.33. the trend of association for rs13330932 on chromosome 16q24.1 was not replicated in the follow-up sample panels from the three populations (supplementary table 7) . association of an ighv3-66 gene variant with kawasaki disease association signals that newly achieved genomewide significance after the meta-analyses of three gwas and follow-up association studies a significant association of rs2857151 located near hla-dob and hla-dqb2 genes with kd susceptibility was reported in the earlier japanese gwas [9] . however, the present study revealed that the association statistics for rs2857151 were not consistent across the other east asian populations (supplementary table 8 ). instead, 7 out of 12 groups of snvs in the 6p21 region examined in the stage 2 analyses showed significant association in the metaanalyses of the data sets in the three gwas as well as in the follow-up studies ( table 1 and supplementary fig. 3a ). to verify that those seven signals were associated independently from rs2857151, we calculated ld between these snvs and rs2857151, and we also performed logistic regression analyses conditioning on rs2857151 using the japanese stage 2 sample set. consistent with information from 1000 genomes, the seven candidates were not in high ld with each other (supplementary fig. 3b ). the association was most significant for rs2857151, and in the conditioned logistic regression analyses, the p value for rs2071473, which was located just 19 kb distal to and in marginal ld with rs2857151 (d′ = 0.99, r 2 = 0.36), became nonsignificant (p > 0.05). after conditioning, p values for the other snvs including rs2857151 itself increased but were still significant (p ≤ 0.05). (supplementary table 9 ). these included snvs with previous information on their functional significance or association with diseases such as rs2857602, where the associated allele is linked to the a allele at rs2239704 (r 2 = 1.0 in the 1000 genomes jpt population), which has been associated with reduced expression of lymphotoxin a [19] , and rs7775228, which was previously associated with asthma in a japanese population [20] . thus, further investigation including that in each ethnic group is needed to unravel the involvement of the variants in this region in kd susceptibility. in the meta-analysis of the stage 1 and 2 studies, a significant association was also obtained for an snv within the chromosome 14q32.33 region represented by rs4774175 (p = 6.0 × 10 −9 ) ( table 1) . five hundred and nineteen snvs, linked with rs4774175 (r 2 > 0.1), and having simulation score of 0.5 or higher were distributed across a 340 kb region (106.88-107.22 mb) of this locus where many ighv genes as well as their pseudogenes are clustered in tandem. similar to the hla region, most ighv genes harbor common nonsynonymous snvs within them contributing to the high level of diversity observed within the immunoglobulin heavy chain repertoire. therefore, we proceeded to analyze the nonsynonymous snvs in that locus. among the 519 snvs, 18 were nonsynonymous and the others were intergenic, intronic, in the untranslated region, or synonymous snvs. when the japanese sample set used in the stage 2 analysis was genotyped for these 18 nonsynonymous snvs, rs6423677 in the ighv3-66 gene showed the most significant association ( table 2) . as expected, some other nonsynonymous snvs also showed a similar trend of association. however, those associations, including that of rs4774175, were considered to be explained by ld with rs6423677 because they were no longer significant after conditioning the logistic regression analyses on rs6423677 ( table 2 ). in contrast, rs6423677 remained significant (p < 0.05) after adjusting for any of the other snvs (data not shown). in a stage 3 analysis, rs4774175 and rs6423677 were further examined in an additional japanese sample set, and rs6423677 achieved genome-wide significance in a meta-analysis of the japanese sample panels (table 3) . meanwhile, the association trend of rs6423677 was weaker in korean and unreproducible in taiwanese subjects (supplementary table 10 ). rs6423677 genotypes and ighv3-66 gene usage in the immunoglobulin heavy chain repertoire the significant association of an snv within ighv3-66 with kd prompted us to investigate the impact of rs6423677 on the function of immunoglobulin molecules or b cell receptors (bcrs) harboring ighv3-66 in their heavy chain variable regions. firstly, we examined ighv usage in different immunoglobulin isotypes (igm, igd, igg, and iga) by analyzing the immunoglobulin heavy chain repertoire in peripheral b lymphocytes from healthy japanese individuals (n = 10) and patients with acute kd (n = 9) by ngs. for every ig isotype, we could identify ighv3-66 clonotypes in each individual and found that the ighv3-66 usage tended to be correlated with the number of c alleles each individual had ( fig. 2a and supplementary fig. 4) . consistent with the correlation trend, we observed significantly skewed usage of the alleles in the analyses of the five patients who were heterozygous for rs6423677, with the protective allele (a) almost completely suppressed in all immunoglobulin classes and time points examined ( supplementary fig. 5 ). similar correlation trend was also observed between rs6423677 genotypes and relative levels of igh transcript for ighv3-64, the closest neighboring gene to ighv3-66. however, the correlations were more modest than that seen for ighv3-66 ( supplementary fig. 6 ). paralogues or pseudogenes of ighv3-66 which have the 'a' nucleotide at the corresponding position of rs6432677 as well as pcr amplification bias in library preparation caused by additional variants interfering with the primer annealing could lead to such results. however, the distinct separation pattern of the allele discrimination plot in the invader assay and the clear electropherogram data in the direct sequencing of pcr-amplified genomic dna from heterozygous patients does not support that possibility ( supplementary fig. 1 ). thus, we consider these observations not to be artificial in origin. we also negated the chance of misassignment of ighv3-66 with the a allele at rs6423677 (ighv3-66*03) to other alleles (*01, *02, or *04) or paralogues such as ighv3-53 by confirming that the migmap software could correctly assign an artificially created sequence with the rs6423677 a allele as ighv3-66*03 (data not shown). to obtain an insight into the role of immunoglobulins using ighv3-66 in their heavy chain variable region in the pathogenesis of kd, we investigated how ighv3-66 usage in the immunoglobulin heavy chain gene repertoire changed over time during the clinical courses of nine kd patients (supplementary table 11 ). proportions of igh clones harboring ighv3-66 in their variable region seemed to be stable or not to have common varying patterns for igm, igd, and iga, while in two patients (patients 2 and 5), transient increases were observed for igg at the third evaluation point (fig. 2b) . then, we investigated the increased clonotypes in the igg heavy chain repertoire more precisely by defining them by the combinations of ighv, ighd, and ighj genes. we found that both patients 2 and 5 had single clonotypes with ighv3-66 that increased 1.0% or more as a proportion of the total from the first to the third evaluation points. however, the gene combinations of them were not the same (table 4) , and cdr3 amino acid sequences corresponding to the v-d-j combinations also differed between the patients (data not shown). five of the remaining seven patients also had one or more igg heavy chain clonotypes with ighv3-66 that increased 0.1% or more at the same follow-up time point. however, cooccurring v-d-j combinations in the increased clonotypes were only seen between patients 2 and 6. on the other hand, some of the cdr3 clonotypes which have recently been reported to dominate in the igm heavy chain repertoire (>0.001%) in the acute pretreatment phase of taiwanese kd patients [21] were also prevalent at a similar time point in the japanese kd patients in this study (supplementary table 12 ). a distinct increase in diversity of the cdr3 clonotypes of igm heavy chain during the convalescent phase of kd, which has also been reported in previous research of taiwanese kd patients [21] , was observed for four of the nine kd patients ( supplementary fig. 7 ). it has generally been considered that the immune-mediated vasculitis of kd is triggered in response to infection with some type of microorganism. this assumption was made based on factors indicative of a primary infection, such as its clinical symptoms, which included fever and skin rash, epidemiologic findings such as its peak age of onset (6 months to 1 year), along with the seasonality of the occurrence of regional outbreaks and nation-wide epidemics [2, 11] . despite tremendous efforts, no single microorganism has been conclusively proven as the pathogen of kd and lack of information about the pathogen has been a significant obstacle to causal treatment and disease prevention. histopathological and immunological studies have revealed activation of neutrophils, macrophages, and monocytes in the acute phase of kd [22, 23] , and now the leading hypothesis for the pathophysiology of kd inflammation is an attack of the dysregulated or hyperactive innate immune system against vascular walls [24] . in addition, genetic studies using a genome-wide approach have identified several robust susceptibility loci/genes for kd [8-10, 12, 25-32] , and an in silico prediction of responsible variants and the types of cells where they have biological significance has highlighted the importance of b cells in the pathogenesis of kd [33] . in previous literature, polyclonal activation and increase of b cells [34, 35] and detection of auto-antibodies against components of vascular endothelial cells or neutrophils in peripheral blood of acute kd patients have been documented [36, 37] . infiltration of oligoclonal plasma cells producing iga into the vascular wall of kd patients was also reported [38] . these previous findings have suggested the involvement of b cells in kd inflammation. however, a recent transcriptomic study revealed downregulation of genes related to bcr signaling in acute kd patients [39] . thus, there have been both supportive and unsupportive pieces of evidence, and there is no consensus view on the role of b cells, as well as of the adaptive immune system in kd pathogenesis. in this study, we identified genetic variants within the ighv region significantly associated with kd in the japanese population. the immunoglobulin heavy (igh) locus spans 1.3 mb (from 106.0 to 107.3 mb on nc_000014.8) of the chromosome clonotypes increased more than 1% during 1st and 3rd evaluation points are bold faced 14q32.33 region and encompasses serially arranged igh constant (ighc), ighj, ighd, and ighv clusters. because of high sequence redundancy which obstructs designing of specific genotyping assays, there is a large blank area (~0.8 mb) which was not covered by the snp arrays and therefore we lack association information about the snvs in the area (supplementary fig. 8 ). however, because snvs within the gap are not in high ld (r 2 < 0.3) with rs6423677 or rs4774175 in the 1000 genomes jpt population ( supplementary fig. 8 ) and we did not observe association signals in the chromosomal region on the opposite side of the blank area, the association signals represented by rs6423677 or rs4774175 might be localized within the region where we could investigate in this study. in contrast to the robust association of rs6423677 in the japanese subjects, it was not consistent in the korean and taiwanese subjects. although neither significant nor consistent with the results in the current study, a marginal trend of association between snvs within the ighv region and linked to rs4774175 (r 2 = 0.45-0.66 in the 1000genomes chb population) and kd in the taiwanese population had already been reported [28] . findings in the previous and the current studies are strongly indicating that variants in the ighv region are commonly involved in kd pathogenesis at least in the japanese and taiwanese populations. however, the robustness of association might not be uniform among the populations. given that multiple pathogens with regionally or seasonally differing epidemic patterns could be triggering kd, it might be possible that various susceptibility genes or alleles corresponding to different antigenicity for the pathogens exist in this locus and are related to the mixed robustness of the association. highly skewed expression of igh transcripts with the risk-associated allele adds support to consider that ighv3-66 is the functional target of the associated variants. the a to c nucleotide change at rs6423677 results in an amino acid alteration from cysteine to glycine within the cdr2 region of ighv3-66. thus, the modification might affect the affinity to some antigens of immunoglobulins carrying ighv3-66. however, we consider that the mechanism of increased susceptibility to kd associated with the c allele might not be due to reduced host defense to particular agents because it is inconsistent with the observation that the a allele, which is protective against kd and expected to have a higher neutralizing ability in this scenario, seemed to be nearly silenced. ighv3-66 has been recognized as one of the functional ighv genes and purported to be utilized at frequencies of around 1% [40] . the average proportions of ighv3-66 clonotypes in the 10 healthy adults in our study (0.88% for igm, 0.50% for igd, 1.0% for igg, and 1.1% for iga), were consistent with that previous information. it is currently unknown in what stage, i.e., somatic recombination, rna transcription, and processing of the pre-mrna, the a allele was excluded and resulted in the significantly skewed allelic usage to the c allele of rs6423677. it is suggestive that usage of ighv3-64, the nearest functional gene to ighv3-66, showed difference among genotypes at rs6423677 which was similar to that of ighv3-66 ( supplementary fig. 6 ). one potential reason is suggested by the predicted binding of ctcf transcription repressor in the 0.4 kb region encompassing rs6423677 ( supplementary fig. 9 ). ctcf has been reported to interact with multiple sites in the igh region and plays essential roles in somatic recombination [41] of the distal area of the ighv gene region. the association data of rs6423677 and the increased usage of igh transcripts with the riskassociated allele are indicative of some active role of the immunoglobulin molecules as antibodies or as components of bcrs in the development of kd. one possible role of such immunoglobulins might be activation of b cells. established kd susceptibility gene products such as b lymphoid tyrosine kinase (blk) [8] [9] [10] and inositol 1,4,5 trisphosphate 3-kinase c (itpkc) [8, 9] are involved in bcr signaling. if ivig acts through competing with such immunoglobulins for agents or antigens relevant to kd pathogenesis, the requirement of a high dose administration (1-2 g/kg) of ivig to treat kd might be reasonable because only a fraction of the igg would contribute to the therapeutic effect, with ighv3-66 expected to only account for up to several percent of the ivig preparations. b cells can be activated by nonspecific binding of microbial products such as superantigens (sags) to bcrs. intriguingly, b cell sags restricted to ighv3 segment of immunoglobulins have been known [42] . however, considering that the innate immune system has been thought to play a central role in the kd vasculitis and that kd can develop in patients with x-linked agammaglobulinemia, who lack or have small numbers of b cells [43] , the activity of b cells or immunoglobulins in kd might be relevant to initiation or enhancement of the innate immune activation but may be substitutable. recently, a significant association of an allele of the ighv4-61 gene (ighv4-61*02) with susceptibility to rheumatic heart disease (rhd), which is a long-term complication of arf, was reported [44] . ighv4-61 is located only 36 kb downstream of ighv3-66 (supplementary fig. 6) . arf develops as a sequela of streptococcus pyogenes (s. pyogenes) infection and, similar to kd, has been recognized to affect genetically susceptible individuals [45] . among reports of gwas for human diseases, a genome-wide significant association of variants in the ighv gene region has been identified only for rhd. although s. pyogenes is not recognized as the cause of kd, considering that kd shares some characteristic symptoms such as skin rash and strawberry tongue with s. pyogenes infection, it is suggestive that the previously discussed role of b cells might be related to some underlying mechanisms of the common symptoms. in 2020, multiple series of patients with pediatric inflammatory multisystem syndrome temporally associated with sars-cov2 infection (pims-ts) or (mis-c) having kd-like symptoms or increase of severe kd patients after the sars-cov2 epidemic were reported from the us and european countries [46, 47] . in the latest studies, overrepresentation of ighv3-53 and ighv3-66 in neutralizing monoclonal antibodies against the receptor binding domain of sars-cov2 spike were also reported [48, 49] . given immunoglobulin with ighv3-66 play a role in kd, it might be possible that kd-like symptoms seen in such patients are mediated by interaction between sars-cov2 and b cells expressing ighv3-66. we also found some commonality between the cdr3 clonotypes that were increased in the igm heavy chains of the taiwanese and the japanese kd patients (supplementary table 12 ). ighv3-66 was used only in one commonly increased cdr3 clonotype (supplementary table 13 ). however, as far as can be understood from the limited number of observations, ighv3-66 seemed not to be important in the igm response in the acute pretreatment phase. future characterization of the endogenous immunoglobulin molecules that are increased in kd patients utilizing information of the light chains that can be obtained simultaneously in single-cell analyses [50] will facilitate identification of the agent triggering kd as well as understanding the mechanism of action of ivig treatment. there are limitations in this study. first, in addition to the gap above where we could not examine the association of the variants, our strategy to focus only on nonsynonymous snvs on ighv genes left the possibility that rs6423677 is just a proxy of the genuinely responsible variant located outside ighv3-66. second, we did not analyze the timecourse change of the immunoglobulin heavy chain repertoire in other infectious diseases. so it is uncertain whether the upregulation of igg heavy chain transcripts with ighv3-66 is a specific observation for kd or not. third, our results might not directly reflect changes of the immunoglobulins at the protein level because we lack information about the correlation between the proportions of particular igh clones in the transcripts from b cells and in the proteins expressed on the cell surface or circulating in the serum. in conclusion, a significant association of a nonsynonymous snv in the ighv3-66 gene with kd was observed. further intensified study of the association in this region and repertoire analyses of immunoglobulins in different ethnicities and subpopulations of the patients with different demographic features would give insights into both the role of b cells in the kd pathogenesis and the causal agent of the disease. author contributions jkl, jyw, ytc, and yo supervised the study. jkl, jyw, and yo conceived the study. jyw, taj, tt, jkl, and yo designed the study. taj, ym, jkl, jyw, and yo wrote the manuscript. ah, hs, hh, th, and japan kawasaki disease genome consortium collected japanese samples. ymh, gyj, swy, jjy, kyl, and korean kawasaki disease genetics consortium collected korean samples. taiwan kawasaki disease genetics consortium and taiwan pediatric id alliance collected taiwanese samples. yml coordinated the multi-center collaboration in taiwan as the project manager and collected samples and clinical information. mk performed gwas assays for the japanese samples. at performed statistical analyses for the japanese gwas data. dy and tp performed statistical analyses for the korean gwas data. jjk conducted a follow-up study (stage 2) for the korean samples. chc performed statistical analyses for the taiwanese gwas data and followed-up meta-analyses for the taiwanese data. ycl supervised the gwas and replication genotyping pipeline, performed the data analyses. lcc performed statistical analyses for the taiwanese gwas data and followed-up meta-analyses for the taiwanese data. cpc performed genotyping and direct sequencing of taiwanese samples. taj, dy, and chc conducted the whole-genome imputation. taj performed p value simulation and meta-analyses. ko, tt, and ki performed genotyping and direct sequencing of the japanese samples. ym and yo performed the ngs data analyses for the igh repertoires. conflict of interest the authors declare that they have no conflict of interest. ethical approval this study was approved by the institutional review board at all involved institutes. informed consent written informed consent was obtained from all subjects. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children epidemiological observations of kawasaki disease in japan coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome nationwide survey of kawasaki disease and acute rheumatic fever high-dose intravenous gammaglobulin for kawasaki disease the treatment of kawasaki syndrome with intravenous gamma globulin a single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute kawasaki syndrome genome-wide association study identifies fcgr2a as a susceptibility locus for kawasaki disease a genome-wide association study identifies three new risk loci for kawasaki disease two new susceptibility loci for kawasaki disease identified through genome-wide association analysis kawasaki disease: a brief history a genome-wide association analysis reveals 1p31 and 2p13.3 as susceptibility loci for kawasaki disease an integrated map of genetic variation from 1,092 human genomes a linear complexity phasing method for thousands of genomes genotype imputation with thousands of genomes fast and accurate genotype imputation in genome-wide association studies through pre-phasing characterizing immunoglobulin repertoire from whole blood by a personal genome sequencer flash: fast length adjustment of short reads to improve genome assemblies allele-specific repression of lymphotoxin-alpha by activated b cell factor-1 genome-wide association study identifies three new susceptibility loci for adult asthma in the japanese population immunoglobulin profiling identifies unique signatures in patients with kawasaki disease during intravenous immunoglobulin treatment neutrophilic involvement in the damage to coronary arteries in acute stage of kawasaki disease activation of peripheral blood monocytes and macrophages in kawasaki disease: ultrastructural and immunocytochemical investigation kawasaki disease: a matter of innate immunity itpkc functional polymorphism associated with kawasaki disease susceptibility and formation of coronary artery aneurysms common variants in casp3 confer susceptibility to kawasaki disease a genome-wide association study identifies novel and functionally related susceptibility loci for kawasaki disease identification of novel susceptibility loci for kawasaki disease in a han chinese population by a genome-wide association study genome-wide linkage and association mapping identify susceptibility alleles in abcc4 for kawasaki disease genetic variation in the slc8a1 calcium signaling pathway is associated with susceptibility to kawasaki disease and coronary artery abnormalities whole genome sequencing of an african american family highlights toll like receptor 6 variants in kawasaki disease susceptibility a genome-wide association analysis identifies nmnat2 and hcp5 as susceptibility loci for kawasaki disease genetic and epigenetic fine mapping of causal autoimmune disease variants immunoregulatory abnormalities in mucocutaneous lymph node syndrome mononuclear cell subsets and coronary artery lesions in kawasaki disease immunoglobulin m antibodies present in the acute phase of kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon antineutrophil cytoplasm antibodies in kawasaki disease oligoclonal iga response in the vascular wall in acute kawasaki disease unique activation status of peripheral blood mononuclear cells at acute phase of kawasaki disease accumulation of vh replacement products in igh genes derived association of an ighv3-66 gene variant with kawasaki disease from autoimmune diseases and anti-viral responses in human ctcf-binding elements mediate control of v(d)j recombination age-associated changes in binding of human b lymphocytes to a vh3-restricted unconventional bacterial antigen autoimmunity in x-linked agammaglobulinemia: kawasaki disease and review in the literature pacific islands rheumatic heart disease genetics network. association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in oceania cumulative incidence of rheumatic fever in an endemic region: a guide to the susceptibility of the population? hyperinflammatory shock in children during covid-19 pandemic clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 potent neutralizing antibodies against sars-cov-2 identified by highthroughput single-cell sequencing of convalescent patients' b cells structures of human antibodies bound to sars-cov-2 spike reveal common epitopes and recurrent features of antibodies high-throughput sequencing of the paired human immunoglobulin heavy and light chain repertoire 23 • taesung park 24 • korean kawasaki disease genetics consortium, taiwan kawasaki disease genetics consortium acknowledgements this study was supported by grants from the millennium project, from the japan kawasaki disease research center (2015 to ym, and 2018 and 2019 to yo), and from the japan agency for medical research and development (jp18ek0410039 to th). this study was also supported by a grant from the ministry of health & welfare of the republic of korea (hi15c1575 to jkl). we are grateful to the kd patients and their family members as well as the medical staff taking care of the patients. we also thank ms. yoshie kikuchi for her technical assistance. key: cord-331249-jrzgqq8q authors: del castillo martín, fernando title: enfermedad de kawasaki date: 2006-06-30 journal: seminarios de la fundación española de reumatología doi: 10.1016/s1577-3566(06)75082-5 sha: doc_id: 331249 cord_uid: jrzgqq8q resumen la enfermedad de kawasaki es una vasculitis sistémica de etiología desconocida que afecta principalmente a niños menores de 5 años. es actualmente la primera causa de cardiopatía adquirida en la infancia en los países desarrollados, lo que la convierte en una enfermedad de suma trascendencia en el momento actual. no se conoce su etiología, aunque existen fuertes sospechas de que sea infecciosa. el diagnóstico se realiza por criterios clínicos de fiebre persistente de al menos 5 días de duración y 4 de 5 criterios clínicos: cambios en extremidades, exantemas polimorfos, inyección conjuntival no exudativa, cambios en los labios y la mucosa oral y adenopatías>1,5cm, habitualmente unilateral. la complicación más frecuente es la dilatación y los aneurismas de las arterias coronarias, la cual ocurre en el 20-25% de los niños no tratados. el tratamiento estándar de la enfermedad es con gammaglobulina intravenosa en dosis de 2g/kg, antes de los 10 días del comienzo de la enfermedad, más ácido acetilsalicílico oral en dosis antiinflamatorias. el riesgo de lesión coronaria en los niños tratados es del 3-5%. abstract kawasaki disease is a systemic vasculitis of unknow etiology that occurs predominantly in children under the age of 5 years. kawasaki disease is the most common cause of acquired heart disease in children in the developed world. the exact cause has not yet been established but there is considerable support for it to be due to an infectious agent. the diagnosis of kawasaki disease is based in clinical criteria: fever persisting at least 5 days and the presence of at least 4 principal features: changes of extremities, polymorphous exanthem, bilateral bulbar conjunctival injection without exudate, changes in lips and oral cavity and cervical lymphadenopathy>1.5cm, usually unilateral. the most common complication is coronary arterial aneurysm and coronay arterial dilatation that occurs in 20-25% untreated children. standard treatment for kawasaki disease include intravenous immunoglobulin as a single 2g/kg dose within the first 10 days and oral acetilsalycilic acid. the risk of coronary damage in treated patient is 3-5%. la enfermedad fue descrita por primera vez en japonés por tomisaku kawasaki 1 en 1967, con el nombre de síndrome mucocutáneo ganglionar. el primer caso visto por el autor fue en 1961 en un niño de 4 años, pero no sospechó que se tratara de una nueva enfermedad hasta un año más tarde al diagnosticar a otro paciente con iguales características 2 . kawasaki comunicó la existencia de los primeros 7 enfermos en un congreso japonés en 1962 con el nombre de "síndrome de la fiebre no escarlata con descamación", sin que tuviera reconocimiento. éste no llega hasta 1968 con la primera publicación de 50 casos en una revista de alergología (dada la dificultad de publicación en revistas pediátricas) con el nombre de "síndrome mucocutáneo ganglionar". sin embargo, la enfermedad no se reconoce en el resto del mundo hasta que se publica en 1974 en lengua inglesa 3 . inicialmente, kawasaki pensó que la enfermedad era autolimitada y sin complicaciones. sin embargo, la autopsia de uno de los primeros casos encontró ya graves alteraciones cardíacas, que se confirmaron más tarde en un estudio nacional realizado en 1970 sobre 10 autopsias de enfermos, en las que se comprobó las terribles secuelas coronarias 2 . esto hizo que en un principio se relacionara a la enfermedad con la periarteritis nudosa en su forma infantil. sin embargo, estudios necrópsicos en ambas enfermedades pudieron demostrar que realmente la periarteritis nudosa en su forma infantil no era sino la enfermedad de kawasaki, así que a finales de los años setenta quedó perfectamente definida como un cuadro clínico y anatomopatológico único 4 . la enfermedad de kawasaki es una vasculitis sistémica de etiología desconocida que afecta principalmente a niños menores de 5 años. es actualmente la primera causa de cardiopatía adquirida en la infancia en los países desarrollados, lo que la convierte en una enfermedad de suma trascendencia en el momento actual. no se conoce su etiología, aunque existen fuertes sospechas de que sea infecciosa. el diagnóstico se realiza por criterios clínicos de fiebre persistente de al menos 5 días de duración y 4 de 5 criterios clínicos: cambios en extremidades, exantemas polimorfos, inyección conjuntival no exudativa, cambios en los labios y la mucosa oral y adenopatías > 1,5 cm, habitualmente unilateral. la complicación más frecuente es la dilatación y los aneurismas de las arterias coronarias, la cual ocurre en el 20-25% de los niños no tratados. el tratamiento estándar de la enfermedad es con gammaglobulina intravenosa en dosis de 2 g/kg, antes de los 10 días del comienzo de la enfermedad, más ácido acetilsalicílico oral en dosis antiinflamatorias. el riesgo de lesión coronaria en los niños tratados es del 3-5%. por sus características, se piensa que la enfermedad tiene un origen infeccioso: signos y síntomas propios de otras enfermedades infecciosas; incidencia estacional con brotes epidémicos frecuentes; enfermedad propia de niños pequeños, pero rara en los primeros meses de la vida (cuando existe aún inmunidad materna transferida) y, también, rara en niños mayores y adultos, posiblemente por adquisición de inmunidad permanente a través de formas oligosintomáticas 5 . sin embargo, hasta este momento no se ha podido identificar un agente causal concreto. se han publicado casos atribuidos a propionibacterium acnes, retrovirus, diferentes virus de la familia del herpes, parvovirus, rickettsia y, en el último año, coronavirus 6 , sin que se haya podido confirmar ninguno de esos agentes, especialmente el último 7, 8 . sin embargo, no sólo no se conoce la etiología, sino que tampoco la patogenia. en los últimos años ha surgido una nueva hipótesis relacionada con la respuesta de superantígeno. la enfermedad por superantígeno se describe por primera vez en el síndrome del shock tóxico causado por la toxina tsst-1, producida por una cepa especial de staphylococcus aureus 9 . los superantígenos son agentes infecciosos, frecuentemente toxinas bacterianas, cuyo mecanismo de acción se basa en estimular una vía anómala de la respuesta inmunitaria 10 . los linfocitos t reconocen los antígenos convencionales no como proteínas completas, sino como fragmentos peptídicos del antígeno inicial procesado por el macrófago para ese fin. una vez procesado el antígeno, el fragmento es colocado en el complejo mayor de histocompatibilidad (cmh), pero en su surco central. este complejo péptido-cmh es reconocido selectivamente por los linfocitos t con la misma forma alélica que el cmh, y en ese momento se produce su activación y la formación de linfocitos con capacidad específica. la vía anómala de la respuesta del superantígeno consiste en que el antígeno se expresa sin procesar en el macrófago, como proteína intacta, y se acopla en uno de sus brazos, y no en el surco del cmh, mientras que por el otro extremo libre se fija al receptor del linfocito t, pero sólo a aquellos que expresan la cadena lateral vβ, y así el linfocito queda activado. esta activación es no sólo inespecífica, sino también masiva, ya que 1 de cada 10 linfocitos presenta la cadena lateral vβ, lo que produce una hiperrespuesta linfoci-taria policlonal inespecífica. esta etiopatogenia se ha confirmado en algunas enfermedades infecciosas, como el síndrome del shock tóxico causado por la toxina estafilocócica o por la estreptocócica y es posible que se encuentre en el origen de algunas enfermedades reumáticas o exantemáticas 9 (fiebre reumática, artritis, psoriasis, dermatitis atópica, escarlatina, escaldadura estafilocócica). el hallazgo por algunos autores de un incremento de linfocitos t vβ en la enfermedad de kawasaki 11, 12 y el aislamiento de cepas de s. aureus de características especiales en estos enfermos 13 hicieron pensar a algunos investigadores en la posibilidad de que los superantígenos causaran la enfermedad de kawasaki. sin embargo, no todos los autores encuentran esta expansión policlonal de linfocitos vβ 14-16 y ninguno ha podido aislar cepas especiales de s. aureus. muy por el contrario, últimamente algunos investigadores han observado una expansión oligoclonal de células plasmáticas iga con formación de infiltrados en la pared vascular en la fase aguda de la enfermedad, lo que es propio de una respuesta antigénica convencional 17, 18 . ese mismo grupo ha detectado por inmunohistoquímica, en el epitelio bronquial de 4 enfermos con la enfermedad de kawasaki en la fase aguda, inclusiones citoplásmicas compatibles con agentes virales 19 , lo que indica a los autores el contagio de un agente viral por la vía respiratoria. no obstante, la hipótesis del superantígeno no puede ser excluida, dado el reciente hallazgo de una expansión natural de linfocitos t con expresión del receptor βv2 y βv6s5 junto con la presencia en el suero de anticuerpos frente a la toxina estreptocócica pirogénica c en niños con la enfermedad y la expansión de estas células en la sangre de individuos sanos al ser estimulados con dicha toxina 20 . todo esto ha conducido a pensar en la posibilidad de que diferentes agentes etiológicos actúen en respuestas inmunitarias diferentes 21 , lo que se ha atribuido, también teóricamente, a otras enfermedades. sin embargo, como dice anne rowley 21 , "la búsqueda de esta fascinante enfermedad continúa… [mientras] la naturaleza del antígeno implicado es un misterio". en este contexto podemos entender la discusión terminológica no resuelta de si hay que llamar a este cuadro síndrome o enfermedad. mientras que la tradición se inclina por el término enfermedad, la más que probable etiología multifactorial hace más lógica la palabra síndrome. en este sentido, no deja de ser curioso que los mismos autores usen indis-tintamente ambos términos según los resultados de su investigación 18, 19 . la lesión propia de la enfermedad es una vasculitis sistémica con afección inicial de la capa endotelial. esta lesión endotelial es la que otorga a la enfermedad de kawasaki sus características especiales y su trascendencia 22 . se afirma habitualmente que la lesión vascular en la enfermedad de kawasaki es propia de arterias de tamaño mediano, especialmente las arterias coronarias. sin embargo, en estudios necrópsicos de niños con enfermedad de kawasaki, se han encontrado lesiones en arterias de pequeño, medio y gran tamaño, como las arterias aorta, ilíacas, pulmonares, renales, suprarrenales, hepáticas, esplénicas, pancreáticas, mesentéricas, espermáticas y testiculares, ováricas y uterinas, musculoesqueléticas y otras, así como en venas de diferentes territorios 4, 23 . igualmente se ha descrito casos clínicos de aneurismas arteriales periféricos con gangrena y amputación de extremidades, aunque estos aneurismas suelen ocurrir generalmente en niños menores de 1 año 24 . estos hallazgos hacen suponer que la lesión vascular periférica y sistémica puede ser más frecuente de lo que actualmente se piensa y sus complicaciones y secuelas tardías podrían ir más allá de las ya conocidas cardíacas 25 . la lesión vascular se origina a partir de la respuesta inflamatoria generada por la noxa hasta ahora desconocida 26 . la intimidad de este proceso ha empezado a conocerse recientemente. en una primera fase habría una activación de células mononucleares con expresión de diferentes moléculas de adhesión (icam-1, vcam-1 y selectinas) en la superficie de las células endoteliales como respuesta al estímulo inflamatorio. esto induciría la adhesión al endotelio de macrófagos, trombocitos y neutrófilos y la secreción del factor de crecimiento de células endoteliales. todo ello favorece el aumento de la permeabilidad vascular y la formación de infiltrados de células inflamatorias en la pared del vaso. en una segunda fase, la producción de citocinas y enzimas proteolíticas por esas células infiltradas en la capa muscular origina su destrucción y el crecimiento de la íntima como respuesta. la sustitución de la capa muscular por un tejido conectivo causa la pérdida de la elasticidad y la consistencia del vaso y su dilatación, con la formación de ectasias o aneurismas. además, la proliferación de la íntima produce agregación plaquetaria intravascular y la creación de trombos que causan obstrucción vascular de diversos grados 26 . existen aneurismas coronarios ya al primer mes del comienzo de la enfermedad y graves estenosis a partir del día 40 27 . no obstante, estudios anatomopatológicos en enfermos fallecidos en distintas fases de la enfermedad encuentran que el engrosamiento de la íntima es la lesión vascular tardía principal, independientemente de que se formen trombos o no 28 . este engrosamiento de la íntima puede ser discreto y modelar la luz vascular, creando la falsa sensación de que se resuelve el aneurisma. sin embargo, esta falta de endotelio es un factor de riesgo de futuras alteraciones vasculares 29 . la enfermedad es propia de niños pequeños, y se presenta en un 80% de los casos en niños menores de 4 años, aunque es rara en lactantes menores de 3 meses. sin embargo, la enfermedad puede ocurrir a todas las edades, incluso en adolescentes y adultos jóvenes. la frecuencia de la enfermedad varía mucho de unos países a otros y, especialmente, de unas razas a otras, pero es mucho más frecuente en individuos orientales que en caucásicos. la incidencia anual en niños menores de 5 años en japón es de 60-90 casos por 100.000 menores de 5 años, mientras que en europa y estados unidos es de 10-15 casos por 100.000 menores de 5 años 30, 31 . estudios recientes encuentran un aumento de la incidencia en japón (111,7/100.000 menores de 5 años 32 ) y en otros países 33, 34 . sin embargo, algunos autores creen que este incremento puede estar más en relación con un mejor diagnóstico de la enfermedad que con un verdadero aumento de la enfermedad. la enfermedad de kawasaki es más frecuente en varones que en mujeres, con una relación varón:mujer de 1,5:1. asimismo, la enfermedad se puede presentar de manera esporádica o en epidemias, con variaciones estacionales, más frecuente en invierno y primavera. en españa no existe demasiada información sobre la frecuencia de la enfermedad. una revisión de lo publicado en nuestro país entre 1973 y 1997 encuentra 238 casos comunicados en 54 revistas españolas, con 3 grandes series de 38, 36 y 23 casos 35 . hay publicaciones posteriores de casos aislados y 2 nuevas grandes series con 33 y 19 casos comunicadas en diferentes congresos pediátricos 36 . la mayoría de las series refieren una media de 2-3 casos por año, aunque algunas llegan hasta 6 casos/año. sin embargo, si es cierta nuestra experiencia, creemos que esta frecuencia está por debajo de la realidad. en 1993 publicamos una serie de 38 casos diagnosticados en nuestro hospital, lo que suponía una media de 2,7 casos/año 37 . a partir de esa fecha, y dado el interés que originó la publicación, comenzamos una búsqueda activa de la enfermedad en el servicio de urgencias, y se diagnosticó entre 1994-1998 una media de 14 casos/año (datos no publicados). en el período siguiente (1999-junio de 2002) otra serie de nuestra área sanitaria recogió una media de 12,8 casos/año, con una incidencia de 7,1 casos/100.000 menores de 15 años y de 15,1 casos/100.000 niños de hasta 5 años 36 , muy parecida a la de nuestro entorno. creemos por ello que la enfermedad de kawasaki está infravalorada en nuestro país. la enfermedad presenta 3 fases 38 . la fase aguda tiene una duración de 1-2 semanas y está marcada por la fiebre. la segunda, o fase subaguda, tiene una duración de unas 4 semanas y se inicia con la desaparición de la fiebre y de la mayor parte de los síntomas y la aparición de la típica descamación subungueal y trombocitosis. en esta fase es cuando aparecen los aneurismas coronarios y se produce el mayor número de muertes. finalmente, la tercera fase, o de convalecencia, se prolonga 6-8 semanas y en ella se normalizan todos los síntomas y los análisis, pero muestra la situación final e irreversible de los daños coronarios. la enfermedad se define por la presencia de fiebre de al menos 5 días de duración acompañada de 4 de estos 5 criterios clínicos: inyección conjuntival, alteraciones de la boca (labios enrojecidos y agrietados y/o lengua aframbuesada y/o enantema), alteraciones de pies y manos (eritema palmoplantar y/o edema duro de pies y manos y/o descamación subungueal), exantemas polimorfos y adenopatías mayores de 1,5 cm. si hay lesión coronaria, es suficiente que se den 3 criterios. muy recientemente se ha considerado que se puede hacer el diagnóstico de la enfermedad con menos de 5 días de fiebre, siempre que se cumplan estrictamente los criterios mencionados 39 (tabla 1). suele ser el primer síntoma en aparecer y la manifestación que determina el diagnóstico. los restantes signos y síntomas aparecen en los días siguientes, pero frecuentemente de manera sucesiva, por lo que podemos decir que la enfermedad se manifiesta a veces más como una película que como una fotografía, de ahí la importancia de una correcta anamnesis 40 . la fiebre es intermitente, con 2 o 3 picos al día que pueden superar los 40 °c, y se acompaña de gran afección general. la duración sin tratamiento es de 1 a 2 semanas, aunque puede prolongarse 4 o 5 semanas. el exantema de la enfermedad de kawasaki es un gran simulador y su interpretación exclusiva conduce frecuentemente a errores diagnósticos 41 . el exantema de la enfermedad de kawasaki es muy variado (polimorfo) y cambiante. las 2 formas de presentación más habituales son la seudourticarial y la maculopapulosa (seudosarampionosa) 38 . también hay erupciones que recuerdan a la escarlatina, con la que frecuentemente hay que confrontar el diagnóstico o, simplemente, exantemas de distribución y aspecto inclasificables con placas eritematosas o maculopapulosas de distribución caprichosa 40 . se debe pensar en esta enfermedad ante cualquier exantema no caracterizado y de distribución arbitraria. también es propio de la enfermedad el as pecto cambiante del exantema, que adopta varias formas durante su evolución 42 , dato, según nuestra opinión, no suficientemente subrayado en la bibliografía. en los lactantes el exantema a veces se acompaña de un intenso eritema del pañal de aparición brusca y febril, y en ocasiones es la única manifestación cutánea 43 . no se ha descrito vesículas ni ampollas y su presencia obliga a pensar en otras enfermedades 39 . las petequias son excepcionales, aunque pueden presentarse. los exantemas, al igual que la fiebre, desaparecen en la fase subaguda. las 3 lesiones descritas son el enrojecimiento con sequedad y, a veces, sangrado de labios, la lengua de frambuesa y el enantema. cualquiera de esas alteraciones labiales se debe considerar como criterio diagnóstico. sin embargo, lo más típico es el enrojecimiento de los labios. éstos están vivos, "como pintados", secos, agrietados e incluso sangrantes. aunque el enrojecimiento desaparece en la fase subaguda, pueden permanecer secos durante varios días o semanas. la lengua está roja e hiperpapilada, lengua aframbuesada. en la boca y la faringe hay un fuerte enrojecimiento sin exudado amigdalar ni lesiones ulcerativas o aftas, cuya presencia debe hacernos pensar en otras entidades 39, 42, 44 . hay un enrojecimiento de la conjuntiva, preferentemente bulbar, no exudativo ni fotofóbico, lo que permite diferenciarlo de la conjuntivitis de otras enfermedades exantemáticas (véase "diagnóstico diferencial"). este enrojecimiento puede ser mínimo y pasar inadvertido si no se busca o intenso y llamativo. igualmente se suele prolongar discretamente en la fase subaguda. en la fase aguda se producen eritema palmoplantar y edema de pies y manos, y en la fase subaguda posfebril, una descamación subungueal. el enrojecimiento de palmas y plantas se manifiesta como un eritema de toda la palma o planta sin lesiones parcheadas, como si el niño se hubiera quemado, con terminación nítida en el borde con el dorso y en el final de la muñeca 42 . este detalle es muy importante, pues con frecuencia en algunas enfermedades el propio exantema de la extremidad se extiende a la mano, falseando este signo. el eritema palmoplantar es difícil de descubrir en el lactante, ya que éste tiende a cerrar fuertemente la mano. la descamación subungueal es tardía, comienza debajo de la uña, llega habitualmente hasta la segunda falange y es excepcional que afecte a la palma o la planta. esta descamación puede ocurrir en todos los dedos o sólo en uno. por su peculiaridad, suele ser el signo que hace pensar en la enfermedad cuando ya, desgraciadamente, las lesiones coronarias están establecidas. la descamación típica se acompaña en ocasiones de una descamación fina, discreta y troncular, de carácter inespecífico. es el criterio menos frecuente. la adenopatía es mayor de 1,5 cm, habitualmente única y cervical, aunque también puede ser múltiple y localizada en otras regiones. nunca supura y típicamente aparece y desaparece bruscamente. se presenta en alrededor del 50% de los casos 42 , aunque en ocasiones puede ser, junto con la fiebre, el síntoma inicial y más destacado 45 . por su poca frecuencia, creemos que no debería ser un criterio mayor, ya que a veces impide el diagnóstico de una enfermedad en la que la suma de criterios es esencial. existe una gran variedad de manifestaciones asociadas a los criterios mayores en la enfermedad de kawasaki, aunque su presencia no es obligada para el diagnóstico (tabla 2). la característica asociada más frecuente, a veces olvidada por no estar incluida en los criterios mayores, erróneamente según nuestra opinión, es la irritabilidad con letargo del niño enfermo 42 . son niños que permanecen postrados y somnolientos, pero que se irritan fácilmente cuando se les molesta, y vuelven a su estado de postración una vez que se les deja. la artritis se presenta en el 30% y la artralgia en el 50% de los casos no tratados, pero son muy raras los tratados 42, 46 . la artritis es más frecuente en niñas mayores. existen 2 formas de artritis relacionada con la enfermedad, una de aparición temprana, un 30-35% de los casos, y otra de aparición tardía, un 65-70% de los casos. la artritis de la fase aguda es poliarticular con afección de pequeñas y grandes articulaciones y una importante alteración del líquido articular con más de 100.000 leucocitos/µl, disminución de la glucosa y aumento de las proteínas. hay otra artritis en la fase subaguda de la enfermedad, pero más oligoarticular, de las grandes articulaciones, especialmente las de carga. el volumen del líquido articular es también grande, pero con menos celularidad que la artritis de comienzo 42 . el pronóstico de la artritis es favorable, y se cura fácilmente con reposo y antiinflamatorios, aunque en algunos enfermos observados por nosotros la mejoría puede ser más lenta y tener manifestaciones articulares durante varias semanas. la curación de la artritis es sin secuelas. no se ha descrito reactivaciones ni lesiones tardías en la edad adulta. desde las primeras descripciones de la enfermedad, se observó que había formas clínicas que no cumplían todos los criterios, pero que, igualmente que las formas completas, se acompañaban de coronariopatías 47 . estas formas fueron conocidas inicialmente como atípicas. sin embargo, recientemente se ha sustituido esa denominación por la más exacta formas incompletas 48 y se limita el concepto de atípico a los casos de la enfermedad que cumplen todos los criterios, pero que de alguna manera tienen una presentación inhabitual, como hepatopatía o nefropatía graves 39, 49 . las formas incompletas son de suma importancia y suponen el mayor reto para el clínico 48 , ya que se presentan más en niños menores de 12 meses, precisamente aquellos en los que la lesión coronaria es más frecuente y más grave 47 . no existía hasta ahora acuerdo entre los investigadores a la hora de establecer criterios diagnósticos comunes para estas formas. sin embargo, recientemente, un grupo de expertos de la academia americana de pediatría y de la asociación americana del corazón han creado un algoritmo no basado en la evidencia, pero que permite racionalizar el diagnóstico de las formas incompletas 37 (tabla 3). para que un caso pueda ser diagnosticado de enfermedad de kawasaki incompleta, debe tener al menos 5 días de fiebre, 2 o 3 criterios clínicos, elevación de los reactantes de fase aguda (proteína c reactiva y/o velocidad de sedimentación) y al menos 3 de las siguientes alteraciones analíticas: albúmina ≤ 3 g/dl, anemia para la edad del niño, elevación de alaninaminotransferasa, plaquetas > 450.000 después de 7 días de fiebre, leucocitos ≥ 15.000/µl y en orina ≥ 10 células/campo. cualquier enfermo que cumpla estos criterios debe recibir un tratamiento con gammaglobulina. hay autores que incluso proponen un tratamiento si el niño es un lactante con fiebre sin foco de más de 5 días de duración, acompañada de aumento de la proteína c reactiva, neutrofilia y trombocitosis después de 7 días de fiebre, pero muy especialmente si tiene al menos uno de los siguientes signos: inyección conjuntival, enrojecimiento de labios o exantema 48 . en estos casos dudosos puede ser útil el examen oftalmológico para detectar la característica uveítis anterior. la frecuencia de los criterios mayores en las formas incompletas varía según los autores. una revi sión de 25 casos, publicados en las décadas de los ochenta y los noventa, encuentra que la fiebre se presenta en el 88% de los casos (según la nueva definición 39 , debería ser el 100%), mientras la frecuencia de los restantes síntomas es de alrededor del 50%, excepto la adenopatía, que sólo se observó en el 36% de los casos 50 . la edad media de los niños fue de 7 meses, el 95% de ellos presentó lesiones coronarias y el 32% falleció. esa serie demuestra la importancia y la gravedad de las formas incompletas de la enfermedad de kawasaki. en la fase aguda hay leucocitosis moderada con neutrofilia y desviación izquierda, con un aumento de los reactantes de fase aguda, como velocidad de sedimentación globular y proteína c reactiva. el recuento de leucocitos aumenta progresivamente en los primeros 10 días, excepto en los enfermos tratados. en la fase aguda, las plaquetas son normales y puede haber una discreta anemia normocrómica. en el 40% de los casos se produce un aumento moderado de las enzimas hepáticas, sobre 2 veces su valor normal; en un 10%, un incremento de la bilirrubina a base de directa, y en un 60%, piuria estéril 42 . los leucocitos y los otros reactantes se normalizan en la fase subaguda, mientras que las plaquetas comienzan a elevarse en el 50% de los enfermos a partir del quinto día del inicio de la enfermedad, casi el 100% en el décimo día, y alcanza su máximo (650.000-2.000.000/mm 3 l) entre los días 10 y 20, para iniciar después un descenso 42 . puede haber también hipoalbuminemia y pleocitosis en el líquido cefalorraquídeo. existe una gran número de entidades que se asemejan a la enfermedad de kawasaki ofrecemos un diagnóstico diferencial matizado por nuestra experiencia y por la de otros autores 25, 42, 51, 52 (tabla 4). quizá era el diagnóstico diferencial más difícil en la época prevacunal 53, 54 . los datos diferenciales más importantes son la afección respiratoria de vías bajas, el característico exantema descendente y las manchas de koplik en el sarampión 50 , signos inexistentes en la enfermedad de kawasaki. la escarlatina también tiene características comunes, como es la lengua aframbuesada y el exantema tipo escarlatiniforme que existe en muchos casos de enfermedad de kawasaki. sin embargo, la escarlatina no tiene conjuntivitis ni labios rojos y la descamación laminar palmoplantar es más rara, y si se presenta, es más extensa, hasta las palmas y las plantas 25 . tampoco tiene hepatopatía, afección neurológica, uretritis ni coronariopatía. según nuestra experiencia, es, junto al sarampión, uno de los diagnósticos diferenciales más difíciles 25, 40 . los exantemas medicamentosos, especialmente los causados por anticomiciales, como carbamazepina, y antiinflamatorios, pueden semejar una enfermedad de kawasaki y puede ser muy difícil diferenciarlos de ella. un enrojecimiento más oscuro, casi vinoso, del exantema y el antecedente de la medicación pueden servir de orientación. estos y otros fármacos también puede producir el síndrome de stevens-johnson, pero las características clínicas son diferentes, pues en un caso hay eritema oscuro y en el otro, medallones en escarapela con ampollas. el síndrome del shock tóxico (sst) supone en ocasiones uno de los diagnósticos diferenciales más difíciles 51 . los criterios mayores del sst son fiebre mayor de 39,5 °c, exantema eritrodérmico, descamación laminar de extremidades y tronco, hipotensión o shock periférico y afección de al menos 3 sistemas: mucosas (hiperemia conjuntival, orofaríngea y genital), gastrointestinal (vómitos y diarrea), muscular (mialgias y elevación de la creatincinasa), renal (uremia y piuria estéril), hepática (elevación de transaminasas), hematológico (plaquetas menores de 100.000/µl) y nervioso central (alteración de la conciencia). el sst presenta leucocitosis con trombocitopenia en la fase aguda y trombocitosis en la de convalecencia. como se puede observar, hay importantes similitudes entre ambos cuadros. hay también rasgos diferenciales: hipotensión arterial o shock periférico, obligado en el sst, excepcional en la enfermedad de kawasaki (si la hay, es cardiogénica); la edad: habitualmente por debajo de los 5 años en la enfermedad de kawasaki, niños mayores o adultos en el sst; trombocitopenia en la fase aguda en el sst; aneurismas coronarios en la enfermedad de kawasaki, no descritos en el sst. esta enfermedad se manifiesta con una eritrodermia escarlatiniforme, fiebre y afección del estado general. sin embargo, no están afectadas las mucosas, aunque puede haber costras periorificiales en boca, nariz y ojos. la eritrodermia del síndrome de la escaldadura se acompaña de ampollas y del signo de nikolski, no presente en la enfermedad de kawasaki. el diagnóstico diferencial más difícil de la escaldadura estafilocócica es con la necrólisis epidérmica tóxica. la net es una de las enfermedades cutáneas más graves y con mayor mortalidad. al comienzo parece un síndrome de la piel escaldada estafilocócica, pero con mal estado y fiebre elevada. luego se forman grandes ampollas, semejantes a las de un enfermo quemado, y aftas en todas las mucosas, con grave esofagitis que impide al enfermo alimentarse. no hay lesiones viscerales, aunque la pérdida de proteínas, la falta de alimento y la fiebre pueden llevar al enfermo al shock. el principal diagnóstico diferencial de esta enfermedad es con la net. sin embargo, las lesiones cutáneas en medallones seudourticariales, la conjuntivitis y la afección orofaríngea pueden hacer pensar en enfermedad de kawasaki. no obstante, tal confusión resulta difícil si observamos que en este síndrome la conjuntivitis es purulenta, las lesiones bucales son aftas muy dolorosas (lo que nunca ocurre en la enfermedad de kawasaki) y los medallones cutáneos forman escarapelas con tendencia a crear ampollas. el exantema de la enfermedad de kawasaki en ocasiones es urticarial, y puede confundirse con una urticaria infecciosa. sin embargo, el diagnóstico diferencial no es difícil, porque la urticaria tiene fiebre poco elevada, un estado general normal, no hay afección de mucosas y su evolución es muy corta. existe además una larga lista de enfermedades de posible diagnóstico diferencial con la enfermedad de kawasaki 50, 52 , como leptospirosis, acrodinia, rubéola, exantema súbito, mononucleosis infecciosa, infecciones por adenovirus, mycoplasma pneumoniae o parvovirus, fiebre de la montañas rocosas y alguna más. no obstante, creemos que resulta difícil confundir estas entidades con la enfermedad de kawasaki, siempre que se la conozca bien y no tenga una expresión demasiado atípica. también se la cita frecuentemente 50, 52 , ya que comparte con la enfermedad de kawasaki algunos signos como fiebre elevada, artritis, linfadenopatía y exantema. no obstante, el exantema de la artritis idiopática juvenil es muy tenue y evanescente, la conjuntivitis es excepcional, las adenopatías son pequeñas y generalizadas, y no hay afección de mucosas, como lengua aframbuesada. además, la ausencia de lesión coronaria permite su diferenciación con la enfermedad de kawasaki 55 . sin embargo, para complicar el problema, muy recientemente se ha descrito lesiones coronarias diagnosticadas por ecografía en 5 de 12 enfermos con artritis idiopática juvenil en su forma sistémica 56 . dos de esos enfermos cumplían inicialmente criterios de enfermedad de kawasaki. la dilatación coronaria fue superior a 2 desviaciones estándar, pero ningún enfermo presentó aneurismas coronarios y todas las lesiones se normalizaron a los 4 meses. los autores discuten este novedoso hallazgo y señalan la posibilidad de que ambas enfermedades presenten un factor etiopatogénico común. en cualquier caso, se debe pensar en enfermedad de kawasaki si un enfermo presenta 25 : 1. exantema febril con importante afección del estado general. 2. exantema generalizado con fiebre que no recuerde a ninguna otra enfermedad eruptiva. 3. cualquier exantema que se modifique o varíe de aspecto durante su evolución. ante todo eritema del pañal intenso, febril y de aparición brusca. cualquier exantema que se acompañe de leucocitosis y neutrofilia. 6. escarlatina en un niño menor de 3 años o de cualquier edad, pero con conjuntivitis. un sarampión sin tos. la enfermedad de kawasaki actualmente es la primera causa de cardiopatías adquiridas en los países desarrollados, y supera a la lesión cardíaca de origen reumático 46 . se ha encontrado en la fase aguda insuficiencia mitral en el 1,1% de los casos, insuficiencia aórtica en el 0,2%, pericarditis en el 16% y miocarditis en el 38% 57 . en esta fase temprana el enfermo puede entrar en shock cardiogénico, bien por infarto de miocardio, bien por miocarditis aguda, aunque el infarto de miocardio es propio de las semanas posteriores. en este caso el diagnóstico diferencial con el síndrome del shock tóxico puede ser difícil, aunque el shock en este caso es vascular periférico 58 . no obstante, el infarto agudo de miocardio es más propio de la fase subaguda o del primer año, y más frecuente en varones, lactantes y niños con aneurismas gigantes. el infarto en niños puede ser asintomático en el 37% de los casos, y el dolor torácico es propio de niños mayores de 4 años. su incidencia oscila en un 0,10-0,12% después del primer mes y es del 1,3% en años posteriores, con una mortalidad del 22-28% y una frecuencia de un segundo ataque del 16% 59 . una revisión de la bibliografia nacional encuentra 6 casos de infarto agudo de miocardio en niños (4 menores de 1 año, 1 de 15 meses y 1 de 30 meses), 5 de ellos fallecidos 35 . la lesión coronaria se presenta en el 20-30% de los enfermos no tratados y en alrededor del 4% de los tratados. la lesión coronaria varía desde pequeñas ectasias arteriales a aneurismas de diferentes tamaños, incluso aneurismas gigantes 60 . un seguimiento angiográfico de 10 a 20 años, realizado en japón entre 1973 y 1983 en 594 niños diagnosticados de enfermedad de kawasaki, encontró un 24,6% de aneurismas en la primera angiografía realizada a los 3 meses, de los que la mitad persiste en el segundo control 1-2 años después, el 40% de ellos sin estenosis y el 10% con estenosis 61 . un tercer control angiográfico entre 3-20 años encontró que el 60% de los aneurismas persiste, el 25% con estenosis. el 30% de los enfermos con aneurismas y estenosis tienen infarto agudo de miocardio, lo que supone el 1,9% de todos los casos iniciales, de los que fallecen la mitad. el mismo grupo en otro estudio posterior en 1.545 niños encontró que casi la mitad de los aneurismas en la fase de convalecencia seguía presentando algún tipo de alteración coronaria después de varios meses de seguimiento, el 26% de los cuales eran aneurismas gigantes, lo que representaba el 5% de todos los casos iniciales 29 . el seguimiento posterior encontró un 3% de enfermedad isquémica, con 21 casos de infarto de miocardio (1,3%) y 8 fallecimientos. esos hallazgos hacen pensar en la posibilidad de que los pacientes que han tenido la enfermedad en la infancia sufran complicaciones cardíacas en edades posteriores. en este sentido, un estudio en-cuentra 74 individuos entre 12 y 39 años con diferentes grados de coronariopatía y el antecedente de haber tenido enfermedad de kawasaki durante la infancia, 18 de los cuales murieron por infarto de miocardio 62 . la mitad de los casos no tenía ningún otro antecedente de riesgo coronario, pero el 50% restante tenía diabetes, hipercolesteronemia, tabaquismo, historia familiar e hipertensión arterial. pero un estudio reciente en adolescentes con historia confirmada de la enfermedad y lesión coronaria encontró que no hay diferencias significativas de las cifras de colesterol total, colesterol de las lipoproteínas de baja y alta densidad y triglicéridos con relación a un grupo control, aunque hay diferencias en el engrosamiento de la íntima y la media de la arteria carótida con rigidez de la pared medida por ultrasonido de alta resolución; este inclina a los autores a afirmar que esos hallazgos pueden estar en el origen de posibles lesiones de aterosclerosis futuras 62 . sin embargo, el corto lapso transcurrido desde el conocimiento de la enfermedad hace que sea necesario que pasen más años para conocer con exactitud la importancia de estos hallazgos 63 . existe la opinión generalizada de que la lesión vascular en la enfermedad de kawasaki es casi exclusiva de las arterias coronarias. sin embargo, en estudios tanto necrópsicos como angiográficos de niños con enfermedad de kawasaki, se han encontrado aneurismas en arterias de todo el territorio vascular 4, 23, 24, 64 . se cree, no obstante, que la mayor participación de ciertas vasos, como arterias coronarias u otras arterias de tamaño intermedio, puede estar más en relación con mecanismos de presión hemodinámicos que con razones de selectividad topográfica 49 . el tratamiento se realiza con gammablobulina intravenosa y ácido acetilsalicílico. la dosis de gammaglobulina es de 2 g/kg de peso, administrada en perfusión continua durante aproximadamente 12 h. dados el riesgo de fallo cardíaco por sobrecarga y la posible reacción anafiláctica, debe monitorizarse el pulso y la presión arterial del enfermo cada 1-2 h durante la perfusión. este tratamiento es muy eficaz y habitualmente el enfermo queda apirético al final de la perfusión. la gammaglobulina debe administrarse preferiblemente en los primeros 7 días de la fase aguda 39 , aunque se discute cuál es el mejor momento en ese período. algunos estudios retrospectivos encuentran mejor respuesta clínica y menos lesiones coronarias si el enfermo es tratado antes del quinto día de enfermedad 70 , aunque estudios prospectivos posteriores con mayor número de enfermos no encuentran diferencias 71 , por lo que en el momento actual se aconseja el tratamiento con gammaglobulina entre los días quinto y séptimo del inicio de la fiebre 39 . la dosis apropiada de ácido acetilsalicílico no está completamente consensuada. la escuela americana recomienda 80-100 mg/kg/día en 4 veces durante el período febril, mientras que la escuela japonesa aconseja 30-50 mg/kg/día. sin embargo, estudios comparativos del tratamiento de la enfermedad no encuentran diferencias significativas entre las diferentes dosis de aspirina 72, 73 . quizá lo aconsejable sea administrar la dosis antiinflamatoria tradicional de 50-60 mg/kg/día. las altas dosis no precisan control de salicilemia, pues la eliminación del salicilato está acelerada en esta enfermedad. una vez que el enfermo está asintomático, se inicia profilaxis antiagregante con ácido acetilsalicílico en dosis de 3-5 mg/kg. esta profilaxis se mantiene 1-2 meses hasta que la cifra de plaquetas y la ecografía son normales. para los enfermos con lesión coronaria permanente, la profilaxis es indefinidamente. en estos casos se debe evitar el uso de ibuprofeno, por su efecto antagonista con la aspirina. se considera fracaso terapéutico de la gammaglobulina la persistencia de la fiebre y de los reactantes elevados ≥ 36 h después de la infusión. alrededor del se debe seguir a los pacientes durante un largo período. existen diferentes guías para el seguimiento de los enfermos, con algunas pequeñas diferencias 39, 60 . la ecografía se repetirá en la segunda semana y entre las 6 y 8 semanas. actualmente no se aconseja realizar más controles si la ecografía es normal, pero si hay lesión coronaria, el seguimiento es de por vida. la escuela japonesa considera anormal el diámetro de la luz vascular cuando es mayor de 3 mm en menores de 5 años y mayor de 4 mm en niños de 5 o más años. no obstante, algunos autores creen que esta consideración debe hacerse según la superficie corporal del niño, y para ello se propone unas tablas 39 . se denomina ectasia al aumento del diámetro de la luz arterial sin dilatación segmentaria y aneurisma a las dilataciones 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coronary function in children with a history of kawasaki disease using (15) o-warwe positron emission tomography impaired andothelial function in the brachial artery after kawasaki disease and the effects of intravenous administration of vitamin c altered myocardial flow reserve and endotelial function late after kawasaki disease kawasaki syndrome: where are the answers? early treatment with intravenous immunoglobulin in patients with kawasaki disease early intravenous gammaglobulin treatment for kawasaki disease: the nationwide surveys in japan the prevention of coronary artery aneurysm in kawasaki disease: a metaanalysis on the efficacy of aspirin and immunoglobulin treatment prevalence of coronary artery abnormalities in kawasaki disease is highly dependent on gammaglobulin dose but independent of salicylate dose kawasaki disease: effect of treatment on coronary involvement treatment of immune globulin-resistant kawasaki disease with pulse doses of corticosteroids effect of initial corticosteroid therapy on coronary artery aneurysm formation in kawasaki disease: a meta-analysis of 862 children key: cord-017161-lcqrd4v0 authors: eleftheriou, despina; brogan, paul a. title: the molecular biology and treatment of systemic vasculitis in children date: 2012-02-23 journal: molecular and translational vascular medicine doi: 10.1007/978-1-61779-906-8_2 sha: doc_id: 17161 cord_uid: lcqrd4v0 primary systemic vasculitides are rare in childhood but are associated with significant morbidity and mortality. the cause of the majority of vasculitides is unknown, although it is likely that a complex interaction between environmental factors, such as infections and inherited host responses, triggers the disease and determines the vasculitis phenotype. several genetic polymorphisms in vasculitides have now been described, which may be relevant in terms of disease predisposition or development of disease complications. treatment regimens continue to improve with the use of different immunosuppressive medications and newer therapeutic approaches such as biologic agents. this chapter reviews recent studies shedding light on the pathogenesis of vasculitis with emphasis on molecular biology where known, and summarizes current treatment strategies. we discuss new emerging challenges particularly with respect to the long-term cardiovascular morbidity for children with systemic vasculitis and emphasize the importance of future international multicenter collaborative studies to further increase and standardize the scientific base investigating and treating childhood vasculitis. systemic vasculitis is characterized by blood vessel in fl ammation, which may lead to tissue injury from vascular stenosis, occlusion, aneurysm or rupture [ 1 ] . apart from relatively common vasculitides such as henoch-schönlein purpura (hsp) and kawasaki disease (kd), most of the primary vasculitic syndromes are rare in childhood, but when present are associated with signi fi cant morbidity and mortality [ 2, 3 ] . the cause of the majority of childhood vasculitides is unknown, although it is likely that a complex interaction between environmental factors, such as infections and inherited host responses, triggers the disease and determines the vasculitis phenotype [ 4 ] . this chapter summarizes the fi ndings of recent studies relating to the pathogenesis of systemic vasculitis, and considers hsp, kd, antineutrophil cytoplasmic antibodies (ancas)-associated vasculitis, polyarteritis nodosa and takayasu arteritis (ta). rarer forms of vasculitis are beyond the scope of this chapter, and the reader is referred elsewhere [ 5 ] . in addition, we discuss current therapeutic approaches and ongoing challenges in the fi eld of paediatric vasculitis research. modi fi cations of the classi fi cation criteria de fi ning hsp described by ozen et al. in 2005 [ 7 ] have recently been made following a formal validation study [ 8 ] . according to the new eular/printo/pres de fi nition, a patient is classi fi ed as having hsp in the presence of purpura or petechie with lower limb predominance (mandatory criterion) plus one out of four of the following criteria [ 8 ] : 1. abdominal pain 2. histopathology showing typical leucocytoclastic vasculitis with predominant iga deposit or proliferative glomerulonephritis with predominant iga deposit 3. arthritis or arthralgia 4. renal involvement (proteinuria or haematuria or presence of red blood cell casts) in cases with purpura with atypical distribution, a demonstration of iga is required at biopsy. this new de fi nition provides sensitivity and speci fi city for classi fi cation of hsp (using other forms of vasculitis as controls) of 100% and 87%, respectively [ 8 ] . as many as 50% of occurrences in paediatric patients are preceded by an upper respiratory tract infection [ 4, 9 ] . several agents have been implicated, including group a streptococci, varicella, hepatitis b, epstein-barr virus, parvovirus b19, mycoplasma , campylobacter , and yersinia [ 4 ] . of note, masuda et al. showed that nephritis-associated plasmin receptor (naplr), a group a streptococcal antigen, may have a pathogenetic role in a subset of patients with hsp nephritis [ 10 ] . among 33 children with biopsy proven hsp nephritis, 30% had segmental or global mesangial deposition of naplr antigen, comparing to 3% in other children with non-hsp nephritis glomerular diseases (half of these children had iga nephropathy) [ 10 ] . the exact pathophysiologic mechanism, if any, and the relationship between naplr and hsp nephritis need, however, further investigation. so far no single infectious agent has been consistently identi fi ed, and it is likely that genetically controlled host responses determine whether or not an individual develops hsp in response to infectious triggers. but despite the fact that the cause of hsp is unknown, it is likely that iga has a pivotal role in the pathogenesis of the disease, a hypothesis supported by the almost universal deposition of iga in lesional vascular tissue [ 11 ] . skin or renal biopsies demonstrate the deposition of iga (mainly iga1) in the wall of dermal capillaries and post-capillary venules and mesangium [ 11 ] . in addition, serum iga levels have been reported to be increased during the acute phase of the disease, and a proportion of patients have circulating iga-containing immune complexes and cryoglobulins [ 12 ] . some studies have found iga antineutrophil cytoplasmic antibodies (iga-ancas) in a proportion of patients with hsp, while others have shown an increase in iga-rheumatoid factor or iga-anticardiolipin antibodies [ 11 ] . recently, galactose de fi ciency of o-linked glycans in the hinge region of iga1 has been reported in adults with iga nephropathy and children with hsp [ 13 ] . these aberrantly glycosylated iga1 proteins form immune complexes that deposit in the mesangium; their binding to mesangial cells stimulates cellular proliferation and overexpression of extracellular matrix components resulting in the typical renal lesions associated with hsp [ 13 ] . recently, hiasano et al. showed complement activation through both the alternative and lectin pathways in patients with hsp nephritis and demonstrated that this complement activation is promoted in situ in the glomerulus [ 14 ] . the formed iga immune complexes, through the activation of complement, lead to the formation of chemotactic factors (such as c5a), which in turn recruit polymorphonuclear leucocytes to the site of deposition [ 15, 16 ] . the polymorphonuclear leucocytes thus recruited by chemotactic factors cause in fl ammation and necrosis of vessel walls with concomitant thrombosis [ 11 ] . this subsequently results in extravasation of erythrocytes from haemorrhage in the affected organs and is manifested histologically as leucocytoclastic vasculitis [ 11 ] . the term leucocytoclasis refers to the breakdown of white blood cells in lesional tissue, particularly the characteristic nuclear debris ("nuclear dust") observed, and is not speci fi c for hsp. several genetic polymorphisms have been linked with hsp in various population cohorts, often with consistent results across multiple studies (summarized in table 2 .1 ) [ 32 ] . many of these polymorphisms relate to cytokines or cell adhesion molecules involved in the modulation of in fl ammatory responses and endothelial cell activation [ 4, 32 ] . the connection between hsp and hla alleles is the most convincing genetic association. in three cohorts from italy, northwest spain and turkey, drb1*01 and drb*11 have each been positively associated (or 1.5-2.5), and drb*07 negatively associated, with hsp in two of the three studies [ 17, 18, 33 ] . hlab35 was associated with hsp in a turkish cohort [ 19 ] , but was only associated with nephritis in a spanish cohort [ 20 ] . null alleles in either of the complement factor c4 genes (c4a or c4b) have shown associations with hsp in multiple cohorts of different ethnicities [ 29 ] , but different fi ndings regarding associations with c4a or c4b alleles, association with heterozygosity or only homozygosity for a null allele, and close linkage of the c4 genes to hla have resulted in debate about the signi fi cance of these fi ndings. polymorphisms in the angiotensin-converting enzyme (ace) gene have been associated with risk of hsp in two cohorts (or 2.3-2.7) [ 24, 25 ] ; several additional studies have focused on association of ace alleles with risk of nephritis but without consistent fi ndings. a high carriage rate of mutations in mefv was recently reported in turkish children with hsp (or 2.06) [ 27 ] . on the whole, however, studies of this nature have been hampered by relatively small patient numbers and thus lack the power to be de fi nitive or necessarily applicable to all racial groups. skin involvement is typically with purpura, which is generally symmetrical, affecting the lower limbs and buttocks in the majority of cases, the upper extremities being involved less frequently [ 34 ] . the abdomen, chest and face are generally unaffected [ 34 ] . angioedema and urticaria can also occur [ 34 ] . around two thirds of the children have joint manifestations at presentation [ 34 ] . three quarters of the children develop abdominal symptoms ranging from mild colic to severe pain with ileus and vomiting [ 34 ] . haematemesis and melena are sometimes observed [ 34 ] . other complications include intestinal perforation and intussusception [ 34 ] . acute pancreatitis is also described, although is a rare complication [ 34 ] . other organs less frequently involved include the central nervous system (cerebral vasculitis), gonads (orchitis may be confused with torsion of the testis) and the lungs (pulmonary haemorrhage) [ 34 ] . reports of hsp nephritis indicate that between 20% and 61% of cases are affected with this complication. renal involvement can present with varying degrees of severity [ 34 ] . this includes isolated microscopic haematuria, proteinuria with microscopic or macroscopic haematuria, polymorphisms in pax2 predispose to renal involvement in hsp [ 30 ] nitric oxide and associated molecules inducible nitric oxide synthase 2a promoter polymorphism predisposes to renal involvement [ 31 ] acute nephritic syndrome (haematuria with at least two of hypertension, raised plasma creatinine and oliguria), nephrotic syndrome (usually with microscopic haematuria) or a mixed nephritic-nephrotic picture [ 34 ] . the large majority of cases of hsp require symptomatic treatment only [ 34 ] . nonsteroidal anti-in fl ammatory drugs (nsaids) may be used to treat arthralgia associated with hsp [ 34 ] . controversies concerning the use of corticosteroids in the treatment of hsp exist with regard to whether or not they can (1) reduce severity or duration of disease, (2) decrease the risk of glomerulonephritis, and (3) prevent relapses of the disease [ 35, 36 ] . chartapisak et al. recently systematically reviewed all published randomized controlled trials (rcts) for the prevention or treatment of renal involvement in hsp [ 37 ] . meta-analyses of four rcts, which evaluated prednisone therapy at presentation of hsp, showed that there was no signi fi cant difference in the risk of development or persistence of renal involvement at 1, 3, 6 and 12 months with prednisone compared with placebo or no speci fi c treatment [ 37 ] . in the largest of these trials, which enrolled children between january 2001 and january 2005, the primary outcome (urinary protein/creatinine ratio at 1 year) was measured in 290 children [ 38 ] . this is the largest study to date showing no signi fi cant bene fi t of prednisone over placebo in preventing persistent renal disease [ 38 ] . that said, there could still be a role for early use of corticosteroids in patients with severe extrarenal symptoms such as abdominal pain and arthralgia, as suggested by the fi ndings of a study performed by ronkainen et al. [ 36 ] . prednisone (1 mg/kg/day for 2 weeks, with weaning over the subsequent 2 weeks) was effective in reducing the intensity of abdominal pain and joint pain [ 36 ] . prednisone did not prevent the development of renal symptoms but was effective in treating them if present; renal symptoms resolved in 61% of the prednisone patients after treatment, compared with 34% of the placebo patients [ 36 ] . of note, nikibakhsh et al. reported recently on the successful treatment with mycophenolate mofetil (mmf) of recurrent skin, articular and gastrointestinal symptoms in children with who failed to respond to systemic steroid therapy [ 39 ] . for patients with rapidly progressive glomerulonephritis with crescentic change on biopsy, uncontrolled data suggest that treatment may comprise aggressive therapy with corticosteroid, cyclophosphamide and possibly plasma exchange [ 34 ] , as with other causes of crescentic nephritis. other therapies such as cyclosporin, azathioprine and cyclophosphamide have been reported to be effective [40] [41] [42] . as hsp is the most common cause of rapidly progressive glomerulonephritis in childhood, more aggressive therapeutic approaches such as plasma exchange have been employed in some cases [ 43 ] . these treatment options, while important in select cases, are not yet supported by rcts. in addition, there are no robust clinical trials to guide therapy for hsp nephritis that is not rapidly progressive (patients may exhibit less than 50% crescents on renal biopsy, sub-optimal gfr; heavy proteinuria which is not necessarily nephrotic range) [ 34 ] . many would advocate corticosteroids [ 34 ] . others advocate the addition of cyclophosphamide to corticosteroids in hsp nephritis with biopsy showing diffuse proliferative lesions or sclerosis, but with <50% crescentic change with ongoing heavy proteinuria [ 34 ] . in patients with greater than 6 months duration of proteinuria, an ace inhibitor may be indicated to limit secondary glomerular injury, although again the evidence to support this therapy is lacking. the majority of children with hsp make a full and uneventful recovery with no evidence of ongoing signi fi cant renal disease [ 34 ] . renal involvement is the most serious long-term complication of hsp [ 34 ] . narchi et al. systematically reviewed all published literature with regards to long-term renal impairment in children with hsp [ 44 ] . persistent renal involvement (hypertension, reduced renal function, nephrotic or nephritic syndrome) occurred in 1.8% of children overall, but the incidence varied with the severity of the kidney disease at presentation, occurring in 5% of children with isolated haematuria and/or proteinuria but in 20% who had acute nephritis and/or nephrotic syndrome in the acute phase [ 44 ] . kd is an acute self-limiting systemic vasculitis predominantly affecting young children [ 2 ] . it is distributed worldwide, with a male preponderance, an ethnic bias towards asian children, some seasonality and occasional epidemics [45] [46] [47] [48] [49] . it is the second most common vasculitic illness of childhood and the most common cause of acquired heart disease in children in the uk and the usa [ 2, 50, 51 ] . the incidence in japan is 138/100,000 [ 52 ] in children younger than 5 years, whereas in the usa it is 17.1 [ 53 ] and in the uk 8.1 [ 54 ] . the aetiology of kd remains unknown, but currently it is felt that some ubiquitous infectious agent produces an abnormal immunological response in a genetically susceptible subject that results in the characteristic clinical picture [ 55, 56 ] . pronounced seasonality and clustering of kd cases have led to the hunt for infectious agents as a cause [ 55, 56 ] . however, so far no single agent has been identi fi ed, a fact most recently highlighted by the negative results that emerged from studies examining the potential link between coronavirus infection and kd in taiwan [ 57 ] . one debate regarding the cause of kd has centred around the mechanism of immune activation: conventional antigen versus superantigen (sag) [ 55, 58 ] . sags are a group of proteins that share the ability to stimulate a large proportion of t cells (up to 30% of the t-cell repertoire compared with one in a million t cells for conventional antigens) by binding to a portion of the t-cell receptor b chain (tcrv b ) in association with the major histocompatibility complex (mhc) class ii molecules with no requirement for antigen processing [ 59 ] . sags have been identi fi ed in a variety of microorganisms, including many of the bacteria and viruses isolated from children with kd [ 55, 59, 60 ] . in 1992, abe et al. were the fi rst to describe the selective expansion of v b 2 and v b 8.1t cells in kd [ 61 ] , indicating t-cell v b skewingthe hallmark of a sag-mediated process. since then, many similar studies have examined t cell v b repertoires in kd, or examined the prevalence of serological conversion or colonization with sag-producing organisms [ 62, 63 ] . an sag is also responsible for induction of coronary artery disease in a murine model of kd (discussed in detail in the "in vivo experimental data in kd" section) [ 55, 59, 60 ] . however, rowley et al. recently reported three fatal cases of kd and observed iga plasma cell in fi ltration into the vascular wall during the acute phase of the illness [ 64 ] . by examining the clonality of this iga response using reverse transcriptase (rt)-pcr in lesional vascular tissue, these researchers observed that the iga response was oligoclonal, suggesting a conventional ag process rather than a sagdriven one [ 64 ] . although the debate continues regarding the mechanism of initial immune activation, different mechanisms are most likely involved with a fi nal common pathway of immune activation responsible for this clinical syndrome. regardless of how t cells get activated, the massive immune response characteristic of kd is translated into systemic in fl ammation manifested clinically as fever and the cardiac features of kd [ 55 ] . experimental mice develop coronary arteritis in response to intra-peritoneal injections of lactobacillus casei wall extract (lcwe) with the resultant vasculitis being similar to kd in children [ 65, 66 ] . young mice (age 4-5 weeks) are more susceptible to lcwe-induced disease compared with older mice [65] [66] [67] [68] [69] . the peripheral immune activation within hours of lcwe injection is followed by local in fi ltration into cardiac tissue at day 3 with the in fl ammatory in fi ltrate comprising mainly t cells [65] [66] [67] [68] [69] . this in fl ammatory response peaks at day 28 post injection and is accompanied by elastin breakdown with disruption of the intima and media, as well as aneurysm formation at day 42 [65] [66] [67] [68] [69] . additionally, an sag found within lcwe contributes signi fi cantly to the development of vascular disease [ 60 ] . the common features between this murine model and the human disease include an infectious trigger leading to immune activation; disease susceptibility in the young; a time course similar to that seen clinically in kd; similar pathology of coronary arteritis; and response to intravenous immunoglobulin (ivig) treatment [ 55 ] . the proposed disease model supported by the in vivo experimental data in this mouse model begins with immune activation by a microbe with superantigenic activity [ 55 ] . the sag found in the lcwe preferentially expands t-lymphocytes expressing tcrv b 2, 4, 6 and 14 positive t cells, and this superantigenic activity is directly correlated with the ability to induce coronary arteritis in mice [ 60 ] . ablation of ifn-g con fi rmed that ifn-g plays an important regulatory role in disease induction in this disease model [ 55 ] . mice with absence of tnf-a activity (blockade of tnf-a ) or tnfr1 knockouts) do not develop coronary disease after lcwe stimulation [ 68 ] . of note, the t cells found in affected vessels express sag-reactive tcrv b families, an unexpected fi nding considering the usual fate of sag-activated t cells, which are actively deleted by apoptosis. moolani et al. have shown that co-stimulation can rescue sag-stimulated t cells from apoptosis [ 70 ] . furthermore, the coronary endothelium is transformed into a professional antigen-presenting cell (apc) by upregulation of co-stimulatory molecules driven partially by the tissue-speci fi c expression of toll-like receptor (tlr) [ 55 ] . increased tlr2 expression in conjunction with tlr2 stimulation by the tlr2 ligand in lcwe leads to increased expression of co-stimulatory molecules facilitating rescue of sag-activated t cells and continued local production of proin fl ammatory cytokines [ 71, 72 ] . this leads to further exacerbation of the in fl ammation at the coronary vessel wall [ 55 ] . ifn-g and tnf-a are involved in transcriptional regulation of matrix metalloproteinases (mmps), with tnf-a upregulating, and ifn-g inhibiting production of mmp-9 [ 55, 73 ] . following that, the enzymatic activity of mmp-9 leads to elastin breakdown and aneurysm formation [ 73 ] . of note, recently alvira et al. have shown that in the coronary arteritis associated with kd, tgf-b suppresses elastin degradation by inhibiting plasmin-mediated mmp-9 activation [ 74 ] . thus, strategies to block tgf-b , used in those with marfan syndrome, are unlikely to be bene fi cial in kd as they lead to worsening of elastin degradation in this murine model of kd [ 74 ] . so in summary, a sustained local immune response together with persistent tnf-a production and leucocyte recruitment lead to upregulation of proteolytic activity, elastin degradation, vessel wall damage and the characteristic coronary artery lesions seen in kd [ 55 ] . although the clinical syndrome and occurrence of epidemics suggest an infectious cause for kd, a genetic contribution to risk is suggested by the much higher prevalence of the disease in japan and korea than elsewhere, and by increased prevalence within families with an increased relative risk to siblings compared to the general population [ 75 ] . recently, a number of polymorphisms have been identi fi ed that appear to be linked with disease susceptibility in kd or the risk of coronary artery aneurysms (caas). these polymorphisms are summarized in table 2 .2 [ 4, 81 ] . in general, candidate gene studies in kd have been dif fi cult to interpret, since most fi ndings have not been replicated. indeed, con fl icting results have been reported for the few genes that have been evaluated in multiple cohorts. furthermore, a genome-wide linkage study using microsatellite markers in japanese families identi fi ed a number of potential loci [ 92 ] . finer scale studies of the 19q32.2-32.3 region led to identi fi cation of a linked group of single-nucleotide polymorphisms (snps) in the inositol 1,4,5-trisphosphate 3-kinase c (itpkc) gene, associated with kd, with an odds ratio of 1.74 [ 75, 92 ] . itpkc mutation was associated with kd not only in japanese but also in us caucasian patients, particularly with the risk for developing coronary artery lesions [ 75, 92 ] . additional data tnf-a -308a associated with increased intravenous immune globulin (ivig) resistance [ 82 ] interleukin-10 (il10) il-10 gene promoter polymorphisms in fl uence risk of caa [ 82 ] vascular endothelial growth factor (vegf) and its receptor (kdr) polymorphisms of both contribute to increased caa risk [ 83 ] chemokines chemokine receptor ccr5 and its ligand ccl3l1 in fl uence disease susceptibility [ 84 ] nitric oxide and associated molecules increased risk of caa [ 91 ] supported a functional signi fi cance for one polymorphism identi fi ed: snp (itpkc_3c) led to reduced splicing of the itpkc gene product and therefore could result in a lower mrna concentration [ 75 ] . of note, however, chi et al. subsequently showed no statistically signi fi cant association between the itpkc gene snp rs28493229 and kd or coronary artery lesions in taiwanese children [ 87 ] . the fi rst genomewide association study (gwas) in kd was notable for assessment of population strati fi cation and for replication of gwas fi ndings in an independent cohort [ 93 ] . gwas of 109 caucasian patients, followed by snp genotyping of the 1,116 most signi fi cant snps in 583 families, then fi ne mapping of known genes near some of the 40 snps that were successfully replicated, led to identi fi cation of eight putative novel susceptibility genes [odds ratio (or) approximately 1.1-1.5] [ 93 ] . the principal clinical features are fever persisting for 5 days or more, peripheral extremity changes (reddening of the palms and soles, indurative oedema and subsequent desquamation), a polymorphous exanthema, bilateral conjunctival injection/ congestion, lips and oral cavity changes (reddening/cracking of lips, strawberry tongue, oral and pharyngeal injection) and cervical lymphadenopathy (acute, nonpurulent) [ 56 ] . for the diagnosis to be established according to the diagnostic guidelines of the japan kawasaki disease research committee, fi ve of six criteria should be present [ 94 ] . if caas are present, fewer features may be necessary for diagnostic purposes [ 48, 95 ] . the cardiovascular features are the most important manifestations of the condition with widespread vasculitis affecting predominantly medium-size muscular arteries, especially the coronary arteries [ 56 ] . coronary artery involvement occurs in 15-25% of untreated cases with additional cardiac features in a signi fi cant proportion of these, including pericardial effusion, electrocardiographic abnormalities, pericarditis, myocarditis, valvular incompetence, cardiac failure and myocardial infarction [ 56 ] . another clinical sign that maybe relatively speci fi c to kd is the development of erythema and induration at sites of bacille calmette-guérin (bcg) inoculations [ 46 ] . other system involvement can occur, including the gastrointestinal tract, the hepatobiliary tract with hydrops of the gall bladder being well recognised, the central nervous system with seizure and meningeal features, the auditory system with deafness, the skeletal system with arthropathy and the urinary system [ 56 ] . early recognition and treatment of kd with aspirin and ivig have been shown unequivocally by meta-analysis to reduce the occurrence of caas [ 96, 97 ] . the prevalence of caa is inversely related to the total dose of ivig [ 97 ] , 2 g/kg of ivig being the optimal dose, usually given as a single infusion [ 96 ] . meta-analysis of rcts comparing divided lower doses of ivig (400 mg/kg/day for 4 consecutive days) versus a single infusion of high-dose ivig (2 g/kg over 10 h) has clearly shown that even though the 4-day regimen has some bene fi t, a single dose of 2 g/kg has a greater therapeutic effect in the prevention of caa [ 96, 97 ] . however, ivig resistance occurs in up to 20% of cases [ 98 ] . in those cases most advocate a second dose of ivig and/or the use of corticosteroids. regarding corticosteroid use in ivig resistant to kd, there are apparently con fl icting data from clinical trials. inoue et al. reported on a randomized control trial of 178 kd patients who were assigned to receive ivig (1 g/kg/day) for two consecutive days, given over 12 h, or ivig plus prednisolone sodium succinate (2 mg/kg/day) three times daily, given by intravenous (iv) injection until the fever resolved and then orally until the c-reactive protein (crp) level normalized [ 98 ] . patients in both groups received aspirin (30 mg/kg) and dipyridamole (2 mg/kg/day) [ 98 ] . the addition of corticosteroid was associated with reduced caa compared with ivig alone: in those receiving ivig and anti-platelet therapy, 11.4% had caa at 1 month, compared with 2.2% in those receiving ivig plus corticosteroids [ 98 ] . also the duration of fever was shorter and crp decreased more rapidly in the group of patients receiving corticosteroids [ 98 ] . in contrast, newburger et al. in a subsequent multicenter, randomized, doubleblind, placebo-controlled trial examined the effect of the addition of a single dose of intravenous methylprednisolone to standard therapy [ 99 ] . they found that this corticosteroid regimen did not improve the caa outcome in these children [ 99 ] . these contrasting results suggest that dose and duration of corticosteroids may be critical when considering this as adjunctive therapy in kd. in fl iximab, a chimeric monoclonal antibody against tnf-a , has been reported to be effective for the treatment of ivig-resistant kd [ 100, 101 ] . in 13 of 16 patients with failed response to a single dose or ivig who received in fl iximab, there was cessation of fever followed by reduction in crp [ 100 ] . more recently, burns et al. reported on a multi-centre, randomized, prospective trial of second ivig infusion (2 g/kg) versus in fl iximab (5 mg/kg) in 24 children with acute kd and fever after initial failed treatment with ivig [ 101 ] . there was cessation of fever within 24 h in 11 of 12 subjects treated with in fl iximab and in 8 of 12 subjects retreated with ivig [ 101 ] . no signi fi cant differences were observed between treatment groups in the change from baseline for laboratory variables, fever or echocardiographic assessment of coronary arteries [ 101 ] . these reports are encouraging but further rcts to establish the optimal management of kd, and in particular ivig-resistant kd, are needed [ 102 ] . in that respect a multi-centre, double-blind, randomized, placebo-controlled trial intended to assess the ef fi cacy of etanercept (a fusion protein combining the tnf receptor 2 and the fc component of human igg1) in reducing the ivig refractory rate during treatment of acute kd is ongoing [ 103 ] . in the convalescent phase of the condition, if aneurysms persist, anti-platelet therapy in the form of low-dose aspirin should be continued long term until the aneurysms resolve [ 56 ] . in the presence of giant aneurysms (greater than 8 mm), warfarin is recommended in addition to aspirin [ 104 ] . some patients may require coronary angioplasty or a revascularization procedure should ischemic symptoms arise or evidence of obstruction occur [ 105 ] . the acute mortality of kd in japan is 1.14 [ 105 ] . about 20% of patients who develop caas during the acute disease will develop coronary artery stenoses, and the risk is greater with large (giant) aneurysms [ 105 ] . however, emerging data suggest that, in spite of seeming recovery, there are long-term cardiovascular sequelae for patients with kd that persist into adult life and that may have important implications [ 106 ] . anca-associated vasculitides (aav) are small-vessel vasculitides characterized by necrotizing in fl ammation of small vessels in association with autoantibodies to neutrophil constituents-in particular, proteinase 3 (pr3) and myeloperoxidase (mpo) [ 107, 108 ] . the aav comprise wegener's granulomatosis (wg, now also referred to as granulomatous polyangiitis, although for the purposes of this review the term wg is used), microscopic polyangiitis (mpa), including its renal-limited (rl) subset designated as idiopathic necrotizing crescentic glomerulonephritis (incgn), and churg-strauss syndrome (css) [ 107, 108 ] . although rare, aav do occur in childhood and are associated with signi fi cant morbidity and mortality [ 109 ] . the pathogenesis of aav is still not fully elucidated, but clinical as well as experimental data strongly suggest a role for autoimmune responses to pr3 and mpo in disease development [ 110 ] . the most accepted model of pathogenesis suggests that anca activate cytokineprimed neutrophils within the microvasculature, leading to bystander damage to endothelial cells themselves and rapid escalation of in fl ammation with recruitment of mononuclear cells [ 111 ] . falk et al. demonstrated in 1990 that ancas in vitro activate neutrophils to produce reactive oxygen species and release of lytic enzymes [ 112 ] . this process requires priming of neutrophils. priming involves the stimulation of neutrophils with low doses of proin fl ammatory cytokines that result, among other things, in surface expression of pr3/mpo on the neutrophil membrane but without full neutrophil activation, before their interaction with anca [ 113 ] . primed neutrophil activation by anca involves interaction with their target antigens on the neutrophil membrane and also with fc g receptors-in particular, fc g riia and fc g riiib [ 113 ] . in addition, reumaux et al. showed that anca-induced neutrophil activation occurs only when neutrophils are attached to a surface and not when fl oating in the circulation [ 114 ] . furthermore, radford et al. demonstrated that anca can directly activate neutrophils to become fi rmly adherent to vessel walls, where they may obstruct fl ow, initiate tissue damage and contribute to the pathogenesis of vasculitis [ 115 ] . these effects can be blocked by antibodies to fc g riia and by antibodies to cd11b [ 115 ] . in more detail, savage et al. showed that activation of neutrophils by anca causes integrin-and cytokine receptor-mediated adherence to cultured endothelial cells and transmigration across the endothelial layer [ 116 ] . in addition, activation of neutrophils with anca causes a conformational change in beta-2 integrins that enhances ligand binding [ 116 ] . a role for adhesion molecules in the interaction between anca-activated neutrophils and vessels also is supported by immunohistologic evidence of upregulated adhesion molecules in glomerular lesions in renal biopsy specimens from patients with aav [ 117 ] . in addition to binding to the surface of endothelial cells, both pr3 and mpo are internalized into endothelial cells, where they have different pathologic effects [ 118 ] . for example, after internalization, pr3 causes endothelial cell apoptosis, whereas mpo causes generation of intracellular oxidants [ 118 ] . these differences in mpo and pr3 interaction with endothelial cells could in fl uence the patterns of tissue injury induced when these antigens react with anca at the endothelial cell surface [ 111 ] . furthermore, there is new evidence that after neutrophil activation by anca, the neutrophils are driven down an accelerated apoptotic death pathway by reactive oxygen species [ 119 ] . these neutrophils develop the morphologic features of apoptosis, but there is dysregulated coordination of cell surface changes that normally accompany apoptosis, including delay in phosphatidylserine expression [ 119 ] , which could contribute to failure of these apoptotic cells to be recognized and safely removed by phagocytes [ 119 ] . apoptotic neutrophils eventually disintegrate, releasing cytotoxic contents within vascular tissue. this process may explain the leucocytoclasia often seen in vasculitic lesions. also pertaining to safe clearance of apoptotic neutrophils are two studies showing that apoptotic neutrophils can express proteinase-3 and myeloperoxidase at the cell surface, which can act as an opsonin for anca [ 120, 121 ] . both apoptotic and anca opsonized apoptotic neutrophils can be phagocytosed by macrophages, but whereas the former induce an anti-in fl ammatory response from the macrophage release of interleukin-10, the latter are taken up more avidly and are proin fl ammatory by inducing macrophage release of interleukin-1, interleukin-8 and tnf [ 120, 121 ] . the signalling cascades that lead to functional responses such as superoxide release are only beginning to be elucidated. tyrosine kinases and protein kinase c are known to be involved [ 122 ] . now, mitogen-activated protein kinases that require tyrosine phosphorylation for activation also have been implicated, particularly in tnf-mediated priming [ 123 ] . furthermore, in wg the granulomatous in fl ammation displays several different morphologies. within a surrounding in fl ammatory background, poorly formed epithelioid cell granulomas, scattered histiocytic giant cells of langhans type or palisading histiocytes around central necrosis may be seen [ 124 ] . the mixed in fl ammatory in fi ltrate in wg is composed of lymphocytes, plasma cells, neutrophils, eosinophils, monocytes, macrophages, histiocytes and giant cells [ 124 ] . since inf-g and t cells play pivotal roles in granuloma formation, alterations of the t-cell and cytokine response could contribute to anomalous autoantigen presentation in ectopic lymphoid-like structures and sustain autoimmunity to pr3 [ 125 ] . skewing of the t-cell phenotype with expansion of the cd4+ and cd8+ t cells lacking cd28 expression is seen in wg [ 126, 127 ] . expansion of cd28 negative t cells is already evident in localized wg and further increases in generalized disease [ 126, 127 ] . abundant ifn-g , cd26 and th-1 type cc chemokine receptor ccr5 expression are seen in granulomatous lesions of the respiratory tract in localized wg, but appear less strong in generalized wg [ 128, 129 ] . moreover, a fraction of th2 type il-4 producing ccr3+ t cells is present in the circulation and tissue lesions in generalized but not in localized wg [ 128 ] . these data suggest that an aberrant th-1 type response favouring granuloma formation might play a role in initiation of wg [ 130 ] . ectopic presentation of the wegener's autoantigen pr3 and autoimmunity to pr3 might be sustained within in fl ammatory lesions and by skewed t-cell and cytokine responses [ 130 ] . progression from localized to generalized wg is associated with the appearance of another subset of th-2 type cells, which could be a consequence of b-cell expansion and t-cell-dependent pr-3 anca production during disease progression [ 130 ] . in addition, th17 cells have been recently described as major effector cells in autoimmune diseases [ 131 ] . it has been demonstrated that stimulation of peripheral blood mononuclear cells from pr3-anca positive patients with wg with the autoantigen pr3 results in production of interleukin (il)-17 and not inf-g , demonstrating that the autoimmune effector cells are th17 cells [ 132 ] . in healthy individuals regulatory t cells (tregs) control the activity of immune effector cells [ 131 ] . there is increasing evidence that the balance between th17 cells and fox p3-positive regulatory t cells is disturbed in autoimmune in fl ammatory conditions [ 131 ] . in patients with wg in remission, the percentage of fox p3-positive tregs was shown to be increased but the cells were functionally de fi cient [ 133 ] . taken together, in vitro studies support a pathogenic role for the autoimmune responses to pr3 and mpo in aav. autoantibodies could be responsible for smallvessel necrotizing vasculitis, whereas dysregulation of t-cell homoeostasis may underlie granulomatous in fl ammation. evidence for a pathogenic role of mpo-anca in aav comes from animal models for mpo-anca-associated vasculitis [ 134 ] . xiao et al. immunized mice de fi cient for mpo with mouse mpo and transferred splenocytes from these immunized mice into immunode fi cient or normal mice [ 134 ] . the recipient mice developed pauci-immune necrotizing glomerulonephritis and haemorrhagic pulmonary capillaritis, similar to the clinical manifestations and the histopathology of mpo-anca-associated vasculitis [ 134 ] . in addition, transfer of igg alone from mpo-immunized mice resulted in pauci-immune focal necrotizing glomerulonephritis in the recipient, demonstrating the pathogenic potential of anti-mpo antibodies [ 134 ] . additional studies showed that both neutrophils expressing mpo and the alternative pathway of complement besides the antibodies are required to induce aav as recipient mice de fi cient for factor b and complement c5 did not develop disease [ 135 ] . also in a rat model of mpo-anca vasculitis, in which rats were immunized with human mpo, the pathogenic potential of anti-mpo antibodies was demonstrated [ 136 ] . of note, however, no animal models for pr3-anca-associated wg have been generated [ 110 ] . a series of early observations have suggested that infectious episodes may trigger relapses of aav [ 137 ] . further studies of upper airway involvement in wg showed good responses to treatment with trimethoprim/sulphamethoxazole [ 138 ] . longterm studies demonstrated that chronic nasal carriage of staphylococcus aureus is a major risk factor for relapse in wg in conjunction with persistence of anca, and maintenance treatment with trimethoprim/sulphamethoxazole reduced the occurrence of relapses by 60% in patients with wg [ 139 ] . possible mechanisms whereby s. aureus could result in fl ares of wg include sag production and t-and b-cell activation, direct tropism of s. aureus for endothelial cells, with binding and internalization of the organism by endothelial cells or by priming of neutrophils [ 140 ] . recently, two studies have shed new light on the possible role of microbial factors in the pathogenesis of aav. in the fi rst study, antibodies to complementary pr3 were detected in serum samples from patients with pr3-anca-associated vasculitis [ 141 ] . complementary pr3 is a protein translated from the antisense dna strand encoding pr3. such a complementary protein is a mirror of the original protein [ 141 ] . as such, antibodies to a complementary protein can induce anti-idiotypic antibodies that react with the original protein [ 141 ] . pendergraft et al. immunized mice with complementary pr3, and these mice then developed antibodies to pr3 [ 141 ] . this complementary pr3 shows homology with a number of microbial proteins, including proteins from s. aureus [ 141 ] . this raises the possibility that infection with s. aureus could lead to antibodies cross-reacting with complementary pr3, which, in turn, evoke antibodies to pr3 by idiotypic-anti-idiotypic interaction. a second study describes antibodies to the lysosomal membrane glycoprotein 2 (hlamp-2) as a sensitive and speci fi c marker for pauci-immune crescentic glomerulonephritis [ 142 ] . hlamp-2 is present on neutrophils and endothelial cells [ 142 ] . anti-hlamp-2 antibodies, raised in rabbits, were able to activate neutrophils and induce apoptosis of human microvascular endothelial cells [ 142 ] . more importantly, these antibodies induced pauci-immune focal necrotizing glomerulonephritis when injected into rats [ 142 ] . eight out of nine amino acids of the p41-49 immunodominant epitope of hlamp-2 were shown to be identical to the p72-80 peptide of fimh, an adhesion molecule of fi mbriae of gram negative bacteria [ 142 ] . immunization of rats with fimh resulted in the generation of antibodies cross-reacting with hlamp-2 and inducing pauci-immune glomerulonephritis [ 142 ] . these observations suggest that infection with gram negative bacteria could result in a loss of tolerance and could lead to aav. a number of candidate gene association studies have identi fi ed variants associated with an increased incidence of aav [ 143 ] . most of the genes described so far encode proteins involved in the immune response and are summarized in table 2. 3 . of note, the genes with variants most strongly associated with aav, the mhc and ptpn22 genes, also have variants associated with other autoimmune diseases, including rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus (sle) [ 143 ] . this suggests that genetic risk factors common to other autoimmune diseases also apply to aav. different variants within each gene may be associated with different polymorphisms-for example, sle associates with the il-2ra snp rs11594656, while aav is associated with rs4129506 [ 143 ] . a gwas of aav is currently ongoing and may be enlightening in that respect. furthermore, ciavatta et al., in an attempt to uncover a potential transcriptional regulatory mechanism for pr3 and mpo disrupted in patients with anca vasculitis, examined the pr3 and mpo loci in neutrophils from anca patients and healthy control individuals for epigenetic modi fi cations associated with gene silencing [ 173 ] . they demonstrated that levels of the chromatin modi fi cation h3k27me3, which is associated with gene silencing, were depleted at pr3 and mpo loci in anca patients compared with healthy controls [ 173 ] . interestingly, in both patients and controls, dna was unmethylated at a cpg island in pr3, whereas in healthy controls, dna was methylated at a cpg island in mpo [ 173 ] . consistent with decreased levels of h3k27me3, jmjd3, the demethylase speci fi c for h3k27me3, was preferentially expressed in anca patients versus healthy controls [ 173 ] . in addition, the mechanism for recruiting the h3k27 methyltransferase enhancer of zeste homolog 2 (ezh2) to pr3 and mpo loci was shown to be mediated by runx3. runx3 message was decreased in patients compared with healthy controls, and may also be under epigenetic control [ 173 ] . dna methylation was increased at the runx3 promoter in anca patients [ 173 ] . these data indicate that epigenetic modi fi cations associated with gene silencing are perturbed at anca autoantigen-encoding genes, potentially contributing to inappropriate expression of pr3 and mpo in anca patients [ 173 ] . wg typically affects the upper and lower respiratory tract and is associated with glomerulonephritis, although the disease can affect any organ system in the body [ 34 ] . from a clinical perspective, it may be useful to think of wg as having two forms: a predominantly granulomatous form with mainly localized disease with a [ 172 ] chronic course; and a fl orid, acute small vessel vasculitic form characterized by severe pulmonary haemorrhage and/or rapidly progressive vasculitis or other severe vasculitic manifestation [ 34 ] . these two broad presentations may coexist or present sequentially in individual patients. symptoms and signs of upper respiratory tract involvement include epistaxis, otalgia and hearing loss (conductive and sensorineural) [ 34 ] . nasal septal involvement with cartilaginous collapse results in the characteristic saddle nose deformity, although this may not be present at initial presentation [ 34 ] . chronic sinusitis may be observed. glottic and subglottic polyps and/or largeand medium-sized airway stenoses can result from granulomatous in fl ammation [ 34 ] . lower respiratory tract manifestations also include granulomatous pulmonary nodules with or without central cavitation and pulmonary haemorrhages that can be relatively asymptomatic but result in evanescent pulmonary shadows on chest x-ray, or catastrophic pulmonary haemorrhage from pulmonary capillaritis associated with respiratory failure and high mortality [ 34 ] . the typical renal lesion is a focal segmental necrotizing glomerulonephritis, with pauci-immune crescentic glomerular changes [ 34 ] . clinical manifestations include hypertension, signi fi cant proteinuria, nephritic and nephrotic syndrome, and ultimately the protean clinical features renal failure [ 34 ] . other manifestations include orbital involvement with granuloma, retinal vasculitis, peripheral gangrene with tissue loss, and vasculitis of the skin, gut, heart, central nervous system and/or peripheral nerves (mononeuritis multiplex), salivary glands, gonads and breast [ 34 ] . non-speci fi c symptoms such as malaise, fever, weight loss or growth failure, arthralgia and arthritis are relatively common [ 34 ] . renal morbidity and mortality is a major concern in the aav, hence therapy aimed at preservation of renal function is a recurring theme for the treatment of aav in adults and children [ 174 ] . treatment for paediatric aav is broadly similar to the approach in adults, with corticosteroids, cyclophosphamide (usually 6-10 intravenous doses at 500-1,000 mg/m 2 [ 2 ] per dose given 3-4 weekly; alternatively given orally at 2 mg/kg/day for 2-3 months), plasma exchange (particularly for pulmonary capillaritis and/or rapidly progressive glomerulonephritis-"pulmonary-renal syndrome") routinely employed to induce remission [ 3, 175 ] . intravenous pulsed cyclophosphamide is increasingly favoured over oral continuous cyclophosphamide in adults because of reduced cumulative dose and less neutropenic sepsis [ 176, 177 ] and is thus increasingly used to treat children with aav as well, albeit without good paediatric evidence. this is followed by low-dose corticosteroids and azathioprine (1.5-3 mg/kg/day) to maintain remission [ 3, 178 ] . anti-platelet doses of aspirin (1-5 mg/kg/day) are empirically employed on the basis of the increased risk of thrombosis associated with the disease process [ 179 ] . methotrexate may have a role for induction of remission in patients with limited wg [ 180 ] , but is less commonly used as an induction agent in children with aav. co-trimoxazole is commonly added for the treatment of wg, particularly in those with upper respiratory tract involvement, serving both as prophylaxis against opportunistic infection and as a possible disease-modifying agent [ 139 ] . recommendations regarding duration of maintenance therapy are based on adult trial data, suggesting that the strongest predictor of relapse is withdrawal of therapy, and hence maintenance therapy should be continued for several years [ 174 ] . as a general therapeutic measure, prophylaxis against osteoporosis, gastrointestinal ulceration and infection (bacterial, protozoal and fungal) is standard for treatment for aav [ 174 ] . as the use of cyclophosphamide contributes to morbidity and mortality [ 3, 174 ] with infection playing a prominent role [ 181 ] , and disease relapses occur in 50% of the patients with aav as drugs are reduced or withdrawn, newer immunosuppressive agents and immunomodulatory strategies are being explored in both adults and children [ 3, 174 ] . such treatments include mmf and rituximab, which have already been reported to be effective at inducing or maintaining remission in adults with aav [ 182, 183 ] . of interest, two recent randomized control trials reported on the ef fi cacy of rituximab compared to cyclophosphamide to induce remission in adults with aav [ 184, 185 ] . jones et al. report on the results of a randomized trial of rituximab versus cyclophosphamide in anca-associated renal vasculitis (rituxivas) and stone et al. report on the results of the rituximab in anca-associated vasculitis (rave) trial [ 184, 185 ] . similar conclusions are reached in the two studies [ 184, 185 ] . both trials showed that rituximab was ef fi cacious in inducing a remission, as compared with intravenous cyclophosphamide (in the rituxivas trial) or oral cyclophosphamide (in the rave trial) [ 184, 185 ] . there are, however, a number of important differences between the two trials. in the rituxivas trial, patients who were randomly assigned to the rituximab group also received at least two doses of intravenous cyclophosphamide, whereas in the rave trial, patients randomly assigned to the rituximab group did not receive any cyclophosphamide [ 184, 185 ] . the trials were similar in that all patients in both trials received both intravenous and oral glucocorticoid therapy [ 184, 185 ] . investigators in the rituxivas trial reported sustained remission for 12 months, whereas outcome data from the rave trial were reported only on the 6-month remission-induction period [ 184, 185 ] . the rave trial data were confounded by the use of glucocorticoid therapy for 5 of the 6 months of follow-up [ 185 ] . in addition, both trials raised concerns about the substantial complications from the use of rituximab and other immunomodulating agents in anca-associated disease [ 184, 185 ] . fewer adverse events would have been expected in patients treated with rituximab as compared with cyclophosphamide. unfortunately, in the rave trial the rate of adverse events was equivalent in the two study groups [ 185 ] . similarly, in the rituxivas study, 6 of 33 patients in the rituximab group died, as did 2 of 11 patients in the control group [ 184 ] . the rave trial also showed an unexpectedly elevated number of malignant conditions detected over a relatively short treatment period [ 185 ] . these studies suggest that rituximab might be considered as an option for fi rst-line therapy for induction of remission of anca-associated disease. it remains unclear whether rituximab should be used with glucocorticoids alone or in combination with intravenous cyclophosphamide. biologic therapy is also increasingly used to treat children with small vessel vasculitis, including aav and anca negative vasculitides [ 186 ] . agents used include rituximab (previously mentioned), anti-tnf-a (etanercept, in fl iximab, and adalimumab), and anakinra (recombinant interleukin 1 receptor antagonist) [ 186 ] . these therapies are mainly reserved for those children who have failed standard treatment, or in those patients where cumulative cyclophosphamide and/or corticosteroid toxicity is of particular concern [ 186 ] . of note is the european vasculitis study group (euvas) mycyc trial (uk and europe), which is comparing induction therapy of wg and mpa using cyclophosphamide (standard therapy) versus mmf (experimental therapy). this is the fi rst euvas trial to include children as well as adults and is actively recruiting patients under the age of 17 years in the uk. for a full list of the past and present euvas trials for avv, the reader is directed to: http://www.vasculitis.org/ . the aav still carry considerable disease-related morbidity and mortality, particularly due to progressive renal failure or aggressive respiratory involvement, and therapy-related complications such as sepsis. the mortality for paediatric wg from one recent paediatric series was 12% over a 17-year period of study inclusion [ 187 ] . the largest paediatric series of wg reported 40% of cases with chronic renal impairment at 33 months follow up despite therapy [ 188 ] . for mpa in children, mortality during paediatric follow up is reportedly less than 14% [ 189 ] . for css in children, the most recent series quotes a related mortality of 18%, all attributed to disease rather than therapy [ 190 ] . systemic polyarteritis nodosa (pan) is rare in childhood. although the epidemiology is poorly de fi ned, pan occurs more commonly in children than in adults, as well as being more common than the aav [ 56 ] . disease manifestations are diverse and complex, ranging from the benign cutaneous form to the severe disseminated multi-systemic form [ 56 ] . the immunopathogenesis leading to vascular injury in pan is probably heterogeneous [ 56 ] . based on animal models, the mechanism of vascular in fl ammation implicated most often is induction by immune complexes [ 56 ] . in addition, there are some data supporting a role for hepatitis b in some patients [ 191 ] and reports of a higher frequency of exposure to parvovirus b19 and cytomegalovirus in pan patients compared to control populations [ 192, 193 ] . hiv has also been implicated and pan-like illnesses have additionally been reported in association with cancers and haematological malignancies [ 194, 195 ] . however, associations between pan and these infections or other conditions are rare in childhood. streptococcal infection may be an important trigger [ 195 ] , and indirect evidence suggests that bacterial sags may play a role in some cases [ 56 ] . in terms of pathogenetic mechanisms, it seems likely that the immunological processes involved are similar to those in other systemic vasculitides and include immune complexes, complement, possibly autoantibodies, cell adhesion molecules, cytokines, growth factors, chemokines, neutrophils and t cells [ 196, 197 ] . of note, immunohistochemical studies performed on biopsied perineural and muscle vessels from homogeneous populations of pan patients showed that in fl ammatory in fi ltrates consist mainly of macrophages and t lymphocytes, particularly of the cd8+ subset [ 198 ] . to date, there is no reliable animal model of the disease. the pan-like disease in cynomolgus macaques, which is very similar to the human disease, occurs only sporadically [ 199, 200 ] . snyder et al. described a pan-like illness arising spontaneously in beagle dogs, but to date this animal model has not provided insight to the pathogenesis of pan in humans [ 201 ] . furthermore, it is assumed that there are probably genetic predisposing factors that may make individuals vulnerable to develop pan, as have also been considered for other vasculitides [202] [203] [204] . an example of this is the link with familial mediterranean fever [ 56, 205 ] . yalcinkaya et al. have recently reported on the prevalence of fmf mutations in 29 children with pan showing that 38% of the patients were carriers of mefv mutations [ 205 ] . the new eular/printo/pres classi fi cation criteria for pan are as follows: histopathological evidence of necrotizing vasculitis in medium-or small-sized arteries or angiographic abnormality (aneurysm, stenosis or occlusion) as a mandatory criterion, plus one of the following fi ve-skin involvement, myalgia or muscle tenderness, hypertension, peripheral neuropathy and renal involvement [ 8 ] . the main clinical features of pan are malaise, fever, weight loss, skin rash, myalgia, abdominal pain and arthropathy [ 56 ] . additional features include ischemic heart and testicular pain; renal manifestations such as haematuria, proteinuria and hypertension; and neurologic features such as focal defects, haemiplegia, visual loss, mononeuritis multiplex and organic psychosis. livido reticularis is also a characteristic feature, and occasionally subcutaneous nodules overlying affected arteries are present. for many years, the treatment of pan has involved the administration of high-dose steroid with an additional cytotoxic agent such as cyclophosphamide to induce remission [ 56, [206] [207] [208] . empirically, aspirin has also been given as an anti-platelet agent by some clinicians [ 209 ] . once remission is achieved maintenance therapy with daily or alternate day prednisolone and oral azathioprine is frequently utilized for about 18 months. adjunctive plasma exchange can be used in life-threatening situations [ 210 ] . biologic agents such as in fl iximab and rituximab are increasingly used [ 185, [211] [212] [213] [214] [215] . treatment for cutaneous pan is typically much less aggressive. agents commonly utilized include low-dose prednisolone, anti-platelet agents, colchicine, hydroxychloroquine or azathioprine [ 56 ] . however, in a few cases cutaneous pan may progress over time to the systemic form of the disease and therefore require more aggressive therapy [ 56 ] . ozen et al. reported on a retrospective series of childhood pan and improved outcome compared to that reported in adults with only 1 (1.1%) death and 2 (2.2%) patients with end-stage renal disease among 110 patients [ 195 ] . of note, however, in that series 30% of patients were classi fi ed as having cutaneous pan, which typically has a more benign course than systemic pan [ 195 ] . ta is a predominantly large vessel vasculitis with a worldwide distribution, although the disease is most common in asia [ 216 ] . onset of ta is most common during the third decade of life but has been well reported in young children [ 216 ] . even though the precise factors responsible for the arterial damage in ta are unknown, it is believed that genetically linked immune responses to unidenti fi ed antigens may incite autoimmune damage by cell-mediated or humoral pathways, resulting in the disease and its relapses [ 216 ] . in the acute phase of ta, the in fl ammatory lesions originate in the vasa varum and are characterized by perivascular cuf fi ng mainly composed of g d t lymphocytes, cytotoxic lymphocytes and t helper cells [ 217 ] . luminal stenosis of advential small arteries due to intimal thickening is relatively common [ 217 ] . in the chronic stage of ta, intimal fi brosis is often accompanied by well-formed fi brous atherosclerotic plaques and calci fi cation [ 217 ] . furthermore, autoantibodies against aortic endothelial cells have been proposed as a key factor in the pathogenesis of ta [ 218, 219 ] . chauhan et al. reported that patients with ta show circulating anti-aortic endothelial cell antibodies (aaecas) directed against 60-65 kda heat-shock proteins (hsps 60/65) [ 218, 219 ] . sera from aaeca-positive patients with ta were found to induce apoptosis of aortic endothelial cells, suggesting that these antibodies may have a role in the disease pathogenesis [ 218 ] . lastly, while previous reports have suggested a link between ta and tuberculosis, additional studies have not supported this association [ 220 ] . familial occurrence of the disease has been extensively reported, leading to a hypothesis for a hereditary basis [ 221 ] . the genetic association of ta with hlab52, and particularly b*5201 that has been observed, with high estimated or (4.7-10.2), in multiple cohorts of diverse ethnicity (east asia, south asia and mexico) [ 222 ] . in addition, a hypothesis was made, based on a japanese cohort, that an even stronger association can be identi fi ed, considering hla alleles that share the motif of glutamate at position 63 and serine at position 67, which characterizes b*3902 as well as b*5201 [ 223 ] . data supporting this hypothesis were recently reported using a mexican cohort [ 222 ] . candidate gene studies have also reported associations with interleukin (il)-12, il-2 and il-6 gene polymorphisms in a turkish cohort but have not been replicated [ 4, 32 ] . clinical diagnosis of ta is commonly challenging for the clinician. it is estimated that one-third of children present with inactive, so-called burnt-out stage of disease, in which clinical features represent vascular sequelae rather than active vasculitis [ 216 ] . the natural history and the time from onset of symptoms to diagnosis are variable. the clinical spectrum at presentation of children with ta differs from that of adults; however, hypertension is the most common symptom in both groups [ 216 ] . cakar et al. recently reported in a series of 19 children with ta that the most common complaints at presentation were headache (84%), abdominal pain (37%), claudication of extremities (32%), fever (26%) and weight loss (10%) [ 224 ] . one child presented with visual loss. examination on admission revealed hypertension (89%), absent pulses (58%) and arterial bruits (42%) in the same cohort [ 224 ] . corticosteroids are still the mainstay of treatment for ta [ 4, 216 ] . in addition, mtx, azathioprine, mmf and cyclophosphamide have been used in children [ 4, 216 ] . ozen et al. described six children with ta, and treatment with steroid and cyclophosphamide induction followed by mtx was suggested as effective and safe for childhood ta with widespread disease [ 225 ] . anti-tnf therapy may be bene fi cial [ 226 ] . surgical intervention is frequently required to alleviate end-organ ischemia and hypertension resulting from vascular stenoses [ 216 ] . the mortality rate in children has been reported as high as 35% [ 216 ] . the outcome depends on the vessel involvement and on the severity of hypertension [ 216 ] . initially considered as a single cell lining of the vascular tree, the endothelium has recently emerged as a dynamic interface responsive to environmental stimuli [ 227 ] . as a result, alteration of the endothelium generates a repertoire of biological responses playing a key role in the control of vascular homeostasis such as haemostasis, in fl ammation or angiogenesis [ 228 ] . as a consequence, the endothelium not only displays altered functions but also loses its integrity. endothelial microparticles (emps) released from activated or apoptotic endothelial cells and whole endothelial cells, circulating endothelial cells (cecs), detached from injured vessels constitute a fundamental feature of these injurious responses affecting the vessel wall [229] [230] [231] . in response to injury, regenerative mechanisms are activated to restore endothelium integrity [ 232 ] . in the past, endothelial repair was considered to solely involve adjacent endothelial cells able to replicate locally and replace the lost cells. since the original study by asahara et al., it has become obvious that the recruitment of endothelial progenitor cells (epcs) represents an additional mechanism for vascular repair [ 232 ] . these stem cells are mobilized from the bone marrow and are able to differentiate into mature cells, restoring endothelial integrity at sites of vascular injury [ 232 ] . this spectrum of endothelial responses can be considered in a dynamic triad "activation/injury/ repair", which has critically transformed our understanding of endothelial biology. cecs and emps are sensitive biomarkers of vascular injury for monitoring disease activity and response to therapy in children with vasculitis [ 233 ] . in addition, preliminary data show altered endothelial repair responses in children with systemic vasculitis, suggesting an unfavourable balance of endothelial injury and repair in childhood vasculitis [ 234 ] . several key aspects of the long-term outcome of vasculitis in the young remain of ongoing concern. histological fi ndings seen in kd arteries at sites of previous aneurysmal lesions long after disease resolution appear to be indistinguishable from atherosclerosis [ 235 ] . dhillon et al. studied vascular responses to reactive hyperemia in the brachial artery using high-resolution ultrasound [ 106 ] . flow-mediated dilation (an endothelial-dependent response) was reduced in kd patients compared with control subjects many years after the illness, even in patients without detectable early coronary artery involvement. in addition, cheung et al. studied a cohort of patients with kd with or without coronary aneurysms compared to healthy controls and demonstrated reduced arterial distensibility (an independent risk factor for cardiovascular morbidity and mortality in adults), as assessed using ultrasound pulse wave velocity in the brachio-radial arterial segments and carotid imt [ 236 ] . similar fi ndings have also been documented in children with pan [ 237 ] . thus, the longterm outlook for patients with systemic vasculitis must remain guarded at the present time. a series of signi fi cant short-and long-term challenges are looming in the fi eld of paediatric vasculitis research. the development of biomarkers that allow reliable non-invasive monitoring of disease activity and guide therapeutic decisions is of great clinical importance [ 233, 238 ] . furthermore, several key aspects of the longterm cardiovascular risk for children who have systemic vasculitis are described [ 239 ] . the emergence of new therapies for the treatment of vasculitis in children provides a real opportunity to limit cyclophosphamide and corticosteroid exposure in the young. these include mmf [ 182, 183, 240, 241 ] and biologic agents such as rituximab [ 184, 185, 187 ] , anti-tnf-a [ 187, 242 ] and thalidomide analogues such as lenalidomide [ 243 ] , amongst others. none of these agents yet has an evidence base to justify their routine use in paediatric vasculitis, although many are increasingly used in this context in individual cases. it is likely that in the future clinical trials in the young will attempt to focus on these agents as alternatives to cyclophosphamide and azathioprine for induction of and/or maintenance of remission of systemic vasculitis. these sorts of trials will require international collaboration if meaningful patient numbers are to be realized, and this remains an important challenge for vasculitis research in children. vasculitis from the pediatric perspective incidence of henoch-schonlein purpura, kawasaki disease, and rare vasculitides in children of 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with in fl iximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis successful treatment of behcet's disease with lenalidomide key: cord-312486-rumqopg0 authors: jacob, chaim oscar title: on the genetics and immunopathogenesis of covid-19 date: 2020-09-10 journal: clin immunol doi: 10.1016/j.clim.2020.108591 sha: doc_id: 312486 cord_uid: rumqopg0 most severe cases with covid-19, especially those with pulmonary failure, are not a consequence of viral burden and/or failure of the ‘adaptive’ immune response to subdue the pathogen by utilizing an adequate ‘adaptive’ immune defense. rather it is a consequence of immunopathology, resulting from imbalanced innate immune response, which may not be linked to pathogen burden at all. in fact, it might be described as an autoinflammatory disease. the kawasaki-like disease seen in children with sars-cov-2 exposure might be another example of similar mechanism. replicate both in the upper and lower respiratory tract might explain why people infected have such different experiences. the virus can start in the throat or nose, producing a cough, disrupting taste and smell, and then end there. or it might work its way down to the lungs and debilitate that organ and the entire organism. it is quite likely that once sars-cov-2 gets down in the lungs, it's probably just as deadly as sars-cov-1. in sum, the assessment expressed in the general media, but sometimes also in professional literature [26] [27] [28] [29] that the virus is entirely -new‖ and that the immune system is -naive‖ namely that it is totally inexperienced when it comes to this virus is exaggerated. a more accurate description of this virus would be a reemergence of a known foe that has a somewhat more optimal organization of its resources making it more suitable to become a pandemic pathogen. the genetic sequence diversity of sars-cov-2 is low. as a consequence of a massive effort to sequence viral samples obtained from humans infected all around the world, there are now thousands of viral sequences available which permits an unprecedented and detailed analysis of the virus's genetic evolution. during the early phase of the outbreak in wuhan two major lineages of sars-cov-2, with different exposure histories, were categorized as l (∼70% of sequences) and s (∼30%) based on two tightly linked single nucleotide polymorphism (snp)s-a synonymous mutation in the orf1ab of the genome, and a non-synonymous s84l amino acid change in orf8. [30] . the s variant was evolutionarily more related to animal cov. the functional consequences of the s84l mutation are not known. nevertheless, the two variants exhibited similar virulence and clinical outcome [31] . a mutation in the spike protein-that mediates sars-cov-2 entry into host cells and potentially of functional importance-was described by several teams of researchers [32] [33] [34] [35] . the d614g mutation at residue 614 of spike (s) protein causes an amino acid change from aspartate to glycine. the mutation that causes the d614g amino change is transmitted as part of a conserved haplotype defined by four snps that almost always track together, although they probably arise independently. beside the d614g mutation the haplotype includes another nonsynonymous mutation (p322l) in the nsp12 viral protein. while the functional consequences of the p322l mutation remain unclear at present, there is strong evidence that the g614 variant is associated with greater infectivity and higher viral loads in the upper airways during infection [29, [32] [33] [34] [35] . the s protein must be cleaved by host proteases to enable membrane fusion, which is critical for viral entry. the g614 mutation creates a novel serine protease cleavage site that can facilitate its cleavage by host serine protease elastase-2 [32] . also g614 mutation increases both spike stability and membrane incorporation [33] . in cell culture, s-g614 pseudovirus infected ace2-expressing cells significantly more efficiently than the s-d614 pseudovirus [29, 34] . even though the g614 variant appears to be more infectious, it did not appear to be more virulent since hospital outcomes were similar with either variant [29, 33] . dynamic tracking of variant frequencies sampled from covid-19 patients from asia, europe, north america, and australia show that the d614 variant was initially dominant, so most subjects infected during december 2019 through the end of february 2020, had this variant [29] . the earliest viral sequence that carried the g614 mutation with the other three snps that characterize the haplotype was sampled in northern italy on february 20 th . during march 2020 both variants could be identified circulating in the population [29, 34] . by april, the g614 variant was circulating almost exclusively in european and in the greater nyc area. this variant continued increasing in frequency over several months so that by june 2020 it has become the dominant variant all over the globe. it is tempting to hypothesize that the successful mitigation of the outbreak in china and several other east asian countries was due, at least in part, to the fact that they faced the less infective d614 variant. the european countries and nyc had to deal with the more infectious g614 variant. similarly, the early outbreak in washington state was caused by the d614 variant [34] . the original march-april outbreak on the western coast of the united states might have been less severe than in the northeastern united states, because it originated from the washington state d614 variant. by june 2020, the g614 became the global dominant variant, and is responsible for the much more infective july phase of the outbreak in the southern and western usa. the viral genetic data presented clearly demonstrate that variants may arise quickly, even in cov, and have profound effects on the spread and consequences of the covid-19 pandemic. prior research has uncovered gene variants that can alter a person's chances of contracting a viral infectious disease. the most famous example is a mutation in the ccr5 gene, which offers protection against hiv. while there are 32 coding variants in human ace2, with some of them in residues considered important for the binding of s-protein in cov [36] , there is no evidence for the existence of cov s-protein-resistant ace2 mutation in any population [37] . neither is there any evidence for ace2 variants that bind more, or less, efficiently to sars-cov-2 s-protein. based on publicly available data from east asia, europe and north america, a group of british epidemiologists conclude that children are half as likely to be infected by sars-cov-2 as adults [38] . the reliability of these estimates are limited by lack of direct assessments of the transmission of the virus between adult to child, and child to child, compared with adult to adult. furthermore, because children tend to have less comorbidities than adults, they experience less disease symptoms, and as such are tested less than adults. hence, the number of children infected may be grossly undercounted. a publication that in this short timeframe has already been cited frequently, seeks to confirm that the incidence of sars-cov-2 infection is lower in children than adults due to a lower density of ace2 receptors in the nasal epithelium of children as compared to adults [39] . the researchers report finding less ace2 rna in cells scraped from the noses of children than in those from adults. the significant difference in this study is reported to be between those under 17, and those aged 18-60. in addition, there was no difference in the amount of ace2 rna detected according to gender, or those with or without asthma. several caveats to consider: the average relative amount of rna ranged from 2.4 for those less than 10 years old, to 3.09 for those 25 and older. the differences are relatively small and the error bars large. while those over 60 are those most affected by covid-19, the study did not include individuals older than 60 years. also, the density of ace2 receptors may not be uniform throughout the nasal mucosa, and no evidence is presented that the entire nasal mucosa was j o u r n a l p r e -p r o o f equally sampled. lastly, it is unknown how many receptors are needed for the sars-cov-2 virus to successfully infect us. in any case, there is no doubt that children of any age can be infected. i am more convinced by the conclusions of dong et al. [40] that children of all ages are susceptible to infection by sars-cov-2 without significant sex differences. although clinical manifestations of children's covid-19 cases seem generally less severe than those of adult patients, young children, particularly infants, are vulnerable to infection. as the aforementioned publication [39] assumes, if ace2 is the sole receptor for viral entry, then the expectation is that high ace2 tissue expression equals higher infectivity and worse outcomes. however, a careful consideration of the role of ace2 in the renin-angiotensin system physiopathology is indicative of it playing a protective role-meaning higher ace2 expression is more likely to protect us from a worse outcome of viral infection. as such, ace2 has an important role in counterbalancing the effects of ace1. angiotensin ii, a product of ace1 cleaving angiotensin i, can cause vasoconstriction, inflammation, and fibrosis. ace2 cleaves angiotensin ii to angiotensin 1-7, which antagonizes the activities of angiotensin ii-hence, it can suppress inflammation, fibrosis, and generate vasodilation. further, a high ace2/ace1 ratio protects the integrity of the endothelium and promotes antithrombotic activity. previous studies have found ace2 playing a protective role in severe lung injury in ace2 knockout (ko) mice [41] . ace2 ko mice challenged with avian influenza h5n1 [42] or h7n9 [43] resulted in severe lung injury, despite that ace2 is not a receptor for avian influenza. in fact infection with avian influenza strains resulted in downregulation of ace2 expression in the lung and increased serum angiotensin ii, both in mice and human subjects infected by the virus [42] . the question is whether ace2 expression levels are pertinent to sars-cov-2 infection only in the tissues relevant to viral entry and the lungs as its major target, [44, 45] or, given that covid-19 in its severe form is a systemic disease with multi-organ disfunction [46, 47] , ace2 expression levels may be important in multiple organs and tissues other than those of the respiratory system. relevant to this question, lungs do not have high expression levels of ace2, and relatively few cell types express ace2 in the lung compared to other tissues [37, 48] . assuming the importance of ace2 expression throughout the human organism, in silico analyses have been undertaken through integrating public genomics, epigenomics and transcriptomics data in multiple tissues, different populations, disease conditions, and age as well as sex considerations. intriguing in silico findings suggest that east asian populations have higher allele frequencies in expression quantitative trait loci (eqtl) variants associated with higher ace2 tissue expression compared to european and african populations [37, 48] . furthermore, ace2 expression increases by estrogens and to a much lesser degree by androgens, which possibly explains the higher ace2 expression in females [48] . the study suggests an inverse age-dependent ace2 expression in both males and females, a reduced expression in type 2 diabetes, and inhibition of ace2 expression by inflammatory cytokines [48] . these interesting suggestions (supporting a protective role of high ace2 expression against sars-cov2 fatality) need to be validated by clinical observations, in vivo, and in vitro experimentation. until such time, the functional consequences of ace2 expression levels to the susceptibility or response to sars-cov-2 remain unclear [49] . in addition to ace2, viral entry requires s-protein cleavage at the s1/s2 and s2' sites allowing fusion of viral and cellular membranes by host proteases. the transmembrane serine protease s2 (tmprss2) is frequently employed for this purpose by sars-cov-1 and sars-cov-2 [20, 50] , but also by mers [51] , and human cov-229e [52] . the functional importance of tmprss2 in cov infections was tested in tmprss2 ko mice infected with sars-cov-1 and mers-cov. results show that lack of tmptss2 in the airways reduced severity of lung pathology after infection by sars-cov-1 and mers-cov, despite that all other host proteases were intact [53] . apart from cov, tmprss2 is an important host protease for influenza viruses, by cleaving the influenza virus hemagglutinin (ha) molecule [54] . furthermore, genetic variants with higher tmprss2 expression increase susceptibility to severe human h1n1(2009) and avian h7n9 influenza [55] . these findings, raise the intriguing question whether genetic variants with higher tmprss2 expression confer higher risk and/or severity of sars-cov-2 infections. a preliminary study from italy suggests that two distinct tmprss2 haplotypes show significant frequency differences between italian and east asian populations [56] . specifically, the rare alleles of these haplotypes predicted to induce higher levels of tmprss2, are more frequent among italians. a snp belonging to one of the haplotypes is the same one found to be associated with increased susceptibility to severe influenza [55] . as will be discussed further, cytokines play an essential role in the pathogenesis of covid-19. while environment, microbiome, genetics, and host factors, each can influence cytokine responses to pathogen stimulation, genetic variations appears to be a main component shaping cytokine responses in humans [57] . for perspective, the microbiome does seem to have a smaller impact on cytokine production capability. it is estimated that microbiome explain only 10% of cytokine production [58] . large-scale studies from the human functional genomics project [57] have shown that different cytokines have different levels of genetic influence. this is an important concept for host defense and disease, as cytokines are fundamental in orchestrating overall immune responses, and can drive pathology when dysregulated, as is the case in covid-19. pertinent to the present discussion, the il-1/il-6 pathway especially, seems to be regulated mainly by genetic factors [57] . my own early work, has provided evidence for the heritability of tnf production capability in mouse and man [59, 60] . notwithstanding the current paucity of such studies in cov, i strongly believe this area of research promises to generate valuable information as for the pathogenesis and potential treatment of covid-19. african americans infected with sars-cov-2 seem to be at a greater risk for severe outcome. while comorbidities and socioeconomic circumstances certainly play a critical role, cytokines may have an important role too. a preliminary study compared expression levels of cytokines and other immune modulators between caucasian americans and african americans using rnaseq data [61] . results show il-1 and il-18 receptor 1 (il18r1), il12r1, tlr7 and tlr9 were significantly higher in african americans suggesting perhaps the tendency to develop higher inflammatory cytokine responses. much more work is needed to validate these observations. genome wide association studies (gwas) allowing the unbiased clustering of genetic variation defining human diseases, require assembly of dna samples from very large number of subjects which usually take a long time to collect. given that we are just six months into the pandemic, it is quite remarkable that a medium size gwas was already completed. it is the first to document a statistically significant association between genetic variants and severe covid-19 [62] . variations at two loci in the human genome were associated with an increased risk of respiratory failure in patients with covid-19; one, j o u r n a l p r e -p r o o f within the abo blood type cluster on chromosome 9, and the other at position 3p21.31. the frequency of the chromosome 3 risk allele was significantly higher in those patients that needed mechanical ventilation, compared to those with less severe disease progress. importantly, this locus is home to six genes, and it is not yet possible to identify which of them is responsible for aggravating the disease course. this locus contains a cluster of chemokine receptors, xcr1, ccr9 and cxcr6 (and several other cytokine receptor genes close by), which have important regulatory functions in the innate immune system. another candidate within the locus, slca20 is an amino acid (proline) transporter expressed at luminal membrane of small intestine and proximal tubule kidney cells and functions in absorption of proline. its expression in rodent intestine depends on the presence of ace2 [63] . however, amino acid transporters have been shown to induce cytokine responses: genetic variation at the slc36a4 amino acid transporter show strong association with pathogen induced il-22 production [57] . also amino-acids or amino acid catabolites have been reported to modulate cytokine production [64, 65] . so it is conceivable that slca20 might influence the course of covid-19 severity by affecting pathogen induced cytokine production, rather than viral entry through ace2. in this respect, the same risk snp in the chromosome 9 abo blood type cluster that affects covid-19 severity has been associated with elevated il-6 levels in childhood obesity in a previous gwas, thus, possibly linking this genetic allele with elevated il-6 levels (with or without full-blown ‗cytokine storm') described in severe covid-19 patients. the study [62] is equally striking for the genes that failed to turn up. pathogen microorganisms, including several viral infections, are controlled by genetic variations at the hla complex at chromosome 6p21 [66, 67] . the class i and class ii gene products of the hla are involved in antigen presentation, a mandatory process to initiate an adaptive immune response geared to restrain a pathogen. but genetic variants at the hla region did not appear to make a difference in the risk of severe covid-19. thus, the so called ‗adaptive' arm of the immune system seems to be less relevant to covid-19 than the ‗innate' immune response. i have offered here a hypothesis for what these genetic associations might actually mean. if correct it has major mechanistic implication as for the pathogenesis. at minimum it suggests avenues for further studies. recognition of a pathogen by the innate immune system triggers the secretion of the crucially important type i/iii interferons (ifn). the result of ifn signaling is the activation of an entire cascade of events that include the release of proinflammatory cytokines which further signal to endothelial cells, which then enable chemokines to spread throughout the blood to recruit innate immune cells to the site of infection. the recruited nk cells, monocytes, and neutrophils interact with activated endothelium to leave the blood stream and migrate toward the site of infection. at the site of infection they can perform effector functions to control infections, such as release of reactive oxygen species (ros) and, where they can perform effector functions to control infections, such as release of reactive oxygen species (ros) and directly killing infected cells, as well activating a pathogen specific adaptive immune response. given the shared sequence homology, the virus-host interactions of sars-cov-2 is likely to be analogous to those involving other cov. however, these interactions might be similar to j o u r n a l p r e -p r o o f other non-cov viruses as well because of limited repertoire and conserved mechanisms of innate immune signaling. sars-cov-2 engages host pattern recognition receptors (prr), and toll-like receptors (tlr) which initiate downstream signaling pathways triggering secretion of cytokines. if present early and properly localized, ifn are considered the most effective in limiting cov infections [68] . ifn induced proteins can interfere with viral entry and s-protein-mediated membrane fusion [69, 70] . however, in a later phase of the infection, ifn can become pathologic (e.g. upregulation of ace2 in airway epithelium [45] and orchestration of inflammatory response contributing to immuno-pathogenesis [127] ). sars-cov-2, similar to other cov, have developed multifaceted mechanisms to inhibit ifn induction and signaling [71] . this is evident by an early impaired ifn signature in severe covid-19 patients [72, 73] , while actively promoting other inflammatory pathways contributing to pathology (e.g. secretion of pro-inflammatory cytokines interleukin (il) 1β (il-1β) and il-18 [74] ). sars-cov-2 is particularly effective in inducing il-6 and il-8, by inhibiting an endogenous nf-kb repressor, nkrf [75] but probably by other mechanisms as well. while the human innate immune system resources remained unchanged, cov employs multiple innate immunity evasion mechanisms as reviewed recently [27, 76] . the earlier cov infections can provide an important road map to understand covid-19 pathogenesis. thus, a clear indication that immunopathogenesis contributes to sars was the observation that sars-cov-1 viral loads were found to be decreasing while disease severity increased [77, 78] . longitudinal in vivo experiments in which ferrets were infected with sars-cov-2 intranasally showed a robust production of cytokines that continued beyond clearance of the virus. by day seven, despite waning viral burden, the cytokine response continued to expend. remarkably, by day fourteen, while the virus was fully cleared, some cytokines and specifically il-6 remained elevated [73] . in fact, il-6 emerges as the dominant cytokine driving the immunopathogenesis. given that old age appears to be an independent risk factor for developing severe covid-19 [79] , it is noteworthy that in a groundbreaking study ter horst et al., have shown a clear and consistent increase in il-6 and il-1ra production in old age [80] . evidence is accumulating in covid-19 patients pointing to dysregulated monocyte driven dendritic cells and macrophage responses, which then drive the characteristic acute respiratory distress syndrome (ards) and cytokine release syndrome (crs) [81] . cd56 dim nk cells, generally thought to contribute to antiviral host defense through cellmediated cytotoxicity, were depleted primarily in severe cases. whereas cd56 bright nk cells, which are considered producers of ifn-γ and tnf-α, were significantly depleted in all covid-19 samples tested [82] . evidence supports recruitment of nk cells from the periphery to the lung. activation of these nk cells in the target tissue in an environment enriched for il-6 (and other cytokines) probably contributes to pathogenesis [76, 83] , as opposed to resolving the infection. severe cases of covid-19 have significant increase in neutrophil levels in circulation [84, 85] and in bronchoalveolar lavage fluid (balf) [86] . together with the upregulation of chemokines, particularly those that act as chemoattractants for neutrophils and monocytes j o u r n a l p r e -p r o o f [73, [86] [87] [88] , these observations support the influx of these cell types into the bronchi. these neutrophils and monocytes probably disrupt the air-blood barrier by causing collateral damage to airway epithelial cells and vascular endothelial cells while increasing cytokine production. the damage to vascular endothelial cells certainly contributes to microthrombosis. though seemingly contradictory to mechanisms of immune evasion, enhanced innate immune activation is central to the morbidity and mortality of covid-19 patients. immune evasion seems to characterize the first phase of infection with sars-cov-2 and this is associated with reduced innate antiviral immunity. however, approximately twenty percent of infected subjects develop an excessive innate immune activation approximately 7-10 days after infection, which i argue is associated only marginally, if at all, with viral load. rather, the massive inflammatory response is a consequence of host dysregulation of the immune system. in line with observations in sars-cov-1 [89] , sars-cov-2 induces a robust cytokine response with low levels of ifn in the early phase, culminating in improper recruitment of inflammatory monocyte-macrophage and neutrophil populations into target organs, resulting in further cytokine production [73] . a recurring theme in covid-19 pathogenesis is that components of the immune system that are generally thought to contribute to antiviral host defense end up promoting disease severity. typically, the complement system can efficiently recognize and eliminate viral pathogens by opsonizing viruses and virus infected cells, inducing an antiviral inflammatory state, increasing virus-specific immune responses, and neutralizing cell-free viruses [90] . however, the activation of multiple complement pathways, dysregulated neutrophil responses, endothelial injury, and hypercoagulability appear to be interlinked with sars-cov-2 infection and instead serve to drive the severity of the disease [91] . the functional importance of complement activation in cov was tested in c3 ko mice infected with sars-cov-1 [92] . the studies showed that complement activation regulates a systemic proinflammatory response and removal of c3 signaling reduced lung injury and respiratory dysfunction, despite equivalent viral loads present in the lungs. this was associated with reduced lung infiltration of neutrophils and monocytes and lower cytokine and chemokine levels in both the lungs and sera [92] . lung biopsy samples from patients with severe covid-19 show widespread complement activation characterized by c3a generation and c3-fragment deposition [93] . the host complement activator masp2, the key serine protease in the lectin pathway of complement activation, was identified as a target of the n (nucleoprotein) protein of sars-cov-1, mers-cov, and sars-cov-2, resulting in aberrant complement activation and aggravated inflammatory lung injury. in mice, lung injury induced by sars-cov-1 or mers-cov n protein was attenuated when its masp2-binding motif was altered, when masp2 was genetically knocked out, or when the masp2-n protein interaction was pharmacologically blocked [93] . earlier i have discussed the gwas that established significant association between severe covid-19 and the abo blood type cluster [62] . having blood type a was linked to an approximately forty-five percent increase in the likelihood that a patient would develop j o u r n a l p r e -p r o o f respiratory failure, while subjects with blood group o were at a thirty-five percent decreased risk for respiratory failure. a possible mechanistic explanation could be that type o patients harbor both anti-a and anti-b natural igm abs. these may help reduce the viral load of their hosts due to early activation of the classical complement pathway followed by viral clearance. such mechanism has been shown to work in vitro, using measles virus produced in cells engineered to express only a-type, b-type or o-type carbohydrate epitopes. measles virus was neutralized by human serum (that did not contain anti-measles ab), utilizing natural abs against the a and b antigens in a strictly complement-dependent manner [94] . these observations support a role for the complement system in enabling natural abo group abs as first line innate immune defense to viral infections. although most early studies concentrated on the lungs as the target organ in sars-cov-2 infection, it is now clear that covid-19 has a wider spectrum of organ involvement. this may be a result of the broad organ tropism of sars-cov-2, but is more likely due to an outof-control host immune response to the virus. indeed, evidence is accumulating in support of vascular cell dysfunction in multiple organs during sars-cov-2 infection [95] . first, sars-cov-2 is able to directly infect engineered human blood vessel organoids [96] . more importantly, histopathological evidence of vasculitis, sometime associated with viral particles, and accumulation of neutrophils and monocytes, and even lymphocytes, in the wall of blood vessels in multiple organs were described [97] . in addition, endothelial apoptosis and pyroptosis might contribute to endothelial cell injury. similarly, bryce et al., found diffuse vascular endothelial inflammation with micro and macro vascular thrombosis in the venous and arterial circulation [98] . the vascular endothelium is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis. endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischemia, inflammation with associated tissue edema, and a pro-coagulant state [99] . vascular endothelial damage could explain why people with pre-existing conditions like hypertension, diabetes, obesity, and cardiovascular disease are at a higher risk for severe complications. all of those conditions, identified as independent covid-19 risk factors, cause endothelial cell dysfunction. the additional damage and inflammation in the blood vessels caused by the viral infection could push them over the edge and cause catastrophic complications [79] . given that vascular endothelial cells express ace2, one likely hypothesis suggests that sars-cov-2 infects endothelial cells directly which induces injury, activates complement, and sets up a perpetual inflammatory state [91] . however, there are alternative mechanisms for activation of endothelial cells and vasculitis induction that do not necessarily require the presence of the virus itself, e.g. neutrophil extracellular traps (nets) [100] and hypoxia [101] . the ability of neutrophils to form nets is considered beneficial in host defense against pathogens, but as observed regarding other innate immune mechanisms, sustained net formation can trigger a cascade of damaging inflammatory reaction. indeed elevated levels of net-specific markers, myeloperoxidase dna, and citrullinated histone h3, were observed in the sera of covid-19 patients [102] . as such, several research groups are supporting a more central role for nets in covid-19 pathogenesis [102, 103] . coagulation disorders in patients with covid-19 were initially thought to be due to systemic disseminated intravascular coagulopathy (dic). however, considerable cross-talk and mutual engagement between the complement and the coagulation cascades is being increasingly documented in covid-19 and seems to be responsible for a prothrombotic environment distinct from dic, leading to serious adverse outcomes [91, 104] . in fact, elevated d-dimer (a fibrin degradation product indicative of hyperactive coagulation) has emerged as a reliable marker of severe covid-19 [105, 106] . interestingly, the interconnected complement and coagulation cascades, which are being increasingly documented in covid-19, has been long recognized in antiphospholipid syndrome (aps) [107] . given that several publications report antiphospholipid antibodies in patients with covid-19 [108] [109] [110] , despite them not fulfilling the sydney criteria for aps [111] , it is difficult to ignore how much the clinical and immunopathological picture of aps resembles that of the autopsy findings of an exaggerated inflammatory state and thrombosis in many covid-19 patients [112, 113] . a study by nicolai et al., provides mechanistic evidence that multisystem disease in severe covid-19 involves coagulopathy driven by dysregulated innate immune response [114] . they show inflammatory microvascular thrombi containing platelets, fibrin, and a large number of neutrophils in the lung, kidney and heart. neutrophils were highly activated in severe cases compared to less severe cases and platelets showed enhanced neutrophil adhesion and net formation in multiple organs. thus, dysregulated immunothrombosis is linked to both ards and systemic hypercoagulability [114] . in sum, an overwhelmed innate immune system is seemingly unable to assemble a balanced response of appropriate cells, cytokines and other molecules to control the infection in a timely fashion. instead, a disoriented, misguided storm of inflammatory cytokines ends up destroying that which it intended to protect. it disintegrated in moderate and severe covid-19-lymphopenia with drastically reduced cd4+ and cd8+ t-cells is the most consistent finding in moderate and severe covid-19 patients, which also correlates with disease severity and mortality [115] [116] [117] [118] . b-cells are decreased as well [119, 120] unlikely to be the case [88] . despite the fact that lymphopenia seems to be a prominent feature of severe covid-19, patients under immunosuppressive therapy are not at a higher risk for infection, and if infected seem not to be destined to have more severe progression. in fact, reviewing the mortality and morbidity reports published on sars-cov-1, mers-cov, and covid-19, no mention is made on immunosuppression as a risk factor for morbidity and mortality. further, no severe complications or fatality is reported to be linked to transplantation, chemotherapy, autoimmune hepatitis, ibd, or other conditions requiring immuno-suppressive treatment for patients at any age [121, 122] . in fact, reviewing the mortality and morbidity reports published j o u r n a l p r e -p r o o f on sars-cov-1, mers-cov, and covid-19, no mention is made on immunosuppression as a risk factor for morbidity and mortality. further, no severe complications or fatality is reported to be linked to transplantation, chemotherapy, autoimmune hepatitis, ibd, or other conditions requiring immuno-suppressive treatment for patients at any age [121, 122] . these observations reinforce the notion that the reduced t and b lymphocytes in covid-19 patients is not the direct cytopathic effect of the virus itself. the possibility that the peripheral lymphopenia observed in patients with covid-19 reflects recruitment of lymphocytes to the respiratory tract or adhesion to inflamed respiratory vascular endothelium has been suggested [31] . although autopsy studies of patients' lungs and single-cell rna sequencing of balf do identify the presence of lymphocytes, the lymphocytic infiltration is modest at best, arguing against sequestration as a main cause of lymphopenia [123] . the most likely scenario is that inflammatory cytokines are key factors behind the observed lymphopenia. indeed, serum levels of il-6 especially have been closely correlated with lymphopenia, while recovered patients show return of lymphocytes numbers towards the normal range with significant reduction in il-6 levels. a likely mechanism is via the downregulation of multiple hla class ii molecules on cd14 monocytes and b-cells by il-6, as demonstrated by multiple studies [82, 119, 120] . hla class i molecule downregulation was less severe and inconsistently observed. a negative correlation between serum levels of il-6 and the number of class ii hla on cd14+ monocytes supports the notion of downregulation of class ii by il-6 [82, 119] . this decrease in hla molecules suggests that severe covid-19 patients might be unable to mount a normal t cell response due to reduced antigen presentation capability to t cell receptors (tcr). such t cells are then eliminated by apoptosis. autopsy studies on lymphoid organs collected from patients who succumbed to the disease revealed massive lymphocyte death, which was linked to high levels of il-6 as well as fas-induced apoptosis [124] . treatment with tocilizumab, an il-6 receptor antagonist, restores, at least partially, the hla class ii molecules on antigen-presenting cells. in addition, it increased the number of circulatory lymphocytes, further suggesting il-6 is a key player in the lymphopenia development [119] . further, nk t-cells are reduced in number and impaired in function in severe covid-19 in an il-6 dependent manner [120] . since cd8+ t cells require antigen presentation by hla class i for activation via tcr, and these molecules are less reduced than class ii molecule, it is unlikely that the same mechanism of apoptosis of inactivated cd4+ t cells would be operating to a similar extent in cd8+ t cells. rather, it is possible that most cd8+ are eliminated due to activation/exhaustion of t cells [116] . intense immune profiling of covid-19 patients show a very heterogeneous immune response. a rigorous comparison between the studies is complicated by major differences in cohort sizes, dissimilar clinical phenotypes used, utilization of different experimental strategies, and emphasis on different parameters by various investigators. the study by giamarellos-bourboulis et al. [119] suggest that severe covid-19 patients developing severe respiratory failure show one of two immune phenotypes: (1) an immune dysregulation phenotype (~75% of patients) characterized by major reduction of hla-class ii molecules on cd14+ monocytes in the absence of elevated ferritin. this is triggered by monocyte j o u r n a l p r e -p r o o f hyperactivation, excessive il-6 production, and profound lymphopenia, but without il-1β elevation; and (2) a mas phenotype (~25%) associated with elevated ferritin, with relatively less reduction of hla class ii molecules on monocytes and triggered by il-1β. further studies will be needed to verify whether these immunophenotypes are generalizable. mathew et al. [125] identified a subgroup of approximately twenty percent of severe covid-19 patients that lack detectable lymphocyte response to the infection, suggesting a total failure of immune activation. further, these investigators emphasize that the typical tcell/b-cell communication and cooperation, the adaptive immune system depends on, is practically nonexistent in some covid-19 patients. lucas et al., [126] confirmed an overall increase in innate cell lineages, reduction in hla class ii molecules on monocytes, and early surge in cytokines with parallel reduction in t cells, observed by many other studies. in addition, according to these investigators the immune responses to pathogens can be roughly grouped into three categories characterized by different sets of immune cells and cytokine signals used: type 1-broadly t h 1 responses directed against viruses and intracellular bacteria; type 2-directed against parasites that do not invade cells; and type 3-directed against fungi and bacteria that can survive outside the cells. type 1 immune response expected in sars-cov-2 infection was seen in mild to moderate cases, while in severe cases the immune system seemed to invest too many resources in non-appropriate type 2 and type 3 immune signaling. this immune disintegration, the investigators have dubbed as -misfiring,‖ seems to extend to the realm of t and b lymphocytes [126] . other investigators describe the catastrophic cov disease as a lack of switch from an innate immune response to an adaptive immune response [13] . these depictions of the immune response in severe covid-19 are symbolically captured in fig.1 . the antigen specificity of sars-cov-2 t cells have just started to be characterized in covid-19 patients [129, 130] and their potential protective role awaits additional research. however, it is already clear that patients who recovered show specificity for multiple sars-cov-2 proteins, not only spike protein. interestingly, cross-reactive memory cd4+ and cd8+ t cells are also found in ~ 50% of subjects who have never been exposed to sars-cov-1/2 [129, 130] . while sars-cov-1/2 unexposed donors can recognize both structural and nonstructural viral proteins, nonstructural orf-1-nsp7/13-specific t cells are often dominant. in contrast, sars-cov-1/2 recovered individual preferentially recognize structural proteins [130] . at present no satisfactory explanation for this phenomenon has been offered. also unclear is how these preexisting memory t cells, which are presumably generated in response to human common cold cov, affect immunity or pathology upon sars-cov-2 infection. heterologous viral t cell immunity and immunopathogenesis-an important consideration that has not yet received sufficient consideration in the current viral pandemic, is highly relevant to the observations of cross-reactive t-cell responses in non-exposed subjects. in fact, only laboratory animals kept in pathogen free conditions are naïve. no human more than a few weeks old is immunologically naïve [131] . the history of previous exposure, not only to related, but also to unrelated microorganisms, can greatly alter the host's immune response to a viral infection and can change the course of disease [131] . in fact, it is very likely that this phenomenon is a common feature of human viral infections. t cells have high levels of j o u r n a l p r e -p r o o f cross-reactivity because the tcr first scans the peptide-hla complex by binding to the hla, and then it molds itself around the peptide. actually, the tcr contacts only 2-4 amino acids in the peptide, so the total energy of the tcr-peptide-hla interaction is heavily influenced by the hla rather than the peptide. the consequence is a highly promiscuous t cell which allows a large variation in peptide sequences without inhibiting the hla-peptide-tcr interaction [132] . hosts that have never experienced a particular virus, might, nevertheless, have memory t cell pools that show specificity for it by virtue of crossreactivity that can shape the repertoire of the primary response. the observation that the same virus can cause widely different pathological manifestations in humans might be due (at least in part) to an established adaptive immunity toward related or unrelated viruses, which results in enhanced protective immunity in some, reduced protective immunity in others, or altered immunopathology, including enhanced disease severity in some hosts [133] . the role of humoral responses in the pathogenesis of covid-19 remains unclear. as in sars-cov-1 infection, most subjects infected by sars-cov-2 seroconvert within 7-14 days after infection and this process is associated with increase in plasma cells, whereas naïve b cells decrease significantly [134] . while recovered patients generate sars-cov-2specific neutralizing abs and spike-binding abs concurrently, their titers are highly variable in different patients [135] . about one third of recovered patients generate very low titers of sars-cov-2-specific neutralizing abs [135, 136] , and some patients (possibly up to 20%) who recover, do not have detectable neutralizing antibodies at all [129, 135, 137] . these observations bring up the question of how the virus was cleared-as it eventually was in all those patients studied-without strong ab responses. we can speculate that t-cell mediated immune responses, or non-specific responses by innate immune cells were responsible for viral clearance. however, since a pathogen that kills off the host that it needs to survive is also threatening its very own existence, the possibility of cov self-clearing should be considered, especially when alternative hosts are plentiful. in a remarkable study [137] the levels of total igg and igg neutralizing antibodies (as measured using a spike protein pseudotyped virus) were quantified in symptomatic and asymptomatic patients eight weeks after release from the hospital (roughly three months after start of infection). the levels of igg and neutralizing antibodies were significantly decreased in the majority of patients in both groups. the decrease in neutralizing abs was more pronounced in asymptomatic (~80%) as compared to symptomatic (~60%) patients. taken together, the finding that ~20% of people infected with sars-cov-2 do not make anti-viral abs, added to the observation that neutralizing abs begin to drop noticeably during convalescence-suggests that infection with sars-cov-2 does not establish long-lasting serological immunity, at least not for those who are asymptomatic or mildly ill (more than 80% of all those infected by sars-cov-2). even more problematic-several studies show significantly higher igg and iga ab responses. this does not correlate significantly with protection, but rather with severity of disease [138] [139] [140] [141] similar to what was seen in sars [142] . at minimum, these studies suggest that a robust ab response is insufficient to protect from severe disease [76] . while it is frequently assumed that anti-sars-cov-2 abs might be either beneficial or irrelevant, there is also the possibility that such abs might actually be detrimental. first, abs can cause immunopathology by binding viral fragments followed by activation of the complement cascade by the ab complex. the consequences of complement activation in the pathogenesis of covid-19 was discussed above (section 4), and extensively reviewed by others [91] . second, ab responses to cov may contribute to pathology via ab-dependent enhancement (ade). ade is mediated by non-neutralizing virus-specific igg engagement of fc-receptors (fcr) expressed on immune cells, particularly monocytes and macrophages, leading to inflammatory activation of these cells. anti-s-igg passive immunization of sars-cov-1-infected rhesus monkeys significantly enhanced the viral induced acute lung injury with massive accumulation of monocytes and macrophages in the lung in an fcγr dependent fashion [143] . further, serum containing anti-s-igg from patients with sars-cov-1 enhances the infection of sars-cov-1 in human monocyte-derived macrophages in vitro [144] . a monoclonal ab isolated from a patient with mers, targeting the s-protein of mers-cov showed fcr dependent adh [145] . high dose iv immunoglobin (ivig) treatment which has shown some efficacy in cov including covid-19 [146] , may diminish adh by blocking fcr mediated activities of monocytes and macrophages. direct evidence for ade was not documented in covid-19 patients so far. however, as argued [147] , ade should be given full consideration in the safety evaluation of emerging candidate vaccines for sars-cov-2. finally, it should be emphasized that at present, neither anti-spike neutralizing abs nor anti-spike t-cell responses have been established as corollaries of protection. patients afflicted with a chronic autoimmune disease have an increased risk of infections including viral infections [148, 149] . likewise, acute viral infections may also exacerbate pre-existing autoimmune disease, and immunosuppressive therapies may render patients with autoimmune disease more vulnerable to viral infections. despite these compounded considerations, patients with systemic or organ specific autoimmune disease are not at increased risk for infection with sars-cov-2. in fact, of the hundreds of reports published, none mention autoimmune conditions as either independent risk factors for disease or as indicative of a more severe outcome if infected. the data actually suggests that the rate of infection with the virus and their clinical course is not any different from that of the general population [150] [151] [152] . those autoimmune afflicted patients that have develop severe covid-19, are likely to have other comorbidities that are independent risk factors for severe disease. while virus infections can cause flares in otherwise stable autoimmune disease, the data suggests that sars-cov-2 infection is not associated with increased incidents of autoimmune flares. i have previously (section 5) discussed and presented evidence that patients under immunosuppressive therapies, including those afflicted with autoimmune conditions are not at increased risk for infection or for more severe outcome [121, 122] . regarding sle, the prototypic systemic autoimmune disease, a group of investigators suggested that inherent epigenetic dysregulation causing hypomethylation and overexpression of ace2, the functional receptor for sars-cov-2, might facilitate viral j o u r n a l p r e -p r o o f entry, viremia, and increased likelihood of cytokine storm in such patients [153] . the aforementioned role of ace2 expression, as discussed above, suggests that higher expression of ace2 might actually benefit the host more than it benefits the virus. in any case, the clinical experience and published data do not support these predictions. moreover, the accumulating scientific information does not support the notion that severe covid-19 is a direct cytopathic viral disease, but rather a disease in which multi-organ insult occurs by the host's own immune system [154] . conditions in which the immune system attacks its own tissues are usually associated with development of autoabs. indeed, gagiannis et al., studied prospectively a group of 22 patients for the possible role of autoimmunity in covid-19 patients [155] . autoab titers ≥1:100 were detected in 10/11 covid-19 patients who required intensive care treatment, and in 4/11 patients with milder clinical course. based on serological, radiological, and histopathological similarities between covid-19-associated ards and acute exacerbation of connective tissue disease induced interstitial lung disease, these authors suggest that sars-cov-2 infection might trigger or simulate a form of organ specific autoimmunity [155] . similarly, zhou et al., report on autoabs in 21 severe covid-19 patients. the prevalence of anti-52 kda ssa/ro ab, anti-60 kda ssa/ro ab, and antinuclear ab (ana) was 20%, 25%, and 50%, respectively [108 ] . ana was reported in over 35% of 45 consecutive covid-19 patients [110] . several studies document different apl abs in covid-19 patients mostly associated with thrombotic phenomena [108-110, 156, 157] . whether apl in covid-19 is transient, as has been documented in many other viral infections, or develops into persistent and pathogenic, is very difficult to judge from the results published so far. pregnancy related morbidity with fetal losses have not been reported in connection with sars-cov-2 infections. however, since an infection often precedes the clinical onset of aps, it is certainly justified to follow up a positive apl test in a covid-19 patient with a repeated test approximately twelve weeks later to further evaluate the possibility of post-infectious aps. a kawasaki-like disease seen in children is the closest link between sars-cov-2 and the appearance of an autoimmune and/or autoinflammatory condition. investigators from italy's pandemic epicenter in bergamo were the first to focus attention on this disorder [158] . d'antiga and his colleagues, quantified the time course and incidence of kawasaki-like disease in children before and after the covid-19 pandemic, documenting a thirty-fold increase in incidence of kawasaki-like disease after the beginning of the pandemic [158] . kawasaki disease is an acute and usually self-limiting vasculitis of medium and small sized arteries with specific predilection for the coronary arteries that affects previously healthy young children typically under the age of five years. in the acute phase of the disease, patients with kawasaki disease might have hemodynamic instability, a condition known as kawasaki disease shock syndrome. same patients with kawasaki disease fulfil the criteria of macrophage activation syndrome (mas). an association between kawasaki disease and various viral infections have been suspected, including viruses of the coronavirus family, however a specific infectious trigger has yet to be identified. sars-cov-2 should be now added to the list of implicated viruses. the most accepted pathogenetic hypothesis supports j o u r n a l p r e -p r o o f an aberrant response of the immune system to one or more unidentified pathogens in genetically predisposed subjects. following the report from bergamo further reports of similar cases from many countries have been published [159] [160] [161] [162] [163] . with approximately 1,000 kawasaki-like cases reported, these studies provide a consistent clinical picture: the disease appears 2-4 weeks after an infection with sars-cov-2 and most patients have serological evidence of infection; patients are on average older than those with classical kawasaki disease; patients experience respiratory and gastrointestinal involvement; signs of hemodynamic instability; greater incidence of myocardial injury; and more intense inflammatory response due to dysregulated immune response. the incidence of coronary aneurism is lower than in kawasaki disease, but this may be a consequence of relatively short follow up. most patients so far have responded well to the same therapies used for classical kawasaki disease. all these results and considerations support the notion that the immune response to sars-cov-2 is responsible for this kawasaki-like disease [158, 163] in susceptible patients. u.k. pediatricians and their national health service defined and named the ‗new', disease -pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (sars-cov-2),‖ or pims-ts [159] . the cdc in the u.s. and the who subsequently published their own differing definitions of the disorder, which they termed multisystem inflammatory syndrome in children (mis-c) [160] [161] [162] [163] . physicians and scientists in the field of biology are prone to giving names that are often more confusing than helpful. i have worked for some years on a cytokine named tumor necrosis factor (tnf) that had practically nothing to do with necrosis of tumors, and from any sensible perspective is as much an interleukin (il) as any of the approximately 50 ils. i am not aware of any clinical, therapeutic, or long term follow up consideration that would benefit from a more nuanced definition and naming such as pims-ts or mis-c, rather than simply kawasaki-like disease. in fact some authors agree that -until more is known about long-term cardiac sequalae of mis-c, providers should consider following kawasaki disease guidelines for follow up‖ [161] . until a much better understanding of the pathogenesis of kawasaki disease and kawasaki-like disease emerges, i do not see a reason to further confuse the literature. as i am writing this essay, the pandemic seems far from being over. it surely looks like we are not even in the end of the beginning. the long-term impact of covid-19 is too early to evaluate. patients who have recovered from the disease report lingering chronic fatigue, muscle weakness, loss of sense of smell, and difficulties in concentration. but this might be just the tip of the iceberg. we already know that impaired liver function continues for some time after patients have apparently recovered and the virus has cleared. it is also probable that some patients will have lasting pulmonary damage due to fibrosis as has been documented in about 25% of patients recovered form sars [164] . similarly, myocardial j o u r n a l p r e -p r o o f scarring will cause cardiac impairment in certain covid-19 recovered patients. moreover, the long-term consequences of the massive inflammatory response affecting many tissues, and its effect on the competence of the immune system itself, are unknown. it is, however, possible that the intense inflammation in many tissues might cause cellular damage and exposure of self-antigens eliciting auto-reactive t and b cells and generating an autoimmune disease. another question that could take years to answer is whether the sars-cov-2 virus may lie dormant in the human body for years and then launch itself later in a different form. for example, after a chicken pox infection, the herpes virus that caused the illness reemerges after decades in form of shingles. similarly the hepatitis b virus causes the appearance of liver cancer years later. a general comment is pertinent at this point: the culmination of an interaction between an infectious agent and the human host, even when -full recovery-ensues, does not mean the organism is restored to its previous state (before the encounter), but rather the organism acquires a new equilibrium. as the french physician and philosopher george canguilhem wrote some 75 years ago: -contrary to orthodox medical teaching, health is not some absolute state of perfect physical and mental wellbeing. it is the margin of tolerance for the inconsistencies of the environment… disease is not simply disequilibrium or discordance; it is an effort on the part of nature to effect a new equilibrium in man‖ [165] . we have learned a tremendous amount about sars-cov-2 and covid-19 in a short amount of time. the efficient transmission of data exhibited during this time, has been surpassed only by the efficient transmission of the virus itself. although originally conceptualized as a primarily respiratory viral disease, covid-19 is now clearly recognized as a far more complex, multi-organ, and heterogeneous illness. as with sars-cov-1 and mers-cov, the important considerations for the delicate balance of the viral-host interaction that are responsible for covid-19 are now increasingly appreciated: (1) fast and robust initial viral replication; (2) early viral inhibition of ifn induction and signaling causing a delayed ifn expression which drives immunopathology; (3) out of balance antiviral innate immune response becomes immunopathogenic; and lastly (4) disintegration of the adaptive immune response. paul ehrlich's prediction of horror autotoxicus-at the turn of the 20 th century-has been realized by the innate immune response to cov in the 21 st century. the language of immunology is rife with war metaphors. for over a hundred years we have been educated to believe in the metaphor that the immune system acts as an army defending our bodies. as richard lewontin has written: -while we cannot dispense with metaphors in thinking about nature, there is a great risk of confusing the metaphor with the thing of real interest. we cease to see the world as if it were like a machine and take it to be a machine. the result is that the properties we ascribe to our object of interest and the questions we ask about it j o u r n a l p r e -p r o o f reinforce the original metaphorical image and we miss the aspects of the system that do not fit the metaphorical approximation‖ [166] . what has sars-cov-2 revealed? for me, the answer is our immune response to covid-19 serves as proof of everything i have long thought was wrong with viewing the (adaptive) immune system as a defense organization: it reacts too slowly. it fights today's threats with the solutions of past problems. it is susceptible to exploitation. it destroys that which it intended to protect. it is large, complicated, elaborate and wasteful [167] . if you stand back and evaluate how ineffective is the immune system as a defense organization, it is only logical to conclude that it was never intended as one. sars-cov-2 will eventually be contained, but not by our immune systems. rather, by the international brotherhood of the scientific community. epidemics have always played a natural part in the fabric of human history, but there has never been a time in history where so many different and powerful tools were available to accomplish this task. of all human conditions that disseminate virulent diseases, hubris emerges across centuries as a key driving force. we should embrace cesar augustus motto -festina lente‖, make haste, slowly-even or especially when you are feeling the crunch, take your time. this is not the time for us to skip corners. table 1 . comparison of transmissibility expressed as reproduction number, r 0 and case fatality rates of selected human viral diseases. adopted with changes from wang et al., [26] . the disintegration of the persistence of memory (1954) (rt) by salvador dali is an oil on canvas reaction to his original work the persistence of memory (1931) . in this version, the landscape from the first painting has been engulfed by water. disintegration of objects is occurring above and below the water. the block and plane from his original (lt) have now been separated into brick-like objects that float. some of the bricks on the left side of the painting begin to disintegrate. a watch beneath the water is coming to pieces and another one that sunk beneath the layer of bricks, leaves bits of debris behind. while persistence of memory (lt) symbolizes the importance of immunological memory as 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factors associated with covid-19-related death using opensafely epigenetic dysregulation of ace2 and interferon-regulated genes might suggest increased covid-19 susceptibility and severity in lupus patients on the alert for cytokine storm: immunopathology in covid-19 covid-19-induced acute respiratory failure-an exacerbation of organ-specific autoimmunity? medrxiv high risk of thrombosis in patients with severe sars-cov-2 infection: a multicenter prospective cohort study an outbreak of severe kawasaki-like disease at the italian epicenter of the sars-cov-2 epidemic: an observational cohort study clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 multisystem inflammatory syndrome in children in new york state multisystem inflammatory syndrome in u.s. children and adolescents acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic long term sequalae of sars: physical, neuropsychiatric, and quality-of-life assessment on the normal and the pathological the triple helix some savage cuts in defense i thank tamar jacob-eliasi for invaluable help with editing and proofreading the manuscript. coj is funded by nih grant r01ar072212. key: cord-027870-cuvfy4pj authors: baselga, eulalia; torrelo, antonio title: inflammatory and purpuric eruptions date: 2020-06-22 journal: neonatal dermatology doi: 10.1016/b978-1-4160-3432-2.50022-4 sha: doc_id: 27870 cord_uid: cuvfy4pj nan infl ammatory and purpuric eruptions this group of eruptions is composed of lesions of variable morphology and diverse etiology. however, all have erythema as a common feature, a refl ection of their infl ammatory nature. several disorders appear to represent hypersensitivity reactions, but for most the etiologic agents are unknown. the differential diagnosis of purpura is extensive in neonates, and includes hematological disorders, infections, trauma, and iatrogenic disorders. annular erythema is a descriptive term that encompasses several entities of unknown etiology characterized by circinate polycyclic lesions that extend peripherally from a central focus. 1, 2 because of subtle differences in clinical features, age of onset, duration of individual lesions, and total duration of the eruptions, a variety of descriptive terms have been coined for these disorders (table 19-1) . for prognostic reasons, it is useful to subdivide annular erythemas into transient and persistent forms. 3 transient forms include annular erythema of infancy and the less well-established entity erythema gyratum atrophicans transient neonatale. persistent annular erythemas include erythema annulare centrifugum, familial annular erythema, and erythema gyratum perstans. other annular erythemas known to be a manifestation of well-defi ned diseases (e.g. neonatal lupus) or with distinctive clinical or histologic features (e.g. erythema multiforme, erythema chronicum migrans, erythema marginatum rheumaticum, and erythema gyratum repens) are not considered under this heading. annular erythema of infancy is a benign disease of early infancy characterized by urticarial papules that enlarge peripherally, forming 2-3 cm rings or arcs with fi rm, raised, cord-like or urticarial borders. [4] [5] [6] adjacent lesions become confl uent, forming arcuate and polycyclic lesions ( fig. 19-1) . neither vesiculation nor scaling is present at the border. the eruption is asymptomatic. individual lesions resolve spontaneously without a trace within several days, but new lesions continue to appear in a cyclical fashion until complete resolution within the fi rst year of life. a few cases lasting for years have been described. [7] [8] [9] the cause of annular erythema is unknown, and there are no associated systemic fi ndings. histologic studies reveal a superfi cial and deep, dense, perivascular infi ltrate of mononuclear cells and eosinophils. no fl ame fi gures are observed. the epidermis is normal or mildly spongiotic. laboratory studies are normal. peripheral eosinophilia does not accompany tissue eosinophilia. immunoglobulin levels, including ige levels, are normal. the differential diagnosis should include other annular lesions of infancy (see the following discussion). no treatment is warranted because of the self-limited nature of the eruption. erythema gyratum atrophicans transiens neonatale is a less well-defi ned entity, 10 characterized clinically by annular plaques with an erythematous border and an atrophic center. the lesions appear in the newborn period and resolve within the fi rst year of life. histologic fi ndings include epidermal atrophy and a mild perivascular mononuclear infi ltrate. immunofl uorescence studies reveal granular deposits of igg, c3, and c4 at the dermoepidermal junction and around capillaries. erythema gyratum atrophicans transiens neonatale possibly represents a variant of neonatal lupus erythematosus. 11 erythema annulare centrifugum is a more persistent type of annular erythema that usually affects adults, 12 but may also occur in children and rarely in newborns. 3, [13] [14] [15] [16] the lesions are clinically somewhat similar to those of annular erythema of infancy, but scaling or vesiculation is seen at the border. the scales lag behind the advancing border, which, in contrast to annular erythema of infancy, is not indurated. individual lesions resolve spontaneously after a few weeks, but new plaques continue to develop for years, or may be a lifelong condition. there is no associated pruritus. erythema gyratum perstans falls within the spectrum of erythema annulare centrifugum. [16] [17] [18] some authors defend the distinctness of erythema gyratum perstans and consider distinctive features of this disorder to be its early onset, a duration of more than 15 years, the presence of slight to severe pruritus, and especially the presence of vesiculation. 16 erythema annulare centrifugum is thought to represent a hypersensitivity reaction to several trigger factors, including infectious agents (candida, 19, 20 epstein-barr virus, 14 and ascaris 21 ), drugs or foods, 22, 23 and neoplasia, especially in adults. intradermal injection of candidin or trichophytin may reproduce the clinical lesions. 13 histologic features consist of a dense, superfi cial, perivascular mononuclear infi ltrate. parakeratosis or epidermal spongiosis may be present. no therapy has been successful in all cases. treatment agents include oral nystatin, 20 oral amphotericin b, 19 topical antifungals, antihistamines, disodium cromoglycate, and interferon-α. 13 familial cases of annular erythema with autosomal dominant inheritance have been described. 25, 26 the onset is in early infancy. scaling, vesiculation, and pruritus may be more common than in erythema annular centrifugum. lesions resolve with residual hyperpigmentation. chronicity is the rule. geographic tongue may be associated. 26 differential diagnosis includes other eruptions with ringlike lesions, such as neonatal lupus, erythema multiforme, urticaria, urticarial lesions of pemphigoid, fungal infections, erythema chronicum migrans, and congenital lyme disease. 7, 27, 28 serum antibody determinations (antinuclear, ss-a, and ss-b) are recommended to exclude neonatal lupus. [29] [30] [31] [32] [33] [34] [35] [36] neonatal lupus erythematosus (nle) is a disease of newborns caused by maternally transmitted autoantibodies. the major manifestations are dermatologic and cardiac. skin fi ndings are transient. cardiac disease, which is responsible for the morbidity and mortality of nle, begins in utero and affects the cardiac conduction system permanently. other fi ndings include hepatic and hematologic abnormalities. mothers of infants with neonatal lupus have anti-ro/ss-a autoantibodies in 95% of cases. anti-la/ss-b and anti-u1rnp autoantibodies have also been implicated in the pathogenesis of nle in a minority of patients. 37, 38 fifty per cent of infants with nle have skin lesions, and congenital heart block is present in about 10%. 29, 36 lesions commonly develop at a few weeks of age but may be apparent at birth, which suggests that ultraviolet (uv) radiation is not essential for the development of skin lesions in nle. 39 clinically, skin lesions are analogous to those of subacute cutaneous lupus in its two variants: papulosquamous and annular. papulosquamous lesions are more common and are characterized by erythematous, nonindurated scaly plaques ( fig. 19-2 ). sometimes the skin lesions have an atrophic appearance ( fig. 19-3 ). ulcerations may be present. 40 in contrast to discoid lupus, scarring and follicular plugging are absent. the annular variant, which occurs almost exclusively in japan, consists of annular, more infl ammatory plaques. 41 lupus profundus and generalized poikiloderma with erosions and patchy alopecia are rare manifestations. 42, 43 nle lesions may be widespread but are most common on the face and scalp, predominantly affecting the periorbital and malar areas and often causing a 'raccoon eyes' appearance . the eruption is frequently precipitated or aggravated by sun exposure. sun exposure is not strictly required, however, as the lesions may occur in sun-protected areas such as the diaper region, palms, and soles. 39, 44, 45 skin lesions are transient and cease to appear around the age of 6 months, after the disappearance of maternal antibodies. transient hypopigmentation and epidermal atrophy may result ( fig. 19-5) . 36 telangiectasia is a more permanent sequela. telangiectasia also may be an initial sign of nle, occurring without preceding identifi able infl ammatory lesions; features of cutis marmorata telangiectatica congenita have been observed. 35, 46 a case of nle with a serological profi le consis-tent with drug-induced lupus has been described in a newborn whose mother was treated with α-interferon during pregnancy. 47 the most signifi cant manifestation is isolated complete congenital heart block. more than 90% of such cases are due to nle. most patients have third-degree block, but progression from a second-degree block has been reported. 48 heart block can often be detected as early as 20 weeks of gestation. transient liver disease, manifesting as hepatomegaly (with a picture of cholestasis) or elevation of liver enzymes, 35, [49] [50] [51] and thrombocytopenia or other isolated cytopenias, may occur. 52 petechiae and purpura have been described as presenting signs of nle. 53 less common fi ndings include thrombosis associated with anticardiolipin antibodies, hypocalcemia, spastic paraparesis, pneumonitis, and transient myasthenia gravis. [54] [55] [56] central nervous system (cns) involvement has been reported in 10 of 11 consecutive infants with nle, in the form of ultrasound and ct scan abnormalities which did not result in clinical neurological manifestations. 57 such cns involvement in nle is probably a transient phenomenon. between 30% and 50% of mothers of infants with nle have a connective tissue disease, most commonly sle or sjögren syndrome. most, however, are asymptomatic. the risk for developing overt connective tissue disease in these mothers is highly debated, with estimates ranging from 2% to more than 70%. 36, [58] [59] [60] [61] [62] [63] it is universally agreed that placentally transmitted maternal igg autoantibodies are necessary for the pathogenesis of nle, but not suffi cient. 64 the most commonly implicated autoantibodies have been anti-ro/ss-a and anti-la/ss-b. more than 95% of nle infants have anti-ro antibody, and 60-80% have anti-la antibodies. a small subset of affected infants do not have detectable anti-ro or anti-la antibodies, but instead have anti-u1rnp. 37, 38 mothers with high titers of anti-ro and anti-la antibodies are at greater risk of delivering an infant with nle. despite initial observations based on immunoblot or elisa testing that anti-52 kda ro antibodies conferred a higher risk of nle than anti-60 kda ro antibodies, more precise testing with line immunoassay has revealed that antibodies to 60 kda ro are signifi cantly more sensitive than antibodies to 52 kda ro and 48 kda la. 65 furthermore, comparing mothers of children with nle with rash alone or with congenital heart block, there is no signifi cant difference in the prevalence of any of the three antibodies between the two groups. 65 however, signifi cantly more symptomatic mothers of children with congenital heart block have anti-la antibodies than do disease-matched mothers with unaffected children. 65 moreover, the mean level of anti-la seems to be higher in mothers of infants with congenital heart block than in mothers of children with cutaneous nle. 66 it is not clear why only less than 5% of mothers with anti-ro and anti-la antibodies give birth to affected children and why mothers of affected infants are often asymptomatic despite having the same antibodies. furthermore, fraternal twins are often discordant for nle, and nle does not occur in every pregnancy. genetic factors may be important for the development of nle in children with maternal lupus antibodies. a link has been suggested between nle rash and the allele hla-drb1*03, as well as a -308a polymorphism in the tnf-α gene. 34 alternatively, maternal and/or sibling microchimerism may play an additional role, as levels of microchimerism have been reported to correlate with nle disease activity. 67 serologic studies for autoantibodies in the mother and infant demonstrate anti-ro, anti-la, and/or anti-u1rnp antibodies. anti-ndna, anticardiolipin antibodies, antinuclear antibody, and rheumatoid factor may also be present. anti-sm antibody, highly specifi c for systemic lupus erythematosus, is not found in nle. the maternal antibody titer is usually higher than the infant titer, which may even be negative if only immunodiffusion techniques are used. more sensitive methods, such as elisa, immunoblotting, or line immunoassay, should be used in such instances. skin biopsy, which is usually not necessary for diagnosis, shows changes characteristic of lupus erythematosus, that is, epidermal atrophy and vacuolization of the basal layer with a sparse lymphohistiocytic infi ltrate at the dermoepidermal junction and in a periappendageal distribution. in many instances, histopathological features in children with nle rash are subtle. direct immunofl uorescence is positive in 50% of cases, demonstrating granular deposits of igg, c3, and igm at the dermoepidermal junction. histopathologic examination of the heart shows replacement of the atrioventricular node by fi brosis or fatty tissue. endomyocardial fi broelastosis and patent ductus arteriosus may also be seen, 68, 69 as well as deposits of igg and complement. 70 the differential diagnosis includes congenital rubella, cytomegalovirus infection, annular erythema of infancy, tinea corporis, and seborrheic dermatitis. congenital syphilis should also be considered, but mucosal lesions are not a feature of nle. false positive serologic tests for syphilis may occur in nle. telangiectasia and photosensitivity may suggest bloom syndrome or rothmund-thomson syndrome. serologic studies for autoantibodies in both infant and mother help to confi rm the diagnosis. skin biopsy for histologic and direct immunofl uorescence studies is seldom necessary. neonates with suspected nle should receive a complete physical examination, electrocardiogram, complete blood count with platelet count, and liver function tests (box 19-1). skin lesions are transient. treatment of skin disease consists of sun protection and the application of topical steroids. pulsed dye laser therapy may be considered for residual telangiectasia. congenital heart block is permanent. half of newborns with complete congenital heart block require implantation of a pacemaker in the neonatal period. 32 mortality from complete congenital heart block in the neonatal period is 15%; another 10-20% die of pacemaker complications. 27, 32 late-onset cardiomyopathy may develop in a few infants. [72] [73] [74] for mothers with anti-ro or anti-la antibodies, the risk of delivering an infant with nle is 1-20%, depending on whether they have asymptomatic or symptomatic sle. 29, 32 the risk of recurrence of congenital heart block in subsequent pregnancies may be as high as 25%. 61 such pregnancies should be closely monitored, with repeated fetal echocardiograms. 75 if signs of intrauterine congestive heart failure are detected dexamethasone or plasmapheresis, or both, have been given. 32, [76] [77] [78] [79] although nle is usually self-limited, sle or other rheumatologic/autoimmune diseases may develop later in life in a small subset of patients. 62, 80, 81 the exact risk is unknown. [82] [83] [84] [85] cutaneous drug reactions are extremely rare in the neonatal period because the ability to generate a drug-induced immune response appears to be lower in infants. [86] [87] [88] furthermore, most drug reactions require time for sensitization, which may range from 1 to 4 weeks or more, as well as re-exposure to the causative drug. finally, newborns and young infants are less exposed to drugs than adults. cutaneous adverse reactions to drugs may be classifi ed according to the clinical characteristics of the eruption (box 19-2). whenever a suspect eruption is observed, a detailed history of medications should be obtained, including drugs administered to the mother, which may be present in breast milk. morbilliform ( fig. 19-6 ) or maculo-papular eruptions (fig. 19-7) are the most frequent type of drug reaction in neonates, and antibiotics are commonly implicated ( fig. 19-8) . distinguishing a drug eruption from a viral exanthem is often diffi cult. emla cream, a local anesthetic that may be used with great frequency in neonatal units, has been noted to produce a localized purpuric eruption. 89, 90 this type of reaction is seen preferentially in neonates, and subsequent applications of the cream do not always reproduce the purpuric lesions. methemoglobinemia is another complication of emla use in this age group. 90 emla cream should therefore be used with caution in infants who are taking methemoglobin-inducing medications such as sulfonamides, acetaminophen, nitroglycerin, nitroprusside, and phenytoin, and particularly in those with a history of methemoglobinemia. vancomycin, an antibiotic frequently administered to premature newborn infants for staphylococcus epidermidis nosocomial infections, may produce shock and rash in newborns (red-baby syndrome). [91] [92] [93] this reaction is characterized by the appearance of an intense, macular, erythematous eruption on the neck, face, and upper trunk shortly after the infusion is completed. it may be accompanied by hypotension and shock. the reaction resolves rapidly in a matter of hours. it is frequently associated with rapid infusion; however, lengthening the infusion to more than 1 hour does not completely eliminate the risk. 92 newborns with aids have an increased susceptibility to drug reactions. 94, 95 reactions to trimethroprim/sulfamethoxazole in patients with hiv infections can be severe and life-threatening. 96 fixed drug reactions of the scrotum and penis, with erythema and edema resulting from hydroxyzine hydrochloride, have been described in early infancy. 97 however, hydroxyzine hydrochloride is administered infrequently in the neonatal period because of the risk of antimuscarinic effects, such as restlessness and excitation. serum sickness-like reaction is a type of drug reaction that occurs predominantly in children and has been reported in infants 5 months of age. 98 it is characterized by fever, an urticarial eruption, and arthralgias. lymphadenopathy may be present. in contrast to true serum sickness, there are no immune complexes, vasculitis, or renal impairment. the most commonly implicated drug has been cefaclor. [98] [99] [100] this type of reaction may be seen in infants with an unknown or presumably viral etiology ( fig. 19-9) hypersensitivity syndrome reaction is a serious drug reaction characterized by fever, skin rash, lymphadenopathy, and internal organ involvement, especially of the liver. 101, 102 the most commonly implicated drugs are anticonvulsants, and therefore it is not rare in children. a fatal case in a 3-monthold infant has been reported, as well as a case in a premature infant. 103, 104 toxic epidermal necrolysis (ten) is extremely rare in newborns. cases of ten in newborns have been related to antibiotics and phenobarbital. 105 all cases described so far proved fatal. vegetant bromoderma is a reaction to bromides characterized by coalescing papules and pustules which form vegetant infl ammatory or pseudotumoral lesions. it usually affects the scalp, face, and legs. most cases of vegetant bromoderma have been described in infants after the ingestion of syrups and solutions containing bromide, which has sedative and expectorant properties, or the spasmolytic agent scopolamine bromide. 106 the eruption ceases after withdrawal of bromide. the risk of systemic intoxication, known as bromism, makes it advisable to avoid bromide use in newborns and infants. other anectodal reports of toxicoderma in very young infants or newborns have been described, such as a papular eruption from g-csf for collection of stem cells (fig. 19-10) , 107 a lichenoid reaction to ursodeoxycholic acid for neonatal hepatitis, 108 and a maculopapular rash from diazoxide used for neonatal hyperglycemia (see fig. 19 -7). urticaria (hives) occurs frequently in childhood but is uncommon in children younger than 6 months and even rarer in the neonatal period. 82, [109] [110] [111] [112] [113] [114] [115] [116] [117] urticaria is usually sporadic; however, familial forms with autosomal dominant inheritance have been described for many of the physical urticarias, such as dermographism, heat urticaria, cold urticaria, and vibratory urticaria. urticaria can be divided into acute (lasting less than 6 weeks) and chronic (lasting more than 6 weeks) types. nevertheless, this arbitrary division has prognostic and etiopathogenic signifi cance. in infants, chronic urticaria is very rare. 111, 118 physical urticarias represent a special subgroup of urticaria in which wheals are elicited by different types of physical stimuli. 119 these include dermographism, cold, pressure, cholinergic, aquagenic, vibratory, and solar urticaria. urticaria is characterized by transient edematous pruritic wheals ( fig. 19-11 ). by defi nition, individual lesions last less than 24 hours. hives may occur on the skin and mucous membranes. angioedema or giant urticaria is a closely related entity in which there is swelling of the deep subcutaneous tissues and diffuse swelling of the eyelids, genitalia, lips, and tongue. it may be seen alone, or more often in association with 'common' urticaria. urticaria in children has certain characteristic features. the hives tend to coalesce, forming bizarre polycyclic, serpiginous, or annular shapes (fi gurative urticaria, fig. 19-12 ; or annular urticaria, fig. 19 -13), and may become hemorrhagic. 109, 112 edema is often pronounced and painful. these features confer a dramatic appearance to the eruption. in children the itching may be absent. urticaria may be more common and recurrent in atopic patients. 112, 115 acute urticaria may be accompanied by signs of anaphylactic shock. in cases of angioedema, abdominal pain, diarrhea, vomiting, respiratory compromise, and joint pain may occur. 82, 113 urticaria develops as a result of an increased permeability of capillaries and small venules, which leads to leakage of fl uid into the extravascular space. mast cell activation and subsequent mediator release are responsible for these changes. histamine is the best-known mediator. many triggers (secretagogues) initiate mast cell degranulation through receptors on mast cell membranes, either via an ige-dependent mechanism or through complement activation (immunologic secretagogues) or by acting directly without the need for receptors (nonimmunologic secretagogues). the most common provocative agents in children are drugs, foods, and infections, which account for 40% of the cases of acute urticaria. 112, 115, 117 antipyretics (primarily aspirin) and antibiotics (amoxicillin, macrolides, and oral cephalosporins) are the most frequently incriminated drugs. food-related urticaria is associated with atopy. 112 cow's milk allergy is one of the main causes of urticaria in infants, being present in 6-35% of cases of cow's milk intolerance. 116, 120, 121 the diagnosis of urticaria is made on clinical grounds. histopathologic examination of a skin biopsy specimen shows vascular dilation, edema, and a perivascular infl ammatory infi ltrate composed of lymphohistiocytic cells, polymorphonuclear cells, and more specifi cally eosinophils. neutrophils may predominate. laboratory tests are not usually necessary for the evaluation of acute urticaria. ige levels can be elevated in some patients. an exhaustive search for an underlying cause not elicited by history alone is not warranted. an erythrocyte sedimentation rate may suffi ce as a screening test in cases of chronic urticaria because it is usually elevated in diseases associated with chronic urticaria (e.g. collagen vascular diseases). in 10-15% of patients no cause is identifi ed. intradermal skin tests to discover suspected allergens are not reliable. urticaria in infants is often misdiagnosed as erythema multiforme, acute hemorrhagic edema, annular erythema of infancy, or kawasaki disease. in an infant with urticaria and dermographism the possibility of diffuse cutaneous mastocytosis without visible cutaneous lesions should also be considered. 122 nomid/cinca (see below) should be considered in young infant with urticaria. the predominance of neutrophils in skin biopsies of children with nomid may help in the differential diagnosis, although it is not 100% specifi c. in case of doubt, genetic testic for nomid is now available. despite its alarming symptoms, urticaria in early infancy is usually benign. exceptions are chronic infantile neurological cutaneous and articular syndrome (cinca) (see below) and the inherited physical urticarias, which may have a lifelong course. if medication is required, antihistamines such as diphenhydramine or hydroxyzine are the mainstay of therapy. however, newborns have an increased susceptibility to antimuscarinic side effects, such as central nervous system (cns) excitation causing convulsions. systemic corticosteroids should be reserved for cases of intractable urticaria. autosomal dominant variants have been described for many of the physical urticarias. although rare, these familial cases begin early in life, even immediately after birth, and have a lifelong course, usually with increased severity. the exact pathogenic mechanism for many of the physical urticarias is unknown. familial cold urticaria (fcu) is an autosomal dominant disorder characterized by the development of burning wheals, and frequently pain and swelling of joints, stiffness, chills, and even fever after exposure to cold, especially in combination with damp and windy weather. [123] [124] [125] [126] the skin lesions appear on exposed areas and generalize afterwards. leukocytosis may be present during the attacks. the reaction may be delayed for up to 6 hours after cold challenge. in contrast to acquired cold urticaria, the reaction cannot be elicited by an ice cube test: rather, the patient must be subjected to cold environmental temperatures or cold water immersion. on skin biopsy a neutrophilic infi ltrate predominates. the symptoms tend to improve with age. responses to h 1 and h 2 blockers and ketotifen are poor. stanozolol has been of limited benefi t. 127 fcu has also been described along with amyloidosis and deafness as muckle-wells syndrome (mws). 128 it has been recently demonstrated that both fcu and mws are due to mutations in the cias1 (cryopyrin) gene: in fact they are the same disorder and may share exactly the same genetic mutation. 129 fcu and mws are also allelic diseases with cinca syndrome (see below), which is also due to cias1 gene mutations. 130 familial dermographism (autosomal dominant) has been described in a single large family. 131 in neonates dermographism can also be a manifestation of 'silent' diffuse cutaneous mastocytosis. 122, 132 vibratory urticaria is an autosomal dominant physical urticaria in which wheals develop after repetitive vibratory stimulation or stretching. 133, 134 the need for repetitive trauma differentiates it from dermographism. familial aquagenic urticaria and familial heat urticaria usually have onset in childhood. [135] [136] [137] chronic infantile neurological cutaneous and articular syndrome (cinca) [138] [139] [140] [141] cinca syndrome, also known as neonatal onset multisystemic infl ammatory disease (nomid), is a chronic systemic infl ammatory disease of neonatal onset characterized by skin rash, arthropathy, and cns manifestations. cutaneous fi ndings are the presenting signs. the disease follows a chronic course with acute febrile exacerbations, lymph node enlargement, and hepatosplenomegaly. two-thirds of patients are born prematurely. a skin eruption is usually the fi rst manifestation of the disease and is present at birth or develops during the fi rst 6 months of life. it is characterized by generalized, evanescent, urticarial macules and papules that migrate over the course of a single day and wax and wane in intensity ( fig. 19-14) . the rash is persistent, although recrudescence of the skin lesions is noted at fl are-ups. the lesions may be pruritic, especially after sun exposure, but are usually asymptomatic. 140, 141 geographic tongue and oral ulcers have been noted in a single patient. 141 symmetric or asymmetric arthropathy is another constant fi nding and is severe in half of patients. it is often absent in the fi rst few weeks of life, but usually develops during the fi rst year. 140, 142 the severity of the arthropathy correlates with an early onset of joint symptoms. the knees are most frequently affected, followed by the ankles and feet, elbows, wrists, and hands. joint swelling and pain are more severe during febrile fl are-ups. on palpation, a bony consistency is characteristic as a result of epiphyseal and growth cartilage involvement and overgrowth of the patellae. joint contractures and severe deformities result. neurologic signs and symptoms such as headache, vomiting, and seizures develop at a variable age. intellectual impairment is also common. both spasticity and hypotonia have been described. eye involvement is an inconstant fi nding. papilledema with or without optic nerve atrophy is the most common feature. other ocular manifestations include uveitis, keratitis, conjunctivitis, and chorioretinitis. 143 these changes may lead to complete blindness in adulthood. progressive sensorineural hearing loss and hoarseness are also common. affected children have a characteristic phenotype. there is progressive growth retardation and increased head circumference with frontal bossing. fontanel closure is retarded. icterus may be present in the neonatal period, especially in patients with severe arthropathy. 140 mutations in the cias1 gene have been identifi ed in 60% of patients with cinca syndrome. 144,145 cias1 encodes a protein called cryopyrin, which is involved in the regulation of apoptosis and the infl ammatory signaling pathway. 145 it is proposed that familial cold urticaria and cinca represent extreme groups of the same disease, defi ned by the magnitude of phenotypic expression. 145 considerable clinical overlapping exists between these disorders. nonspecifi c fi ndings typical of a chronic infl ammatory process include microcytic anemia; leukocytosis with high neutrophil and eosinophil counts, elevated platelet counts, sedimentation rates, and acute-phase reactants; and polyclonal hyperglobulinemia g, a, or m. rheumatoid factor and antinuclear antibodies are usually absent. liver enzymes may be mildly elevated. csf examination shows pleocytosis and high protein levels. radiologic studies of the affected joints show irregularly enlarged, bizarre, spiculated epiphyses with a grossly coarsened trabecular appearance. 140, 142 there is periosteal new bone formation, and growth cartilage abnormalities are frequent. with time, there is bowing deformity of long bones and shortening of diaphyseal length. ct scans of the head have demonstrated hydrocephalus and cerebral atrophy. histopathologic examination of the skin reveals interstitial and perivascular neutrophilia. 141, 142 neutrophilic eccrine hidradenitis has been described. 141 biopsies of lymph nodes, liver, and synovium show nonspecifi c signs of chronic infl ammation. nomid must be differentiated from systemic onset juvenile arthritis. the main differences are its neonatal onset, persistent rash, the short duration of bouts of fever, absence of morning stiffness, and central nervous system involvement. the arthropathy is more deforming, and the radiographic fi ndings of enlarged and disorganized epiphyses are distinctive. in addition, the response to nsaids is poor. urticaria should also be considered and the predominance of eosinophils in skin biopsy may be a relative clue. the disease follows a chronic course with acute febrile exacerbations. occasionally it causes death in the fi rst or second decade. nonsteroidal anti-infl ammatory drugs may be effective for pain relief but do not alter the course of the disease. prednisone has been palliative in doses ranging from 0.5 to 2.0 mg/kg/day. 142 chlorambucil and penicillamine have been tried, with limited success. 146, 147 thalidomide has shown benefi cial effects in a single patient. 148 other choices include methotrexate, the recombinant human il-1 receptor antagonist anakinra, [149] [150] [151] [152] and the anti-tnf-α agent etanercept. 153 erythema multiforme (em) is an acute, self-limited disorder of skin and mucous membranes. [154] [155] [156] it has been considered a spectrum of disorders, designated em minor, consisting of skin involvement only or of both the skin and the mouth, and as em major (stevens-johnson syndrome; sjs), which involves at least two mucous membranes with variable cutaneous lesions. some authors include toxic epidermal necrolysis within this spectrum as a severe form of sjs. recent evidence suggests that em and sjs have distinct clinical features and different precipitating factors, so perhaps the terms em major and em minor are best avoided. 157, 158 em is a common disease in children 155 but extremely unusual in the neonatal period. 94, 155, [159] [160] [161] [162] toxic epidermal necrolysis is discussed in chapter 10. the prototypic lesion of em is a 1-3 cm erythematous, edematous papule that develops a dusky vesicular, purpuric, or necrotic center. a raised edematous ring of pallor surrounded by an erythematous outer ring is often present. these concentric color changes produce the typical target, or iris, lesion. in many cases only two zones are seen, with a single ring around the central papule (atypical target lesions). the lesions are distributed symmetrically and acrally on the extensor surface of the extremities. they may extend to the trunk, fl exural surfaces, palms, and soles. in children, lesions on the face and ears are common, but are rare on the scalp 163 (fig. 19-15 ). in sjs, the lesions are more centrally located, predominating on the trunk. the targets are atypical and are usually fl at. individual lesions tend to coalesce in large patches. areas of epidermal detachment may occur, but usually affect less than 10% of the body surface area. mucosal lesions occur frequently in em and are requisite for a diagnosis of sjs. mucous membrane involvement is characterized by erythema or blisters that rapidly evolve to confl uent erosions with pseudomembrane formation. the oral mucosa and conjunctiva are most commonly involved, but genital, anal, pharyngeal, and upper respiratory tract involvement may be seen. the number of mucous membranes involved has been considered one of the main distinguishing features of em and sjs. mild, nonspecifi c, prodromal symptoms of cough, rhinitis, and low-grade fever are occasionally present in em. fever, arthralgias, and prostration are common in sjs. em has been considered a hypersensitivity phenomenon to multiple precipitating factors such as infectious agents or drugs. three etiologic factors have been well documented: herpes simplex for erythema multiforme, and mycoplasma infections and drugs for sjs. herpes simplex (hsv-1 or hsv-2) is considered to be responsible for more than 80% of em in children, even if clinical infection is inapparent. 164 hsvassociated em follows the lesions of herpes by 1-3 weeks and is often recurrent. however, not every episode of recurrent herpes is followed by em. hsv-specifi c dna has been detected by polymerase chain reaction and in situ hybridization in lesional skin from a large number of children with em, whether 'idiopathic' or clearly hsv related. 164 erythema multiforme fig. 19-15 target lesions of erythema multiforme in a newborn. cow's milk intolerance has been described as a cause of erythema multiforme in a neonate. 159 drugs are the most common cause of sjs. sulfonamides, phenylbutazone, diphenylhydantoin, and penicillin derivatives are most frequently implicated. 163 vaccinations were the only known possible causative agents in a newborn and two infants with erythema multiforme. 162, 165 in cases of extensive involvement an elevated sedimentation rate, leukocytosis, and mild elevation of transaminases may be seen. electrolyte imbalance and hypoproteinemia may be encountered in sjs. eosinophilia may be seen in drug-related cases. histopathologic examination of early lesions reveals a lymphocytic band-like infi ltrate at the dermoepidermal junction, with exocytosis and individual necrotic keratinocytes in close proximity to lymphocytes ('satellite cell necrosis'). there is vacuolization of the basal layer with focal cleft formation at the dermoepidermal junction. the upper dermis is edematous. over time, more extensive confl uent necrosis of the epidermis supervenes, resulting in subepidermal blister formation. in em a lichenoid infi ltrate predominates, whereas in sjs epidermal necrosis predominates. in typical cases em or sjs is rarely confused with other entities. urticarial vasculitis may be considered in some cases. kawasaki disease may produce target-like lesions; however, associated fi ndings should allow differentiation. serum sickness-like reactions often associated with the use of cefaclor or other antibiotics, or even without any known etiology, can also produce targetoid lesions (see fig. 19-9 ). erythema multiforme is usually self-limited. individual lesions heal in 1-2 weeks, with residual hyperpigmentation. conservative supportive care is the preferred form of treatment. possible underlying causes should be sought. treatment of underlying infection and discontinuation of nonessential drugs are indicated. corticosteroids are unnecessary and may even worsen a concurrent infection. 166, 167 in hsv-associated em, early intervention or even prophylactic treatment with oral aciclovir may be benefi cial. 168 sjs has a less favorable prognosis, with a mortality rate of 5-15% if left untreated. the use of corticosteroids in sjs is more controversial. 166, 167, 169, 170 no controlled study has proved their effi cacy, and in some studies patients treated with corticosteroids have had a worse prognosis. 171 corticosteroids may predispose to secondary infection while suppressing the signs of sepsis. supportive care is extremely important. sweet syndrome, or acute febrile neutrophilic dermatosis, is a benign disease characterized by tender, raised erythematous plaques, fever, peripheral leukocytosis, histologic fi ndings of a dense dermal infi ltrate of polymorphonuclear leukocytes, and a rapid response to systemic corticosteroids. [172] [173] [174] [175] [176] only a few pediatric cases have been reported, [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] the youngest being 5 weeks of age. 180 two brothers with sweet syndrome starting at 2 weeks of life have been reported. 188 the lesions of sweet syndrome have an acute, explosive onset and are characterized by indurated, tender, erythematous plaques or nodules that vary in size from 0.5 to 4 cm ( fig. 19-16 ). tiny pustules may appear at a later stage. the borders may be raised, mammillated, or even vesicular. some of the lesions may show central clearing, forming annular or gyrate plaques ( fig. 19-17) . the lesions are usually multiple and distributed over the face and extremities or, more rarely, the trunk. without treatment, they tend to heal spontaneously within a few months. in some patients, especially children, the lesions heal with areas of secondary cutis laxa, also known as marshall syndrome. 179, 189, 191 a high, spiking fever is characteristic but may be absent in up to 50% of patients. 176 arthralgias or asymmetric arthritis may be associated, and conjunctivitis or iridocyclitis may be seen in one-third of patients. 176 renal involvement manifesting as proteinuria or hematuria, as well as lung involvement with infi ltrates visible on chest radiographs, has also been described. central nervous system involvement may occur in rare instances and manifest as headaches, convulsions, or disturbance of consciousness. cerebrospinal fl uid pleocytosis with lymphocyte predominance is usually found in such cases. 192 the pathogenesis is unknown. many of the patients reported have had a preceding respiratory tract infection or elevated antistreptolysin o titers. 176 ten per cent of the cases have been seen in the setting of a variety of hematologic malignancies, particularly acute myeloid and myelomonocytic leukemias. 193 sweet syndrome has also been associated with solid tumors, infl ammatory bowel disease, connective tissue diseases, and chronic granulomatous disease, or it may occur as an adverse reaction to drugs, [194] [195] [196] particularly granulocyte colonystimulating factor 197 or after vaccination. 198 because of these associations and the rapid response to systemic corticosteroids, sweet syndrome is thought to represent a hypersensitivity reaction to infectious agents or tumoral antigens. an elevated erythrocyte sedimentation rate and peripheral leukocytosis are frequent accompanying abnormalities. eosinophilia, microcytic anemia, mild elevation of liver enzymes, and urinalysis abnormalities may be present occasionally. antineutrophil cytoplasmic antibodies have been detected in some cases. 176 α 1 -antitrypsin defi ciency has been documented in one case of marshall syndrome. 191 the histopathologic fi ndings are diagnostic. 173 there is a dense perivascular infi ltrate composed almost entirely of neutrophils. the dermis appears edematous, and subepidermal blisters may form. spongiosis, exocytosis, and intraepidermal vesiculation may be seen. there is endothelial swelling and nuclear dust, but true vasculitis is characteristically absent. the lesions of sweet syndrome may initially resemble those of em or acute hemorrhagic edema. lesions on the lower extremities may resemble those of erythema nodosum, but lesions more characteristic of sweet syndrome are usually present in other locations. sweet syndrome is a benign disease but may be a marker of malignancy. if left untreated it resolves spontaneously over weeks to months. recurrences are common. marshall syndrome may have a poorer prognosis, with the development of elastolysis in the lungs or cardiovascular involvement. oral corticosteroids are the treatment of choice and usually elicit a prompt response. 199 potassium iodide administration has been successful in a few cases, 200 as have colchicine, 201 dapsone, 202 clofazimine, 189 and intravenous immunoglobulin. 184 kawasaki disease is an acute systemic vasculitis involving small and medium-sized muscular arteries, especially the coronary arteries, of young children. in the past, many cases were called infantile polyarteritis nodosa. the disease is characterized by fever lasting at least 5 days, nonpurulent conjunctivitis, a polymorphous exanthem, erythema and swelling of the hands and feet, infl ammatory changes of the lips and oral cavity, and acute nonpurulent cervical adenopathy. [203] [204] [205] [206] coronary artery aneurysms or ectasia develop in 15-25% of untreated children and may lead to ischemic heart disease or sudden death. kawasaki disease occurs predominantly in children under 5 and has a peak incidence between 9 and 11 months. [207] [208] [209] it is infrequent before 6 months of age, although it has been reported in patients less than 2 weeks of age [210] [211] [212] boys are affected 1.5 times as often as girls. kawasaki disease is an endemic disease with epidemic and geographic clustering. there is seasonal predominance in late winter and spring, although this may differ in different countries. 213, 214 it is most common in japan, with an annual incidence of 112 cases per 100 000 children under 5, and is steadily increasing. 215, 216 familial cases in household contacts have been described. 217 the recurrence rate is 3%, with some patients having two or more recurrences. 205, 218 the skin is involved in 99% of patients. the fi rst sign often consists of diffuse erythema and painful induration of the hands and feet. between 1 and 3 weeks after disease onset the eruption characteristically begins to desquamate beneath the distal nail plates, and peeling may extend to involve the entire palm and sole. horizontal depressions in the nail plates (beau's lines) usually result. a polymorphous exanthem on the trunk and proximal extremities usually appears within 5 days of onset of fever ( fig. 19-18 ). it is a nonspecifi c, diffuse maculopapular or kawasaki disease fig. 19-18 morbiliform eruption in an infant with kawasaki disease. morbilliform eruption, but may be urticarial, scarlatiniform, targetoid, or even pustular. bullous or vesicular eruptions have not been described. the rash is usually in the perineum, which is a distinctive feature at this early stage, and it desquamates within 48 hours, preceding fi nger-tip and toe-tip desquamation 219 (fig. 19-19) . plaque-type, guttate, and pustular psoriasis have been described, either during the acute or the convalescent phase of the disease, which supports a superantigenmediated etiology. [220] [221] [222] [223] changes in the lips and oral mucosa include erythema, swelling and fi ssuring of the lips, strawberry tongue, and erythema of the oropharynx. oral ulcerations and pharyngeal exudates are not seen. intermittent acrocyanosis has been observed in infants younger than 6 months of age, 209 as well as peripheral gangrene. 224 infl ammatory changes with necrosis at the site of a previous bcg inoculation have been reported. [225] [226] [227] [228] extracutaneous findings 205, 206, 218, 229 prolonged fever for at least 5 days is the cardinal and initial feature of the disease. it begins abruptly and is high, with peak temperatures generally >39°c (102°f) and in many cases >40°c (104°f), with several spikes each day (remittent fever). in the absence of appropriate therapy, fever persists for a mean of 11 days, but it may continue for 3-4 weeks and, rarely, even longer. bilateral nonexudative conjunctival injection, involving mainly the bulbar conjunctivae, begins shortly after disease onset and may already be resolved at time of fi rst consultation. anterior uveitis is frequently noted on slit-lamp examination but is rarely symptomatic. cervical lymphadenopathy is the least common diagnostic sign, with a prevalence of approximately 65%. it is usually unilateral, and confi ned to the anterior cervical triangle. the lymph nodes are often fi rm, nonfl uctuant, and only slightly tender. cardiac conditions are the main cause of long-term morbidity and mortality. the pericardium, myocardium, endocardium, and coronary arteries may all be involved. myocarditis may manifest in the acute phase, and arrhythmias due to ischemia, congestive heart failure, and valvular involvement, usually mitral, may occur. occasionally there may low cardiac output syndrome or shock. cardiac auscultation of the infant or child with kawasaki disease in the acute phase often reveals a hyperdynamic precordium, tachycardia, a gallop rhythm, and an innocent fl ow murmur. a pansystolic regurgitant murmur may be heard in children with signifi cant mitral regurgitation. electrocardiography may show arrhythmia, prolonged pr interval, or nonspecifi c st and t-wave changes. pericardial effusion may be detected by an echocardiogram in 30% of patients. without treatment, coronary artery aneurysms develop in 20% and are most commonly detected 10 days to 4 weeks after onset. risk factors for the development of coronary aneurysms include age younger than 1 year, male gender, fever for more than 2 weeks, recurrent fever, and delayed treatment. aneurysms may also develop in systemic medium-sized arteries and result in peripheral gangrene. 224 polyarticular arthritis and arthralgias may occur in the fi rst weeks of the illness. it affects small as well as large joints. irritability is usually prominent. lethargy and other signs of aseptic meningitis may be present. abdominal symptoms such as vomiting, diarrhea, and pain are common. in rare instances acute abdominal pain, mimicking a surgical abdomen, may herald the onset of the disease. mild hepatitis occurs frequently, as does acute distension of the gallbladder (hydrops). transient unilateral peripheral facial nerve palsy occurs rarely. respiratory symptoms due to pulmonary nodules, infi ltrates, or pleural effusion may also be observed. [230] [231] [232] rare fi ndings include testicular swelling, hemophagocytic syndrome, 233 and transient high-frequency sensorineural hearing loss (20-35 db). 234 [235] [236] [237] epidemiologic and clinical data suggest that kawasaki disease has features of infectious disease in an immunologically susceptible host and of an immune-mediated vasculitis. many etiologic agents, ranging from bacteria such as propionibacterium, staphylococcus, streptocuccus, chlamydia and yersinia to viruses such as epstein-barr, parvovirus, adenoviruses, retroviruses, and a novel human coronavirus, have been linked to kawasaki disease in different geographic outbreaks, but none has been consistently demonstrated. 235 much of the continuing debate in the literature concerns whether kawasaki disease is caused by a superantigen or a conventional antigen. 235, 237 evidence of a superantigen-mediated disease process includes the identifi cation of superantigen-producing organisms, isolation of bacterial superantigens, or fi nding the hallmark of superantigen activation in affected children, such as selective expansion of vβ2 and vβ8 t-cell receptor families. however, the immune response in kawasaki disease is oligoclonal (antigen driven, i.e. similar to a response to a conventional antigen) rather than polyclonal (as found typically in superantigen-driven responses), and immunoglobulin a (iga) plasma cells play a central role. 235, 237 regardless of the cause, evidence points to a generalized immune activation with production of various proinfl ammatory cytokines and endothelial cell activation which lead to coronary artery alteration. [238] [239] [240] [241] the most studied cytokine has been tnf-α, which is usually elevated in children with kawasaki disease. enzymes, including matrix metalloproteinases that are capable of damaging arterial wall integrity, may also be important in the development of aneurysmal dilatation. various chemotactins that attract neutrophils and monocytes to coronary arteries may also play an important role. 242 host genetic determinants play a role in both susceptibility and coronary artery outcome in kawasaki disease. 243 the fig. 19-19 early perineal desquamative eruption of kawasaki disease. incidence rate in siblings is 10 times the population incidence. 217, 244, 245 the risk of occurrence in twins is higher than in ordinary siblings. parents who had kawasaki disease in childhood are more likely to have affected children, and children with recurrent disease. 246 in the acute phase, laboratory studies show leukocytosis (>15 000/mm 3 ) with a left shift, normochromic normocytic anemia, increased sedimentation rate and other acute-phase reactants, depressed albumin, and elevated igm and ige levels. the degree of elevation of esr and c-reactive protein may show discrepancy, and both should be measured. furthermore, elevation of esr can be caused by ivig therapy and therefore can not be the sole determinant of the degree of infl ammatory activity. 218 plasma lipids are altered in the acute stage, with depressed plasma cholesterol and hdl. 247, 248 there may be mild elevation of transaminases and polyclonal hypergammaglobulinemia. in the subacute stage, in the second and third weeks of illness, there is a marked and almost universal thrombocytosis, which returns to normal in 4-8 weeks. thrombocytopenia is rarely seen in the acute stage and may be a sign of disseminated intravascular coagulation. antineutrophil cytoplasmic antibodies may be detectable as a nonspecifi c epiphenomenon. there may be sterile pyuria with mild proteinuria. cerebrospinal fl uid shows a mononuclear pleocytosis with normal protein and glucose levels. skin biopsy fi ndings are not specifi c. there is edema in the papillary dermis, with a mild perivascular mononuclear cell infi ltrate. vasculitis of medium and large arteries is observed. there is no single diagnostic test for kawasaki disease and therefore clinical criteria have been established to guide treatment decisions (box 19-3) . the classic diagnosis has been based on the presence of 5 days of fever and four of the fi ve principal clinical features. clinical features usually appear sequentially and are not all present at a single point in time, therefore watchful waiting is sometimes necessary before a diagnosis can be made. to avoid holding treatment until more than four clinical criteria are met, and the recognition that many patients with 'incomplete' kawasaki still develop coronary artery disease, one may diagnose and treat kawasaki on day 4 of illness in the presence of four principal criteria. 230, 249 also, the diagnosis can be made in patients with fever for 5 days and fewer than four principal features when coronary artery disease is detected by two-dimensional echocardiography (2de) or coronary angiography. kawasaki disease should be considered in the differential diagnosis of a young child, specially under 1 year of age, with unexplained fever for 5 days that is associated with any of the principal clinical features of this disease, or even in the presence of other clinical and laboratory fi ndings that are not classic criteria but which are commonly encountered in this disease (box 19-3). 218 for example, an elevated crp or esr and elevated platelet count after 7 days of illness are uncommon in viral infections but are universally seen in children with kawasaki disease. echocardiography may be useful in evaluating 'incomplete kawasaki disease' and should be considered in any infant under 6 months with fever of more than 7 days' duration, laboratory evidence of systemic infl ammation, and no other explanation for the febrile illness. 218 although aneurysms rarely form before day 10 of illness there may be signs of coronary arteritis, decreased contractibility, mitral regurgitation, and pericardial effusion. with all these considerations a new algorithm has been proposed to help in deciding which patient with incomplete kawasaki disease should undergo echocardiography or receive ivig treatment (fig. 19-20) . 218 the morbidity and mortality of kawasaki disease depend primarily on coronary artery lesions. [250] [251] [252] [253] [254] coronary artery aneurysms or ectasia develop in 15-25% of untreated children and may lead to ischemic heart disease or sudden death. with early treatment the risk is reduced to around 5-12%. 215, 216 small aneurysms resolve completely within the fi rst 2 years after disease onset in 30-60% of these patients. 255 however, coronary aneurysms, especially if giant (>8 mm), may persist and be complicated by thrombotic occlusion or the development of stenosis at the outlet of the aneurysm. stenotic lesions as well as early coronary atherosclerosis may develop gradually over several years, so long-term follow-up is warranted. 252, 253, 256, 257 several scoring systems have been developed to predict risk for coronary artery aneurisms. 258 the harada score is one that is used in japan. 259 sometimes kawasaki disease may be 'atypical,' presenting at onset with clinical features that are not generally seen, such as acute abdominal pain, renal impairment, meningeal irritation, pneumonia, or retropharyngeal abscess. many diseases mimic kawasaki disease, including viral infections, streptococcal infection, juvenile rheumatoid arthritis, erythema multiforme, staphylococcal scalded skin syndrome, toxic shock syndrome, drug hypersensitivity reactions, rocky mountain spotted fever, leptospirosis, mercury hypersensitivity reaction (acrodynia), and bacterial cervical adenitis. low white blood cell count, lymphocytosis and low platelet count may be useful in suggesting a viral infection instead of kawasaki disease. because the major sequelae of kawasaki disease are related to coronary artery systems, cardiac imaging is critical in the evaluation of all patients with suspected kawasaki disease, and serial echocardiograms are recommended. echocardiography should focus on coronary artery visualization and measurement, but also on left ventricle contractibility, valve function, the presence of pericardial effusion, and measurement of the aortic root. 260 an initial examination should be performed as soon as the diagnosis is suspected and is useful as a baseline for follow-up. thereafter, for uncomplicated cases it should be repeated at 2 weeks and at 6-8 weeks after disease onset. 218 for those who develop coronary artery aneurysms or other cardiac abnormalities more frequent evaluation is recommended. other noninvasive imaging modalities, such as mri, mra, and ultrafast ct, as well as cardiac stress testing, are being evaluated in the management of kawasaki disease. until the aneurysm resolves a stress test may be needed to guide recommendations for physical activity and the need for angiography. treatment in the acute phase of the disease is directed to reducing infl ammation in the coronary artery wall and preventing coronary thrombosis, whereas long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction. intravenous γglobulin (ivig) combined with high-dose aspirin is the treatment of choice in the acute phase of the disease. 229 aspirin alone does not appear to reduce the frequency of the development of coronary abnormalities, but together with ivig it has an additive anti-infl ammatory effect. in the acute stage aspirin is given in doses of 80-100 mg/kg divided into four. the duration of high-dose aspirin varies in different centers. in many institutions the dose is reduced after the child has been afebrile for 48-72 hours. others continue until day 14 of illness and >48-72 hours after fever cessation. following this acute phase low-dose aspirin (3-5 mg/kg) is given as an antiplatelet agent until there is no evidence of coronary changes at 6-8 weeks from disease onset. for patients who develop coronary abnormalities, low-dose aspirin is continued until regression of coronary artery aneurysms, but some clinicians continue indefi nitely. ibuprofen should be avoided in children taking aspirin for its antiplatelet effect because it antagonizes platelet inhibition. ivig has been shown to reduce the incidence of coronary artery aneurisms from 20% to 3-4%. [261] [262] [263] [264] a single dose of 2 mg/kg has been shown to be superior than lower doses for 4 consecutive days. 261,262 ivig should be started early, within 10 days of disease onset and preferably within 7 days. treatment before day 5 does not appear to prevent cardiac sequelae and may be associated with an increased need for ivig retreatment. 265, 266 treatment after day 10 should be considered if there are still signs of ongoing infl ammation (elevated esr or crp) or persistent fever. 267 not all patients respond to a single dose of ivig and may have persistent or recrudescent fever 36 hours after completion of the initial treatment, and require a second dose. it has been observed that those children who received ivig very early in the illness are more prone to require a second infusion. vaccination with live or other vaccines should be deferred for at least 11 months after high-dose ivig treatment, both to ensure correct immunization and to avoid fl ares of kawasaki disease. 268 the usefulness of steroids in combination with ivig in the initial therapy of kawasaki disease is not well established. steroids shorten the duration of fever and lower esr and crp, but do not seem to infl uence the coronary outcome. 269, 270 steroids have also been used for ivig treatment failures, but their role in preventing or reversing coronary anomalies is uncertain. it has been recommended to restrict their use in children who have persistent fever after two infusions of ivig. 218 the most common regimen is intravenous pulse methylprednisolone, 30 mg/kg for 1-3 days. because of its inhibition of tnf-α messenger rna transcription, pentoxifylline may have a theoretical benefi t in the initial treatment of kawasaki disease, although there are only small clinical trials reported. 271 the role of tnf-α antagonists such as infl iximab; abciximab, a platelet glycoprotein iib/iia receptor inhibitor; plasma exchange; and cytotoxic agents for patients with refractory kawasaki disease, remains uncertain. 218, 272 acute hemorrhagic edema (ahe), purpura en cockade, or finkelstein disease, is an acute, benign leukocytoclastic vasculitis of limited skin involvement occurring in children under 2 years of age. [273] [274] [275] [276] [277] [278] [279] [280] ahe has been considered an infantile variant of henoch-schönlein purpura; however, because of clinical and prognostic differences it is sometimes regarded as a separate entity. the disease is characterized by the abrupt onset of fever; tender edema of the face, eyelids, ears, scrotum, and acral extremities; and ecchymotic purpura on the face and extremities. the trunk is usually spared. individual lesions often have a darker center and expand centrifugally, giving them a cockade or target-like confi guration. lesions range in size from 0.5 to 4.0 cm and may become confl uent, forming polycyclic, annular plaques ( fig. 19-21 ). necrotic 279, 281 and bullous lesions may be seen. 279, 282 petechiae in the mucous membranes have also been described. 283 except for fever, there are no associated manifestations. in many patients there is a preceding upper respiratory tract infection. the dramatic cutaneous fi ndings contrast with the general wellbeing of the patient. acute hemorrhagic edema fig. 19-21 acute hemorrhagic edema. the cause of ahe is unknown. it is thought to represent an immune complex-mediated disease precipitated by a preceding infection, particularly an upper respiratory tract infection, drug intake, or immunization. staphylococci and streptococcus spp. and viruses (adenoviruses, rotavirus) have been implicated most commonly. leukocytosis (both lymphocytic and granulocytic), thrombocytosis, eosinophilia, and an elevated esr may be present. urinalysis, tests for occult blood in the stool, immunoglobulin, and complement levels are usually normal or negative. circulating immunocomplexes may occasionally be found. 282 histopathologic examination of skin biopsy specimens demonstrates a small vessel leukocytoclastic vasculitis. direct immunofl uorescence shows deposition of c3 and fi brinogen in the vessel wall. igm, igg, iga, and ige deposition has also been noted in up to one-third of cases. 282, [284] [285] [286] the differential diagnosis includes henoch-schönlein purpura, child abuse, meningococcemia and other infectious purpuras, erythema multiforme, kawasaki disease, and sweet syndrome. 273, 283 distinction from henoch-schönlein purpura may be impossible 280 (table 19 -2). perivascular deposits of iga are not useful for differentiation because they may be present in both entities. the prognosis is excellent. the eruption resolves spontaneously without sequelae in 1-3 weeks. treatment with corticosteroids is not necessary and may lead to complications and worsen the prognosis. 284 exacerbations may be observed during the clinical evolution, with new crops of lesions and fever, 281,285 but true recurrences weeks or months after the fi rst episode are rare. 280, 283 there has been a single report of a fatal ileoileal intussusception in an infant with cutaneous lesions otherwise typical for ahe. 281 [287] [288] [289] [290] [291] [292] [293] [294] [295] the porphyrias are a group of diseases characterized by abnormalities of porphyrin-heme metabolism. each type results from defi cient activity of one of the enzymes of the heme biosynthetic pathway, which leads to an accumulation of heme precursors within plasma, red blood cells, urine, and feces. 295 the genes for these enzymes have been characterized. 287, 289, 295 porphyrias are mainly inherited in an autosomal dominant manner with incomplete penetrance, but autosomal recessive and more complex patterns of inheritance are also possible. porphyrias are classifi ed as hepatic or erythropoietic, according to the organ site in which the underlying defect of heme synthesis is predominantly expressed (see table 19 -3). cutaneous manifestations in porphyrias may be classifi ed as acute photosensitivity with burning pain, edema, and erythema shortly after sun exposure, or delayed photosensitivity manifesting as skin fragility, subepidermal blisters, milia, disorders of pigmentation, and sclerodermoid signs. hepatic porphyrias usually manifest acute neurovisceral attacks and delayed photosensitivity, and rarely present before puberty except from the homozygous variants. elevated porphyrins may be detected in the stool or urine. erythropoietic porphyrias are characterized by acute cutaneous photosensitivity from early childhood. the more delayed photosensitivity, although less characteristic of this type of porphyria, may be also present. 293 erythrocyte and plasma porphyrin levels are elevated in erythropoietic porphyrias. photosensitivity in porphyrias is maximum for ultraviolet wavelengths between 400 and 410 nm ('soret band'), the spectrum of maximum absorption of porphyrins. the pathophysiologic mechanisms involved in the cutaneous manifestations of the porphyrias are multiple and involve the creation of reactive oxygen specimens. [296] [297] [298] childhood porphyrias are relative uncommon and their exact incidence is unknown. only those porphyrias manifesting early in infancy are reviewed here. congenital erythropoietic porphyria (cep), also called günther disease, is a rare autosomal recessive disorder caused by deficient activity of uroporphyrinogen iii (urogen iii) synthase which leads to nonenzymatic conversion of hydroxymethylbilane to uroporphyrinogen i, a nonphysiologic substrate that is converted to coproporphyrinogen i; these porphyrinogen i isomers are then oxidized to uroporphyrin i (uro-i) and coproporphyrin i (copro-i), which are phototoxic compounds. elevated levels of uro-i and copro-i in erythrocytes result in massive hemolysis, and the released porphyrins accumulate in peripheral blood, skin, bone, and teeth and are excreted in large amounts in the urine and feces. 292, 299, 300 cep presents with severe photosensitivity from birth or early infancy with formation of vesicles and bullae on areas exposed to sun, phototherapy devices, or even ambient lighting. 301 there is also marked skin fragility. as a result of the phototoxic injury and the increased skin fragility, there are severe mutilations, mainly of the fi ngers, hands, and face, particularly the nose and ears, but also in sun-protected areas. hypertrichosis of the face and extremities, scarring alopecia of the scalp and eyebrows, and pigmentary changes (hyperpig histologic examination of skin biopsy specimens from blisters reveals subepidermal cleavage (within the lamina lucida) and minimal infl ammatory infi ltrate. perivascular accumulation of pas-positive, diastase-resistant, homogeneous hyaline material (porphyrins) may be seen, which is best viewed with fl uorescence microscopy. see table 19 -3 for porphyrin excretion profi le. measurement of uro iii synthase activity is available. prenatal diagnosis from amniotic fl uid is possible by either measurement of uroproporphyrin i or direct gene mutation analysis. [307] [308] [309] [310] other photosensitivity diseases presenting early in life (box 19-4) or diseases manifesting with blisters, such as epidermolysis bullosa and bullous pemphigoid, should be considered. determination of porphyrins is diagnostic and allows differentiation from other porphyrias presenting early in life with photosensitivity. the clinical severity of cep is highly variable, ranging from hydrops fetalis, hepatosplenomegaly, and severe anemia in utero to adult-onset disease with only cutaneous manifestations. 311 in most cases, however, patients survive well into adulthood, albeit with severe mutilations or major disfi gurement. mentation and hypopigmentation) are also common. over time, severe facial mutilation results, with destruction of nasal and auricular cartilages, ectropion, and eclabium, as well as shortening and contraction of the fi ngers. milder phenotypes may have onset later in childhood. 302 the accumulation of porphyrins in deciduous and permanent teeth produces red discoloration (erythrodontia) and reddish fl uorescence on wood's light examination, which is pathognomonic. the urine is also reddish, which causes pink discoloration of the diapers that fl uoresces -an early bed-side diagnostic sign. porphyrins accumulate in the amniotic fl uid and brownish amniotic fl uid may be observed. severe hemolytic anemia and secondary splenomegaly occur. anemia may be so severe as to lead to hydrops fetalis and death in utero. patients with late-onset disease may not develop hemolytic anemia but only thrombocytopenia and myelodysplasia. ocular changes include ectropion, photophobia, and keratoconjunctivitis. 303 other manifestations include osteodystrophy with increased bone fragility, and porphyrin-rich gallstones. the gene for urogen iii synthase is localized on chromosome 10. several mutations have been identifi ed, 304 protection from sun exposure is essential. chemical sunscreens do not achieve good protection against soret band radiation, so protective clothing and physical sunblocks are necessary. long-wavelength, uv-absorbing fi lms are encouraged on car windows and windows at home. children with the severe phenotypes and severe hemolysis benefi t from repeated erythrocyte transfusions and hydroxyurea to suppress erythropoiesis. hematocrits should be maintained above 32%, with appropriate iron chelation. the effi cacy or repeated erythrocyte transfusion may decrease at puberty. subsequent splenectomy is often needed to control hemolytic anemia. 313, 314 activated charcoal, [315] [316] [317] [318] and β-carotene 319, 320 have been used, with inconsistent results. bone marrow transplantation or stem cells from cord blood offer the possibility of correcting enzyme activity. [321] [322] [323] [324] [325] replacement gene therapy has been accomplished in vitro. 326, 327 erythropoietic protoporphyria 287, 298, 328 erythropoietic protoporphyria (epp) is the most common form of cutaneous porphyria apart from porphyria cutanea tarda (pct). epp is caused by defi cient activity of ferrochelatase, leading to the accumulation of protoporphyrin in erythrocytes, plasma, and feces. clinical symptoms typically begin in infancy or early childhood, with a peak incidence between 2 and 4 years of age. epp is usually inherited as an autosomal dominant condition, but most individuals who are heterozygous for the inherited mutations are asymptomatic, because of halfnormal ferrochelatase activity 329 for protoporphyrin to accu-mulate suffi ciently to cause photosensitivity, a reduction of enzymatic activity to below a critical threshold of about 35% of normal is required. some families may have autosomal recessive inheritance. [329] [330] [331] clinical manifestations are those of an acute phototoxic reaction, which triggers an episode of crying within minutes of sunlight exposure due to burning pain or stinging sensations on exposed areas (the face and the dorsal aspect of hands). some patients are photosensitive to fl uorescent lighting. 328 erythema, edema, and urticarial lesions occur, but vesicles and bullae are rare (fig. 19-22) . fine petechiae may occur on sunexposed areas after prolonged exposure. some patients have only subjective symptoms. 328 with chronic exposure there is characteristic thickening and wrinkling of the knuckle pads, furrowing around the mouth (pseudorhagades), and shallow elliptical scars on the nose, cheeks, and forehead. hemolytic anemia is absent, but in some patients a mild hypochromic, microcytic anemia may occur. protoporphyrinrich gallstones may develop in childhood. fatal liver failure resulting from the progressive accumulation of protoporphyrin in hepatocytes is a possible outcome in about 2.5% of patients, altering the prognosis for an otherwise clinically benign disorder. recessive inheritance may predispose to severe liver disease. 329 families. 329, 333 in most symptomatic patients inheritance of a second mutation is needed in order to reduce the enzymatic activity to a critical threshold where clinical symptoms are caused. autosomal recessive inheritance has been demonstrated in 3% of patients with epp. 329 histopathologic examination of skin biopsy specimens of sunexposed areas shows marked concentric deposits of a hyaline material around dermal blood vessels. this material is pas positive and diastase resistant. patients with epp should undergo frequent liver function tests, and those with persistent abnormalities should have a liver biopsy. children with high erythrocyte protoporphyrins should have periodic determination of blood, urinary, and fecal porphyrins because increased excretion of copropophyrins, high erythrocyte protoporphyrins and reduced excretion of faecal protoporhyrins can predict liver failure. 334 the diagnosis of epp is established by detecting elevated levels of protoporphyrin in erythrocytes, plasma, and feces. in addition, fecal and erythrocyte coproporphyrins may be increased. a rapid microfl uorometric assay for free erythrocyte protoporphyrins and examination of a blood smear for fl uorescent erythrocytes may also be used as screening tests. 335 the differential diagnosis includes other types of porphyria, but causes of immediate photosensitivity such as pmle or solar urticaria do not occur in infants. the mainstay of treatment for erythropoietic protoporphyria is sun avoidance and the use of physical sunscreens. 336, 337 topical dihydroxyacetone may be helpful in some patients by producing brown pigment. 287 oral administration of βcarotene (30-90 mg/day for children) has been shown in uncontrolled studies to increase tolerance to sun exposure because it quenches the formation of free radicals. 334, 338, 339 narrowband ultraviolet b phototherapy has been proposed, as this wavelength does not cause photosensitivity. 340 desensitization with puva therapy has also been used. oral iron, intravenous hematin, transfusion therapy, and a highcarbohydrate diet have been used to prevent protoporphyrin accumulation in the liver by reducing protoporphyrin production, but their effi cacy is unproven. 334 cholestyramine or activated charcoal have been used to interrupt the enterohepatic circulation of protoporphirins. 341 avoidance of alcohol and drugs that interfere with hepatic excretory function is also essential. liver transplantation has been performed in a few patients with liver failure, although the enzymatic defect is not thereby corrected and hence the long-term outcome is poor. [342] [343] [344] [345] modifi cation of the lighting in the operating room is necessary to avoid photoxicity to exposed organs. hepatoerythropoietic porphyria (hep) is an extremely rare disorder caused by a marked defi ciency of uroporphyrinogen decarboxylase due to a homozygous state. [346] [347] [348] [349] clinical manifestations begin in infancy, or more commonly in early childhood, and resemble both porphyria cutanea tarda and günter disease. the disease usually presents with darkening of the urine and delayed-type cutaneous photosensitivity, with vesicles, skin fragility, milia, and scarring. with time, hypertrichosis, sclerodermoid changes, and mutilation similar to the manifestations of günter disease become apparent. anemia, hepatosplenomegaly, and abnormalities of liver function of varying degrees may also occur, but are less common than in congenital erythropoietic porphyria. the porphyrin excr etion pattern resembles that of porphyria cutanea tarda (pct), with elevated urinary uroporphyrins and 7-carboxylated porphyrins, and a smaller elevation of coproporphyrins, 6-and 5-carboxylated porphyrins. increased isocoproporphyrins in feces are characteristic. unlike in pct, erythrocyte proto is increased. treatment is directed to sun protection. hypertrichosis in hepatoerythropoietic porphyria has been treated successfully with high-intensity pulses of noncoherent light. 350 other porphyrias with onset of symptoms in infancy or early childhood include homozygous variants of aminolevulinate dehydratase (alad) defi ciency, homozygous coproporphyria (harderoporphyria), homozygous variegate porphyria, and homozygous acute intermittent porphyria. 351 alad defi ciency porphyria is rare (fewer than 10 patients reported) and usually manifests later in childhood or adulthood, but neonatal onset has been reported. 352 clinical manifestations from birth are recurrent attacks of pain, vomiting, hyponatremia, and symptoms of polyneuropathy affecting motor functions, including respiration. raised levels of 5aminolevulinic acid and coproporphyrin in urine are found. very low erythrocyte aminolevulinate dehydratase activity is diagnostic. liver transplantation in patients with neonatal onset has little effect. 353 in harderoporphyria, neonatal jaundice, hemolytic anemia, and hepatosplenomegaly dominate the clinical picture. [354] [355] [356] [357] blisters may occur during phototherapy for neonatal jaundice. diagnosis depends on detecting very low coproporphyrinogen oxidase activity, elevated coproporphyrin in urine, markedly homozygous variegate porphyria may present shortly after birth with marked photosensitivity or, more commonly, with erosions, blisters, and milia following minor trauma in sunexposed areas. [358] [359] [360] acute attacks are absent, but mental and growth retardation, seizures, nystagmus, and clinodactyly have been described. homozygous variant of acute intermittent porphyria may present early in life with ataxia, mental retardation, convulsions, cataracts, and hepatosplenomegaly, but acute attacks typical of acute intermittent porphyria do not occur in these children. [361] [362] [363] [364] there are no cutaneous manifestations. markedly increased porphobilinogen and alad in urine are found and are responsible for the orange urine. [365] [366] [367] [368] transient increases in porphyrin levels have been described in neonates with hemolytic disease of the newborn and in a neonate with severe liver failure due to tyrosinemia type 1. 368 these infants develop erythema, violaceous discoloration, purpura, erosions, and blisters in areas exposed to phototherapy, with sharp demarcation at photoprotected sites. sensitivity to sunlight may occur. elevated levels of plasma/urine porphyrins (mainly coproporphyrin) and/or erythrocyte protoporphyrin are found, which normalize spontaneously during the fi rst few months. the cause of transient porphyrinemia is unclear but is probably due to cholestasis. other factors likely to be involved include blood transfusions and drug use. purpura in the neonate is almost always an emergency and should prompt an immediate search for an underlying disorder. apart from trauma, purpura in the newborn may be due to coagulation defects, platelet abnormalities, or infections (see . extramedullary erythropoiesis also causes purpuric lesions by a different mechanism. in the evaluation of a neonate with purpura it is important to obtain a maternal and familial history of bleeding diathesis and thromboembolic phenomena, drug intake, and symptoms of infectious diseases. a general physical examination and workup for sepsis is warranted. laboratory studies should include hemoglobin and hematocrit values, platelet count, white blood count, coagulation studies, and torch serologies. persistence of the erythropoietic activity of fetal dermal mesenchyme into the newborn period produces a characteristic purpuric eruption for which the term blueberry muffi n baby was coined. the eruption, fi rst observed in newborns with congenital rubella (fig. 19-23) , may be the result of other intrauterine infections (fig. 19-24 ) and hematologic dyscrasias. [369] [370] [371] a blueberry muffi n-like eruption may also represent metastatic infi ltration of the dermis by congenital malignancies, without true extramedullary erythropoiesis (fig. 19-25 ). the cutaneous lesions of blueberry muffi n babies consist of dark blue or magenta, nonblanchable, round to oval papules ranging in size from 1 to 7 mm and have a generalized distribution, with emphasis on the head, neck, and trunk ( fig. 19-26 ). the papules are fi rm to palpation, with an infi ltrative quality that distinguishes them from petechiae and purpura, which often coexist in the same patient. these lesions evolve into dark purple to brown macules and involute spontaneously within 2-6 weeks. 273 blueberry muffi n lesions caused by infi ltrative processes are usually larger, more nodular, less hemorrhagic, fewer in number, and fi rmer to palpation. accompanying abnormalities vary with the underlying cause. in the prevaccination era rubella was the most common cause of dermal erythropoiesis, but now congenital cytomegalovirus (cmv) infection is the major cause. 369, 370 dermal erythropoiesis has been associated with other intrauterine infections, such as coxsackie b2 369 and parvovirus b19, 372 as well as hematologic dyscrasias such as rh incompatibility (fig. 19-24) , 373, 374 maternofetal abo incompatibility, 369 spherocytosis, 375 and the twin transfusion syndrome 210, 216 (box 19-6) . in rare instances it may occur in otherwise healthy newborns. 369, 376 histopathologic examination demonstrates poorly circumscribed collections of nucleated and nonnucleated red blood cells, predominantly confi ned to the reticular dermis and extending to the subcutaneous tissue. [369] [370] [371] occasionally a few myeloid precursors may be interspersed. laboratory fi ndings depend on the underlying cause. in the evaluation of a blueberry muffi n baby the following tests are indicated: peripheral blood count, hemoglobin level, torch serologies, viral cultures, and a coombs' test. skin biopsy is not always necessary for diagnosis, but may be helpful if an infi ltrative process is suspected. the differential diagnosis includes other causes of neonatal purpura, such as coagulation defects, platelet abnormalities, and infections. 273 neoplastic diseases that produce infi ltrative metastases in the neonatal period, such as neuroblastomas, [377] [378] [379] rhabdomyosarcomas, 380 the lesions of true dermal erythropoiesis fade and resolve spontaneously 3-6 weeks after birth. treatment is directed at the underlying condition. neonatal purpura fulminans is a rare condition characterized by massive and progressive hemorrhagic necrosis of the skin accompanied by thrombosis of the cutaneous vasculature in the neonatal period. [386] [387] [388] [389] [390] [391] occasionally larger vessels and other organs are involved. the primary pathologic event is widespread thrombosis, which is responsible for a hematologic picture of disseminated intravascular coagulation (dic). in neonates, purpura fulminans is usually the result of inherited thrombophilic disorders that are attributable to protein c deficiency, protein s defi ciency, or resistance to activated protein c due to factor v mutations. neonatal purpura fulminans manifests 2-12 hours after birth. in rare instances, delayed onset of up to 6-10 months of age has been described. 392 cutaneous lesions consist of extensive ecchymoses in a diffuse and often symmetric distribution that rapidly evolve into hemorrhagic bullae and purple-black necrotic skin lesions, which ultimately form a thick eschar ( fig. 19-27 ). the initial ecchymotic areas are sharply defi ned from the surrounding skin and usually have a red, advancing infl ammatory rim. they are most common at sites of trauma or pressure, the buttocks, extremities, trunk, and scalp. mucous membranes may rarely be involved. 393 if treatment is instituted in the fi rst 1-3 hours, before necrosis ensues, the initial lesions may be reversible. 390 other organs may be affected by the microvascular thrombosis, most commonly the cns and eye, but also the kidney and gastrointestinal tract. cavernous sinus involvement, which may occur in utero, can result in hydrocephalus, seizures, intracerebral hemorrhage, and mental retardation. 388, 394, 395 microphthalmia, cataracts, and blindness due to vitreous or retinal hemorrhage may be seen. 388, 389 deep venous thrombosis and pulmonary embolism have also been described. 394 purpura fulminans in the neonatal period is almost always caused by inherited thrombophilic states such as homozygous protein c and s defi ciency or resistance to activated protein c. severe bacterial infection associated with dic can also induce purpura fulminans in the neonate, although it is more common in infancy or early childhood. 396, 397 proteins c and s are vitamin k-dependent glycoproteins with antithrombotic properties. 398, 399 protein c defi ciency is an autosomal dominant disease with incomplete penetrance. 399 homozygous or compound heterozygous patients have a severe clinical phenotype and usually present with neonatal purpura fulminans, although they may be asymptomatic or present later in life with recurrent thrombosis. 400, 401 protein s defi ciency is also transmitted as an autosomal dominant trait with incomplete penetrance. 399 homozygous patients may develop neonatal purpura fulminans, although the risk is lower than in patients with homozygous protein c defi ciency. 387, 402 neonatal purpura fulminans may also be caused by activated protein c resistance due to a mutation in the factor v gene. 393, 403 resistance to activated protein c may coexist with protein s and protein c defi ciencies, becoming an additional genetic risk factor for purpura fulminans or thromboembolic complications, and explaining in part the incomplete clinical penetrance of inherited thrombophilic disorders. 404 blood coagulation studies demonstrate evidence of dic, including prolonged prothrombin and partial thromboplastin times, increased fi brin split products, reduced fi brinogen, and reduced platelets. microangiopathic hemolytic anemia may occur. biopsy of the early skin lesions demonstrates occlusion of dermal blood vessels by microthrombi. hemorrhage and dermal necrosis are present in the more advanced stages. necrosis of the overlying epidermis with subepidermal hemorrhagic bullae occurs in later phases. secondary fi brinoid necrosis of dermal vessel walls may be present in the necrotic areas, but primary vasculitis is absent. 390, 405 a defi nitive diagnosis of protein c and s defi ciency is established by measurements of protein c and s levels. 399 protein c defi ciencies can be identifi ed by immunoenzymatic assays measuring the actual concentration of the protein in plasma, and two functional assays measuring the enzymatic activity and the anticoagulant activity. these tests distinguish two types of protein c defi ciency. in type i, which is the most common, reduced synthesis of the normal protein leads to a low plasma concentration in all three assays. in type ii, a qualitative defi ciency, levels are normal but functional assays are abnormal. for protein s defi ciency, functional and immunoenzymatic assays are available, and both the free form and the inactive form that circulates bound to c4b-binding protein have to be measured. 399 type i defi ciency is characterized by low total and free protein s, type ii by normal free protein s and low activity, and type iii by low free protein levels with normal total levels. interpreting the results of the assays may be diffi cult because protein c and s levels are physiologically reduced in the neonatal period, and may be undetectable in sick newborns with liver disease, respiratory distress syndrome, dic, or sepsis. 389, 390, 396, 397, 406 a complete sepsis workup is therefore recommended in any case of neonatal purpura fulminans. serial determination of protein levels in patients and other family members is necessary to exclude a transient defi ciency and confi rm true congenital defi ciency. the cutaneous lesions of purpura fulminans are very characteristic and rarely mistaken for any other condition. other causes of purpuric eruptions in the newborn may be considered (see . without treatment, neonatal purpura fulminans is often fatal. if the diagnosis is suspected, therapy should be initiated immediately without waiting for the results of protein c and s measurements. prompt treatment may completely reverse early skin lesions. initial therapy consists of the administration of fresh frozen plasma (10-15 ml/kg/12 h) or prothrombin complex concentrate, sources of protein c, protein s, and activated protein c. 389,390 a protein c concentrate has been developed that has the advantage of avoiding blood volume overload and does not carry the risk of transmission of viral fig. 19-27 neonatal purpura fulminans due to protein c defi ciency. ment therapy to avoid coumarin-induced skin necrosis. experience with long-term treatment using protein c infusions is limited. there are few case reports of a successful liver transplant for homozygous protein c defi ciency. 409, 410 this benign, transient purpura in transfused neonates who undergo phototherapy is characterized by raspberry-colored, nonblanching lesions at exposed sites, sparing sites that are protected from lights (e.g. leads and temperature probes). 206, 208 the eruption develops after 1-4 days of phototherapy and clears spontaneously after discontinuation of light therapy. histologically there is extravasation of red blood cells in the dermis without epidermal damage. the pathogenesis of this disease is unknown, although transient porphyrinemia has been detected in some patients. 367, 411 the purpuric nature of the eruption and the absence of 'sunburn cells' differentiate this eruption from 'sunburn' caused by exposure to uva from fl uorescent lamps. 412 congenital erythropoietic porphyria and transient elevated porphyrin levels in neonates with hemolytic disease may also cause photosensitivity. 411 drug-induced phototoxicity in neonates who have received photosensitizing chemicals such as fl uorescein dye, furosemide or methyleneblue must be considered. [413] [414] [415] [416] diseases. 407, 408 protein s concentrate is not yet available for clinical use. replacement therapy should be continued until all lesions have healed, usually after 4-8 weeks. long-term treatment involves careful administration of oral anticoagulants, starting at very low doses and with protective replacethe annular erythemas persistent' annular erythema of infancy an annular erythema of infancy annular erythema of infancy annular erythema of infancy congenital annular erythema persisting in a 15-year-old girl persistent annular erythema of infancy erythema annulare centrifugum: report of a case with neonatal onset erythema gyratum atrophicans transiens neonatale erythema gyratum atrophicans transiens neonatale: a variant of cutaneous neonatal lupus erythematosus reactive erythemas: erythema annulare centrifugum and erythema gyratum repens erytheme annulaire centrifuge de darier à debut neonatal avec 15 ans de suivi. effi cacité de l'interféron et role de 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protoporphyria beta carotene treatment and erythrocytic protoporphyrin levels erythropoietic protoporphyria: treatment with antioxidants and potential cure with gene therapy erythropoietic protoporphyria treated with narrowband (tl-01) uvb phototherapy liver failure in protoporphyria: long-term treatment with oral charcoal liver transplantation for erythropoietic protoporphyria: report of a case with medium-term follow-up liver transplantation for erythropoietic protoporphyria liver disease long-term follow-up after liver transplantation for erythropoietic protoporphyria roles and pitfalls of transplantation in human porphyria hepatoerythropoietic porphyria: a new uroporphyrinogen decarboxylase defect or homozygous porphyria cutanea tarda? hepatoerythropoietic porphyria: a variant of childhood-onset porphyria cutanea tarda. porphyrin profi les and enzymatic studies of two cases in a family porphyrie hepato-erythroctaire, une nouvelle forme de porphyrie hepatoerythropoietic porphyria: clinical, biochemical, and enzymatic studies in a three-generation family lineage successful and safe treatment of hypertrichosis by high-intensity pulses of noncoherent light in a patient with hepatoerythropoietic porphyria hepatic porphyrias in children aminolaevulinate dehydratase porphyria in infancy. a clinical and biochemical study liver transplantation in a boy with acute porphyria due to aminolaevulinate dehydratase defi ciency structural basis of hereditary coproporphyria characterization of mutations in the cpo gene in british patients demonstrates absence of genotypephenotype correlation and identifi es relationship between hereditary coproporphyria and harderoporphyria a molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria harderoporphyria: a variant hereditary coproporphyria homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene homozygous variegate porphyria: 20 year follow-up and characterization of molecular defect molecular characterization of homozygous variegate porphyria a retrospective study of a patient with homozygous form of acute intermittent porphyria identifi cation of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias skin signs of systemic disease: an update neonatal bullous eruption as a result of transient porphyrinemia in a premature infant with hemolytic disease of the newborn purpuric phototherapy-induced eruption in transfused neonates: relation to transient porphyrinemia cutaneous porphyria in a neonate with tyrosinaemia type 1 dermal hematopoiesis in neonates: report of fi ve cases dermal erythropoiesis in neonatal infants: a manifestation of intrauterine viral disease dermal erythropoiesis in congenital rubella. description of an infected newborn who had purpura associated with marked extramedullary erythropoiesis in the skin and elsewhere anemia, blueberry-muffi n rash, and hepatomegaly in a newborn infant dermal erythropoiesis in rh hemolytic disease of the newborn neonatal dermal erythropoiesis associated with severe rhesus immunization: amelioration by highdose intravenous immunoglobulin dermal erythropoiesis in a neonate blueberry muffi n syndrome: cutaneous erythropoiesis and possible intrauterine viral infection blanching subcutaneous nodules in neonatal neuroblastoma blueberry muffi n baby: neonatal neuroblastoma with subcutaneous metastases cutaneous metastases in neuroblastoma congenital alveolar rhabdomyosarcoma presenting as a blueberry muffi n baby transient blueberry muffi n appearance of a newborn with congenital monoblastic leukemia acute myelomonocytic leukemia with skin localizations analysis and review of the world literature with report of an additional case blueberry muffi n baby': hematopoiese extramedullaire neonatale? leucemie monoblastique congenitale involutive? ou histiocytose congenitale involutive? histiocytoses langerhansiennes congenitales cutanees. a propos de 7 cas purpura fulminans. a cutaneous manifestation of severe protein c defi ciency homozygous protein s defi ciency in an infant with purpura fulminans neonatal purpura fulminans: a genetic disorder related to the absence of protein c in blood report of the working party on homozygous protein c defi ciency of the subcommittee on protein c and protein s, international committee on thrombosis and haemostasis neonatal purpura fulminans due to homozygous protein c or protein s defi ciencies purpura fulminans in a newborn baby homozygous protein c defi ciency with delayed onset of symptoms at 7 to 10 months neonatal purpura fulminans in association with factor v r506q mutation homozygous protein c defi ciency manifested by massive venous thrombosis in the newborn severe homozygous protein c defi ciency severe acquired neonatal purpura fulminans causes of purpura fulminans protein c pathway in infants and children protein c and protein s defi ciencies late-onset homozygous protein c defi ciency asymptomatic homozygous protein c defi ciency homozygous protein s defi ciency due to a one base pair deletion that leads to a stop codon in exon iii of the protein s gene the discovery of activated protein c resistance blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases dermatopathology of skin necrosis associated with purpura fulminans neonatal purpura fulminans and transient protein c defi ciency homozygous protein c defi ciency -management with protein c concentrate replacement therapy with a monoclonal antibody purifi ed protein c concentrate in newborns with severe congenital protein c defi ciency en bloc heterotopic auxiliary liver and bilateral renal transplant in a patient with homozygous protein c defi ciency successful treatment of homozygous protein c defi ciency by hepatic transplantation transient erythroporphyria of infancy ultraviolet light burn: a cutaneous complication of visible light phototherapy of neonatal jaundice methylene-blue-induced hyperbilirubinemia and phototoxicity in a neonate methylene blue-induced phototoxicity: an unrecognized complication fluorescein phototoxicity in a premature infant phototoxic blisters from high frusemide dosage key: cord-024189-t7mbsr25 authors: weyand, cornelia m.; goronzy, jörg j. title: vasculitides date: 2008 journal: primer on the rheumatic diseases doi: 10.1007/978-0-387-68566-3_21 sha: doc_id: 24189 cord_uid: t7mbsr25 despite the spatial closeness of blood vessels and inflammatory cells, blood vessel walls are infrequently targeted by inflammation. giant cell arteritis (gca) and takayasu’s arteritis (ta) are characterized by inflammation directed against the vessel wall. gca and ta display stringent tissue tropism and affect defined vascular territories in a preferential manner. gca predominantly affects the secondto fifth-order aortic branches, often in the extracranial arteries of the head. the aorta itself may also be affected in gca, albeit less often than other regions. in contrast, in ta, the aorta and its major branches are the prime disease targets. despite the spatial closeness of blood vessels and infl ammatory cells, blood vessel walls are infrequently targeted by infl ammation. giant cell arteritis (gca) and takayasu's arteritis (ta) are characterized by infl ammation directed against the vessel wall. gca and ta display stringent tissue tropism and affect defi ned vascular territories in a preferential manner. gca predominantly affects the second-to fi fth-order aortic branches, often in the extracranial arteries of the head. the aorta itself may also be affected in gca, albeit less often than other regions. in contrast, in ta, the aorta and its major branches are the prime disease targets. in both gca and ta, clinical symptoms of vascular infl ammation and vascular insuffi ciency are usually accompanied or preceded by a systemic infl ammatory process not localizable to a single tissue or organ. systemic infl ammation is also characteristic of polymyalgia rheumatica (pmr), a syndrome of muscle pain and stiffness in the neck, shoulders, and hips. pmr can accompany, precede, or follow gca, but it also occurs independently. in a subset of pmr patients, gca is present but not clinically evident. giant cell arteritis is the most common primary form of vasculitis among adults in the united states and europe. the disease occurs almost exclusively in individuals aged 50 years and older, and its incidence increases progressively with age (1) . women are more likely to be affected than men. the prevalence is highest in scandi-navian countries and in regions settled by people of northern european descent, with incidence rates reaching 15 to 25 cases per 100,000 persons aged 50 years and older. gca occurs much less frequently in southern europeans (6 cases per 100,000 individuals) and is rare in blacks and hispanics (1-2 cases per 100,000 individuals). the histological hallmark of gca is a mononuclear cell infi ltrate dominated by t lymphocytes and macrophages. the infl ammatory infi ltrate penetrates all layers of the arterial wall ( figure 21a-1) . the infi ltrates can be granulomatous with the accumulation of histiocytes and multinucleated giant cells. granuloma formation is most likely to be observed in the media. although the presence of multinucleated giant cells inspired the name of the disease, they are often absent, and the mononuclear infi ltrates lack a complex organization. if present, giant cells lie in close proximity to the fragmented internal elastic lamina. their presence correlates with increased risk for ischemic complications. gca can also present with perivascular cuffi ng of vasa vasorum or t cell-macrophage infi ltrates in the adventitia, sometimes arranged along the external elastic lamina. this fi nding is consistent with recent studies suggesting that the adventitia is a critical site in the disease process. the infl ammation causes a series of structural changes to the arterial wall. among the fi rst pathologic changes observed is the fi nding of a lymphoplasmacytic infi ltrate in the adventitia. with progress of the infl ammatory process, the media of the arterial wall becomes thinner. as the medial smooth muscle cell layer loses thickness, the intima becomes hyperplastic, compromising or occluding the arterial lumen. although the vessel lumen may become critically narrowed, thrombosis is not the central event. hyperplasia of the intimal layer with scarring in the media and fragmentation of the elastic lamina are irreversible changes that persist beyond the stages of active arterial infl ammation. fibrinoid necrosis is rare and should raise the suspicion for other forms of vasculitis. polyarteritis nodosa, microscopic polyangiitis, and wegener's granulomatosis, for example, are known to affect the temporal artery as well as other more typical vascular beds. when these forms of vasculitis affect the temporal artery, their fi rst pathological manifestations may be lymphoplasmacytic infi ltrates within the adventitia, indistinguishable at an early stage from gca. the immune response in the arterial wall experimental evidence supports a t-cell-mediated immunopathology of gca (2) . humoral immunity does not appear to be important: b cells are not found within the arterial wall; no pathognomic antibodies have been identifi ed; and hypergammaglobulinemia is absent. t cells enter the vessel wall from the vasa vasorum in the adventitia, not from the macroendothelium. recruitment and activation of tissue-invading t cells is controlled by dendritic cells (dcs) in the adventitia. dcs are an indigenous cell population in normal mediumsized and large vessels. in the adventitia, they are typically localized at the outside of the external elastic lamina, close to the adventitia-media junction. evidence suggests that these vascular dcs utilize toll-like receptors (tlrs) to scan their environment for signs of infection, specifi cally for pathogen-related molecules. in gca and pmr, such adventitial dcs are strongly activated, produce chemokines, and express t-cell stimulatory ligands. this model is supported by experiments in human artery mouse chimeras. in these experiments, human temporal arteries from gca patients are implanted into severe combined immunodefi ciency mice. depletion of either t cells or dcs from the implanted vascular lesions terminates the infl ammatory response, with subsequent clearing of the infl ammatory infi ltrate. in contrast, administration of tlr ligands to chimeras implanted with normal temporal arteries followed by the adoptive transfer of t cells is suffi cient to induce the initial steps of vasculitis (3) . based on these studies, it has been proposed that the vessel wall, in its physiologic state, is an immunoprivileged site. in gca, activation of vascular dcs by microbial products can break this immunoprivilege and lead to the recruitment and stimulation of t cells. the nature of the peptide antigens recognized by these t cells is histomorphology of giant cell arteritis. a typical temporal artery biopsy specimen is shown. characteristic changes include a panmural mononuclear infi ltrate, destruction of the internal and external elastic laminae, and concentric intimal hyperplasia. undetermined, but it may be that common self-antigens are suffi ciently immunogenic when dcs are activated. macrophage function in gca is known to be multifaceted, with specifi c commitments of these cells linked closely to their topographical arrangements within the cell wall (4) . interferon (ifn) gamma, a t-cell cytokine, regulates both macrophages and giant cells. macrophages in the adventitia, intermingling with activated t cells, produce interleukin (il)-1, il-6, and transforming growth factor (tgf) beta. macrophages in the medial layer are specialized in the production of metalloproteinases, and also contribute to oxidative damage. end products of lipid peroxidation, a cell injury mechanism driven by oxygen radicals, are typically found on medial smooth muscle cells (5) . macrophages recruited to the intimal layer are committed to the production of nitric oxide synthase-2. nitric oxide is suspected to be involved in tissue injury, cellular activation, and vascular remodeling. multinucleated giant cells, once assumed to function in the removal of indigestible debris, are actually active secretory cells, producing molecular mediators relevant in structurally changing the arterial wall. the presence of giant cells in gca corresponds with the presence of high adventitial levels of ifn-gamma (6). the assumption that all pathogenic mechanisms in infl amed arteries are mediated by tissue-infi ltrating immune cells is simplistic. t cells and macrophages in the arterial wall do not live and function in isolation, but rather closely interact with stromal components of the blood vessel in a bidirectional pattern (7) . the major vascular abnormality leading to clinical disease is a nonthrombotic luminal occlusion, caused by rapid and concentric growth of the intima. these structural alterations result from the response to injury elicited in arterial cells ( figure 21a -2). intimal hyperplasia is generated by the mobilization of smooth muscle cells, their directed migration towards the lumen, and their proliferation and matrix deposition. this process is under the control of growth factors. platelet-derived growth factor (pdgf), a factor with the capability of supporting the outgrowth of the hyperplastic intima, is present in infl amed arteries. pdgf derives from macrophages and multinucleated giant cells. patients with low pdgf production have no or minimal lumen-occlusive intimal proliferation. in contrast, those with excessive pdgf production are at a risk for ischemic complications (8) . a second pathway of the arterial injury-response program relates to the formation of new capillaries. the media and intima of normal arteries are avascular, but intense neoangiogenesis is induced in gca (9) . vascular endothelial growth factor (vegf) is critical in driving the generation of neovessels in the media and intima. vegf, like pdgf, originates from macrophages and multinucleated giant cells. the arterial response pattern initiated by the production of pdgf and vegf leads to profound structural arterial abnormalities with subsequent stenosis and tissue ischemia, emphasizing that the immune system coerces the artery toward a counterproductive pattern of reaction. however, the infl ammation also leads to the induction of protective response patterns that are aimed at healing and tissue repair. an example is the upregulation of the enzyme, aldose reductase (10) , which metabolizes and detoxifi es end products of oxidative damage. the activation of vascular dcs as an early step in the pathogenesis of gca has two major implications: (1) infl ammation and immune activation are not limited to vascular lesions; and (2) a systemic component of gca is an independent dimension of the disease process and not simply a spillover from vessel wall infl ammation. further evidence for this systemic component is the activation in gca patients of circulating monocytes, which produce il-1 and il-6. elevated levels of il-6, a potent inducer of acute phase responses, are characteristic of gca. in this model, gca is a systemic infl ammatory disease, with vasculitis of medium and large arteries as a consequence of the disease process. age is the major risk factor for gca. no other environmental risk factors, including a variety of infectious agents, have been demonstrated convincingly to play important roles in this disease. the high incidence rates of gca in all geographical regions settled by people of scandinavian ethnicity strongly suggest inherited risk factors (1) . the best available information is for human leukocyte antigen (hla) genes. hla-dr4 haplotypes are associated with increased disease risk. several allelic variants of hla-dr4 are enriched among patients. selective binding of antigenic peptides has been proposed as the mechanism underlying this genetic association. in contrast to other hla-dr4-associated diseases such as rheumatoid arthritis, hla polymorphisms do not correlate with clinical phenotypes and disease severity. many other genetic risk factors have been suggested, but none have been proven to date. the diagnostic category of gca encompasses multiple variants ( figure 21a-3) . each of these subtypes has characteristic clinical features (11) ; however, the clinical manifestations of the different subtypes overlap substantially, and none of the clinical symptoms is unique for any one of the variants. increased awareness of gca, a growing population of individuals older than 50 years of age, and improvement in diagnostic procedures (e.g., the availability of magnetic resonance angiography to image the aorta and its branches) have led to increased detection of cases formerly considered to be atypical presentations. giant cell arteritis presents with two major symptomatic complexes, signs of vascular insuffi ciency resulting from impaired blood fl ow and signs of systemic infl ammation. in general, vascular changes are those of occlusion; arterial wall dilatation only occurs when the aorta is involved. giant cell arteritis, also known as temporal arteritis, has a predilection for involving the extracranial branches of the carotid arteries. the temporal artery, which courses just below the skin over the temple region, is the vessel most amenable to biopsy. in 80% to 90% of patients, histopathology of vasculitis is detected in the extracranial arterial tree, most often in the superfi cial temporal artery; the vertebral, ophthalmic, and posterior ciliary arteries; and, less frequently, the internal and external carotid and central retinal arteries. patients complain of throbbing, sharp, or dull headaches that are usually severe enough to prompt clinical evaluation. the headaches may or may not be associated with scalp tenderness. in classic cases, the patients notice temporal tenderness when wearing glasses, grooming, or lying on a pillow. on physical examination, involved vessels may be thickened, tender, and nodular. pulses may be reduced or absent. abnormalities are most frequent in the temporal arterial branches, but they can also be detected in the occipital arteries or other superfi cial scalp vessels. in one third of the patients with biopsy-proven gca, the temporal arteries are normal on physical examination. focal arteritic lesions in the ophthalmic artery produce the most feared complication of gca: vision loss. the disease is an ophthalmological emergency, because prompt recognition and treatment can prevent blindness. ischemia anywhere along the visual pathway can lead to visual loss, but anterior ischemic optic neuropathy is the most common cause. visual loss is sudden, painless, and usually permanent. amaurosis fugax, reported as fl eeting visual blurring with heat or exercise or posture-related visual blurring and diplopia, may precede partial or complete blindness. on ophthalmologic examination, anterior ischemic optic neuropathy is recognized by optic disc edema, eventually followed by sectoral or generalized optic atrophy with optic disc cupping. besides optic neuropathy, the spectrum of ophthalmic complications is wide, ranging from pupillary defects to orbital ischemia and from ocular motor ischemia to anterior and posterior segment ischemia. a relatively disease-specifi c manifestation of gca that is present in about half of the patients is jaw claudication: pain in the masseter or temporalis muscles caused by compromised blood fl ow in the extracranial branches of the carotid artery. prolonged talking and chewing produce pain in the muscles of mastication. the onset of jaw claudication following the initiation of chewing is surprisingly swift. cases of trismus have been described. claudication of the tongue is less frequent, but tongue infarctions have been reported. vasoocclusive disease of the carotid and vertebrobasilar arteries results in ischemia of the central nervous system (cns), manifesting as transient ischemic attacks or infarcts. neurologic manifestations are increasingly being recognized and can be expected in 20% to 30% of patients. true intraparenchymal cns vasculitis in gca is rare, but reported. occult presentations of gca are common. gca is the cause of fever of unknown origin in up to 15% of elderly individuals, for example. nonspecifi c symptoms of pain in the face, neck, or throat are other warning signs of possible gca. chronic nonproductive cough can be an initial presentation of gca. the involvement of cough receptors (present throughout the repiratory tree) by the vasculitic process is believed to be the cause of cough in gca. symptoms related to systemic infl ammation are frequently present. laboratory abnormalities are detectable in more than 90% of patients. in a subset of patients, the disease process is dominated by a systemic infl ammatory syndrome. fever of unknown origin with spiking temperatures and chills usually leads to diagnostic evaluations designed to exclude infections and malignancies. in less dramatic cases, malaise, anorexia, weight loss, low-grade fever, and fatigue eventually become severe enough to prompt medical attention. physical examination of the scalp arteries is often negative, and symptoms of vascular insuffi ciency can be absent. temporal artery biopsy, even if the artery is normal on clinical examination, remains the diagnostic procedure of choice. clinical spectrum of the giant cell arteritis/ polymyalgia rheumatica syndrome. in at least 10% to 15% of patients, gca involves the large arteries in a clinically evident manner. (the percentage of cases with subclinical large vessel disease may be substantially higher.) preferred vascular beds are the carotid, subclavian, and axillary arteries. vasculitis of the femoral arteries is infrequent. the major clinical presentation is that of aortic arch syndrome, producing claudication of the arms, absent or asymmetrical pulses, paresthesias, and (rarely) symptoms of digital ischemia. patients with the large vessel variant of gca often lack evidence of cranial involvement; they do not complain about headaches, have normal temporal arteries on examination, and almost 50% of temporal artery biopsies are negative for vasculitis (12) . aortitis in gca can coexist with cranial arteritis. whether the patient subset with subclavian-axillary gca is distinct from the subset progressing to aortic involvement is not known. overall, the risk of patients with gca to develop thoracic aortic aneurysm is increased 17-fold (13) . the elastic membranes supporting the aortic wall are destroyed and replaced by fi brotic tissue. the resulting histopathology can be indistinguishable from that of ta. most cases of aortitis have been diagnosed several years after the initial diagnosis of gca, raising the possibility that smoldering aortitis is more common than previously expected (14) . the spectrum of clinical manifestations ranges from silent aneurysm to aortic dissection and fatal rupture. in 1990, the american college of rheumatology (acr) formulated classifi cation criteria for gca. these criteria, not intended for the purposes of establishing a clinical diagnosis of gca, are shown in appendix i. the diagnosis of gca should be considered in patients aged 50 years and older with recent onset of unexplained headache, signs of tissue ischemia in the extracranial vascular territory, loss of vision, symptoms of limb or jaw claudication, or polymyalgia rheumatica. laboratory evidence of an acute phase response heightens concern about gca. the diagnostic procedure of choice is the histological verifi cation with the superfi cial temporal artery. in a recent meta-analysis, positive clinical predictors of a positive biopsy were jaw claudication, diplopia, and abnormalities of the temporal artery biopsy on physical examination (15) . all other symptoms, including vision loss, elevated sedimentation rate, headaches, and constitutional symptoms, were not particularly helpful in predicting the results of temporal artery biopsies (i.e., in diagnosing gca). the presence of synovitis was a negative predictor of gca, indicative of the fact that most patients with true arthritis have another diagnosis, such as rheumatoid arthritis. even the most specifi c fi ndings for history, physical examination, and routine laboratory testing have sensitivities of only (at best) 50%. in view of the fact that rendering the diagnosis of gca commits a patient to long-term course of glucocorticoid therapy, confi rmation of the diagnosis by temporal artery biopsy is essential whenever possible. true negative results are expected in more than 50% to 70% of all patients undergoing biopsies at most institutions. false-negative biopsies, which occur as frequently as 10% of the time, can be minimized by taking a suffi cient length of biopsy, by examining serial sections, and by removing the contralateral temporal artery when the fi rst biopsy is free of arteritis. short-term glucocorticoid treatment (up to 2 weeks, or even signifi cantly longer) is unlikely to interfere with the results of a temporal artery biopsy. prednisone should therefore not be withheld if a biopsy cannot be performed immediately. a pathognomic laboratory test for gca does not exist. specifi c autoantibodies have not been identifi ed. highly elevated acute phase responses are typical for gca but are not present in all patients. although a high erythrocyte sedimentation rate (esr) is usually considered a hallmark of gca, in a recent study 25% of all patients with positive temporal artery biopsies had normal esrs before the initiation of glucocorticoid therapy (16) . other markers of acute phase response, particularly creactive protein (crp), may be more sensitive than esr in some patients, but studies have not demonstrated this consistently. some evidence indicates that the most sensitive serum marker for ongoing systemic infl ammation in gca (both before and after glucocorticoid therapy) is il-6. il-6, a strong inducer of acute phase reactants, probably functions upstream in the disease process. unfortunately, reliable il-6 measurements are not widely available, and knowledge about how (or if) to adjust therapy in the context of changing il-6 levels remains incomplete. there is currently no evidence that treatment decisions should be predicated upon the results of laboratory tests-esr, crp, or il-6-in the absence of clinical symptoms. other laboratory abnormalities in gca include mild-to-moderate normochromic or hypochromic anemia. elevated platelet counts are common. liver function tests, particularly alkaline phosphatase, can be abnormal. precise mapping of the vaso-occlusive process still requires angiography. angiography is also essential for patients with signifi cant stenoses in vessels to all four extremities, for the purpose of measuring central aortic pressure directly. alternatives to conventional angiography, however, have made great strides in recent years (17) . magnetic resonance angiography (mra) permits evaluation of vessel wall thickness and perivascular edema-signifi cant advantages over conventional angiograms, which evaluate only the vascular lumen. in the proper clinical context, therefore, certain mra fi ndings may be diagnostic of large vessel vasculitis. the noninvasive nature of mra also lends important advantages in serial monitoring. unfortunately, the appropriate interpretations of some mra fi ndings, for example, enhancement of the vessel wall following gadolinium administration and the presence of vessel wall edema, remain uncertain and require additional longitudinal studies. computed tomography angiography, another promising technique, has not been evaluated thoroughly in large vessel vasculitis. position emission tomography (pet) with 18 f-fl uorodeoxyglucose also holds promise for the assessment of the degree of disease activity in large arteries, but has not yet been validated for general clinical use. other noninvasive vascular studies, including fl uorescein angiography, transcranial doppler fl ow studies, and doppler ultrasonography, are useful in assessing certain vascular beds, for example, the retinal, vertebral, or subclavian arteries. these techniques only identify vascular insuffi ciency in cases with pronounced, lumen-stenosing disease, however, and do not provide specifi c information useful from the standpoint of diagnosis. although doppler ultrasound was once hypothesized to be useful in the diagnosis of gca, the value of identifying a "hyperechoic halo" on ultrasound in the temporal artery has not been confi rmed in subsequent studies (18) . glucocorticoids are explicitly effective in suppressing clinical manifestations of gca. since the introduction of glucocorticoids, the rate of gca-related blindness has declined, documenting the effectiveness of this immunosuppressive approach. in almost all patients, glucocorticoids induce relief within 12 to 48 hours. the excellent response of the disease to this therapy has been suggested by some as a diagnostic criterion. in view of the severity of gca-related morbidity, initial doses of 60 mg prednisone or equivalent have been recommended. glucocorticoids cannot reverse intimal hyperplasia but may help attenuate the ischemic insult by reducing tissue edema. in ophthalmologic emergencies (e.g., amaurosis fugax occurring in suspected gca), pulse glucocorticoids may be appropriate (19) . initial doses should be maintained until reversible manifestations of the disease have responded and the systemic infl ammatory syndrome is suppressed. subsequently, under close monitoring for clinical signs of disease reactivation, the dose of prednisone generally can be tapered by 10% every 1 to 2 weeks. so far, the use of glucocorticoid-sparing agents to allow a more rapid taper has been unsuccessful (17) . initial positive results with methotrexate could not be confi rmed in a subsequent study (20) . a recent randomized, controlled trial of tumor necrosing factor (tnf) alpha blockade found this therapy to be ineffective as a glucocorticoid-sparing medication (21) . a recent study suggests that a more aggressive induction therapy at the onset of the disease, including three daily pulses of 1 gram of methylprednisolone, may allow for a rapid tapering of glucocorticoids and, in particular, a discontinuation of glucocorticoids in the second year of disease (22) . aspirin is an important adjunctive treatment for gca patients without contraindications. retrospective studies have indicated strong reductions in the risks of visual loss and central nervous system ischemic events among patients taking aspirin for other reasons at the time their gca was diagnosed (23) . the mechanism of aspirin's effi cacy in this setting is not entirely clear, but the medication may exert its effect through the selective suppression of interferon gamma production (17) . although the optimal dose of aspirin has not been established, doses ranging from 81 mg/day to 325 mg/day may be benefi cial. the most signifi cant morbidity of gca relates to reduced blood fl ow to the eye and optic nerve as well as hypoperfusion of the brain (19) . if diagnosed and treated promptly, progression of the downstream effects of arterial wall infl ammation, in particular lumen occlusion with tissue ischemia, can be prevented. side effects of high doses of glucocorticoids given over a prolonged period of time can be serious, especially in patients older than 50 years, and treatment should therefore only be initiated if the diagnosis is confi rmed. in the majority of patients, gca does not enter remissions that are sustained indefi nitely after discontinuation of glucocorticoids. in a prospective study of 25 patients with biopsyproven gca, all of the patients responded to 60 mg prednisone with disappearance of clinical signs of the disease (16) . however, 60% of patients had disease relapses that occurred throughout the course of treatment. typically, reactivation of the disease produced symptoms of systemic infl ammation or polymyalgic symptoms, but no vascular complications were seen. polymyalgia rheumatica is diagnosed in patients presenting with pain and stiffness in the muscles of the neck, shoulder girdle, and pelvic girdle of at least 4 weeks' duration (24) . the myalgias are combined with signs of systemic infl ammation manifesting clinically as malaise, weight loss, sweats, and low-grade fever. most patients have laboratory abnormalities such as elevated esr, elevated crp, and anemia, which are indicative of a systemic infl ammatory syndrome. upregulation of acute phase reactants is helpful in distinguishing pmr from other pain syndromes, yet (as in gca and ta) not all patients with active disease have elevated markers of infl ammation within their serum. no pathognomic test for pmr is available; exclusion of other diseases with similar clinical presentations is essential. the systemic infl ammatory syndrome associated with pmr is exquisitely sensitive to glucocorticoid therapy, such that prompt improvement of clinical symptoms with glucocorticoid therapy has been proposed as a diagnostic criterion. the pathophysiology of pmr is related closely to those of gca. pmr is now often considered a form of gca that lacks fully developed vasculitis. because pmr remains a clinical diagnosis, epidemiological studies are diffi cult. pmr affects the same patient population as gca, but occurs approximately two to three times more frequently (24) . women are affected more often than men, and the diagnosis is extremely unlikely in individuals younger than 50 years of age. in high-risk populations, such as scandinavians and other peoples of northern european descent, annual incidence rates have been estimated at 20 to 53 per 100,000 persons over the age of 50 years. in low-risk populations, such as italians, the annual incidence rates for individuals aged 50 years and older are only 10 cases per 100,000. although the sudden onset of intense infl ammation is suspicious for an infectious etiology, no causative agent has been identifi ed. most pathogenic abnormalities in pmr patients are reminiscent of those in gca, supporting the concept that pmr is a variant of gca characterized by the dominance of the systemic infl ammatory over the vascular component. human leukocyte antigen polymorphisms that are genetic risk factors for gca are also associated with pmr. there is no evidence that the hla has a role in determining whether the disease process will remain limited to pmr or progress to fully developed gca. polymyalgia rheumatica appears to be associated with a global activation of the innate immune system, including circulating monocytes that produce il-1 and il-6. activated dcs render arteries susceptible to vasculitis. in many patients with pmr, in situ cytokine production can be demonstrated in biopsy specimens, although in lower quantities than in gca. of note, ifngamma is absent in pmr, but abundant in gca (25) . a subset of pmr patients develops infl ammation of periarticular structures, for example, bursae. whether these patients comprise a different subset from those susceptible to developing frank vasculitis remains unclear. patients complain about aching and pain in the muscles of the neck, shoulders, lower back, hips, thighs, and occasionally the trunk. in typical cases, the onset is abrupt and the myalgias symmetrical; they usually affect the shoulders fi rst. often the patients have pain during the night and have diffi culties rising and dressing themselves. weight loss, anorexia, malaise, and depression are common. fever and chills should raise the suspicion of fully developed gca. pmr is frequently diffi cult to distinguish from forms of seronegative polyarthritis. in particular, male patients can present with proximal aching and diffuse edema of the hands and feet that is highly glucocorticoid-responsive. polymyalgia rheumatica includes patients with mild disease that is promptly responsive to therapy and remits within a few months (26) . in many patients, however, reactivation of myalgias occurs when glucocorticoid doses are tapered. some patients require higher initial doses of glucocorticoids than are usually considered to be effective in pmr. patients with pmr must be carefully evaluated for possible gca. a negative temporal artery biopsy does not exclude the possibility of large vessel vasculitis targeting primarily the subclavian and axillary arteries and the aorta. signs of vascular insuffi ciency, including claudication in the extremities, bruits over arteries, and discrepant blood pressure readings should alert the physician to the possibility of gca (12) . mra can be helpful in confi rming the concomitant diagnosis of large vessel vasculitis. in pmr patients with infl ammation of periarticular structures, the most prominent fi ndings are subdeltoid and subacromial bursitis (27) . biceps tendonitis and glenohumeral synovitis may also be present. ultrasonography reveals fl uid accumulation in the bursae; t2-weighted mri shows thickening and edema. these involved areas show increased uptake on pet scans. the clinical symptoms of pmr can be mimicked by a number of arthropathies, shoulder disorders, infl ammatory myopathies, hypothyroidism, and parkinson's disease. the differential diagnosis also includes malignancies and infections. no clear guidelines have been developed to determine whether patients with pmr should be screened for occult malignancies. lack of the typical and impressive improvement upon initiation of therapy can provide a clue towards reevaluating the diagnosis of pmr. polymyalgia rheumatica is dramatically responsive to glucocorticoid therapy. currently there are no data documenting glucocorticoid-sparing effects of other medications. however, almost all patients with pmr can be safely managed with glucocorticoids; doses for long-term treatment are low and unlikely to cause serious side effects. a critical decision in treating pmr is the dose of glucocorticoids required for successful suppression of symptoms and infl ammation. the glucocorticoid requirements may differ quite markedly among patients. two thirds of patients can be expected to respond with remission of pain and stiffness when started on 20 mg/day or less prednisone (25) . some patients will need doses as high as 40 mg/day for complete clinical control. such patients may be at higher risk of full-blown gca. patients initially controlled on 20 mg/day of prednisone can usually taper the dose by 2.5 mg every 10 to 14 days. more protracted tapering may be necessary once daily doses of 7 to 8 mg prednisone are attained. dose adjustments should be based mainly on clinical evaluation, not exclusively on laboratory abnormalities. in many patients, pmr can go into long-term remission, and prednisone can be discontinued. occasionally, successful suppression of recurrent myalgias and stiffness may only be achieved by giving very low doses of prednisone over an extended period. patients should be warned about the potential of pmr progressing to gca and should be monitored for vascular complications, particularly when discontinuing glucocorticoid therapy. the prognosis of patients with pmr is good. in the majority of patients, the condition is self-limited. a proportion of patients will eventually present with typical symmetrical polyarthritis, fulfi lling the criteria for the diagnosis of seronegative rheumatoid arthritis. such patients may require disease-modifying antirheumatic drug (dmard) therapy. takayasu's arteritis is a vasculitis of the large elastic arteries, specifi cally the aorta and its main branches. the disease may also affect the coronary and pulmonary arteries (28) . infl ammatory injury to the vessel wall leads to patchy disappearance of the elastica and smooth muscle layer and subsequent intimal hyperplasia, resulting in vascular stenosis in virtually all patients and dila-tation and aneurysm in about 25%. complete occlusion of upper extremity arteries results in the loss of palpable pulses, which is why ta is also termed the pulseless disease. the preference for the aorta and its primary branches is signifi ed in another alternative name, aortic arch syndrome. the acr has developed a set of criteria to distinguish ta from other vasculitic syndromes (see appendix i). takayasu's arteritis is a rare disease that primarily affects adolescent girls and young women. the diagnostic criteria include an age of less than 40 years at disease onset; however, ta can start later in life, particularly in asians (29) . (in addition, the diagnosis is often not made until the patient is older than 40, but symptoms may have begun years before the diagnosis.) incidence rates are highest in asia (japan, korea, china, india, and thailand), with estimates of approximately 1 case per 1 million persons annually. ta can occur in all races and geographic regions, but south american countries have recently been recognized as additional areas of relatively high incidence. an international survey among 20 countries has indicated differences in the clinical spectrum of ta in different ethnic groups. takayasu's arteritis is a granulomatous polyarteritis. the adventitia is characterized by striking thickening, often with intense perivascular infi ltrates around the vasa vasorum. granuloma formation and giant cells are predominantly found in the media of the large elastic arteries. the medial elastic smooth muscle cell layer is destroyed in a centripetal direction and replaced by fi brotic tissue, leading (in the aorta) to vessel wall dilatation and aneurysm formation. smooth tapering, narrowing, or complete occlusion of the vascular lumen results from proliferation of the intima, occasionally with thrombosis. the etiology of ta remains unknown. in view of the systemic features of the syndrome, microbial infections have been implicated, but no conclusive evidence for infectious organisms has been provided. cd8 t cells are a major component of vascular infi ltrates, setting ta apart from gca. cytotoxic activities of tissue infi ltrating cd8 t cells, mediated by the release of the poreforming enzymes perforin and granzyme b, have been suspected of contributing to smooth muscle cell damage (30) . support for a role of cd8 t-cell-mediated cytolytic tissue injury has come from the observation that selected hla class i molecules, specifi cally hla-b52, are overrepresented among ta patients (31) . cd8 t cells recognize antigens when bound to hla class i molecules. the role of cd4 t-cell responses and the contribution of macrophage effector functions in the vascular lesions are not understood. the focus of lymphocytic infi ltrates on the adventitia and accumulation of t cells around vasa vasorum makes it less likely that the macroendothelium has major involvement in the pathogenesis of ta. a generalized infl ammatory syndrome with fever, night sweats, malaise, anorexia, weight loss, and diffuse myalgias often dominates initial manifestations of ta. these symptoms are frequently misdiagnosed as infection. the clinical pattern of ischemic complications that emergeoften years later-directly refl ect the vascular territory targeted by the disease (figure 21a-4) . involvement of the carotid and vertebral arteries leads to neurologic and ophthalmologic symptoms, including dizziness, tinnitus, headaches, syncope, stroke, and visual disturbances. atrophy of facial muscles and jaw claudication are mostly late manifestations. occlu-sions of the brachiocephalic and subclavian arteries impair blood fl ow to the upper extremities, presenting as arm claudication, pulselessness, and discrepant blood pressures. the detection of bruits can be helpful in making the diagnosis. cardiac disease, including ischemic coronary disease, arrhythmia, and congestive heart failure, can be related to aortitis of the ascending aorta or severe hypertension. aortic regurgitation, a serious complication requiring prompt clinical attention, is a consequence of aortic dilatation. coronary arteries can be involved directly or indirectly, producing classical symptoms of myocardial ischemia. progressively enlarging aneurysms and possible rupture are a major concern in patients with ta of the aortic arch and the descending thoracic aorta. patients from india, china, and korea often have lesions in the abdominal aorta and its branches (particularly the renal arteries, causing renovascular hypertension). the proximal ends of mesenteric arteries are less frequently affected, but gastrointestinal symptoms, such as nausea, vomiting, and ischemic bowel disease can be seen in patients with ta. patients presenting (%) clinical spectrum of takayasu's arteritis in relationship to vascular bed involvement. a combination of vaso-occlusive disease and systemic infl ammation in a young patient should immediately raise suspicion for ta. typically, the diagnosis is made by characteristic fi ndings on vascular imaging (32) . tissue is rarely available. the fi ndings on conventional angiography can be diagnostic for ta in the proper clinical setting. angiography reveals long, smooth taperings of involved vessels, with a remarkable web of collateral blood vessels in advanced cases. as in gca, conventional angiography is essential in many patients with ta in order to measure accurately the central aortic blood pressure. several noninvasive imaging techniques are informative for assessing progression of occlusive disease, but currently lack standardization and are subject to investigator bias and experience. far more problematic than assessing the degree of stenosis within a given blood vessel is the reliable assessment of infl ammatory activity by imaging. mri/a has largely replaced conventional angiography for serial assessments of the distribution and degree of vessel involvement, and also permits evaluations of the vessel wall as well as the lumen. mri/a is particularly important in the longitudinal monitoring of ta although, as noted, the correct interpretation of all mri/a fi ndings is not always clear. mri/a has clear utility in monitoring the progress or stability of vascular stenoses, provided that serial studies are compared carefully for changes. doppler ultrasound provides a good assessment of cervical vessels. computed tomography angiography can be used to survey the aorta and proximal vessels, but rigorous serial studies of its use in ta remain to be performed. the role of pet scanning in gauging the degree of ongoing infl ammation (as opposed to uptake that might be related to a process of healing or fi brosis) has not been established. although some patients with ta have disease that appears to "burn out," becoming quiescent after years of active disease, most patients have progressive or relapsing/remitting disease and require long-term immunosuppressive treatment (33) . glucocorticoids are the therapy of choice for management of ta. recommendations of initial doses have varied, but 40 to 60 mg of prednisone may be necessary to control vascular as well as systemic infl ammation. monitoring of acute phase reactants (esr, crp) is only helpful in a subset of patients. in a national institutes of health (nih) cohort, 50% of patients had active progressing disease despite nonelevated acute phase reactants (34) . prednisone doses are tapered as clinically indicated and tolerated, usually by 5 mg/day every 2 weeks until a maintenance dose of 10 mg/day is reached. further dose reductions must be tailored to the individual patient. low-dose aspirin or other antiplatelet agents should complement glucocorticoid therapy. methotrexate, given in weekly doses of up to 25 mg, has shown promise in improving remission rates and sparing glucocorticoids (35) , but has never been tested in a randomized trial (the same is true for all other potential steroid-sparing agents). azathioprine, mycophenolate mofetil, cyclosporine, and tnfalpha blockers have been used with reported success in individual patients, but controlled studies are required. contrary to other vasculitides, cyclophosphamide does not play a major role in this disease because of its toxicity and uncertain effi cacy. stenotic lesions are irreversible. surgical management and angioplasty or stent placement have a role in selected patients, but for most patients revascularization attempts of vessels to the extremities are not necessary because of the exuberant collateralization that develops in ta. when revascularization is necessary, bypass grafts are generally successful, while stenting appears to have a high rate of reocclusion (33) . angioplasty is reserved for short stenotic segments. treatment of hypertension secondary to renal artery stenosis may or may not benefi t from revascularization, depending on the location of the lesion leading to renovascular hypertension. decisions about whether or not to attempt revascularization should be undertaken in consultation with experts accustomed to the management of complex hypertension cases. for much of the past several decades, ta has been viewed as an inevitably devastating disease. the diagnosis was seldom made before damage from prolonged vascular infl ammation was already extensive. more recently, the potential for earlier diagnosis, effective immunosuppressive therapy, and astute surgical management have led to an improved prognosis for many patients. long-term follow up of almost 1000 japanese patients found stable clinical conditions in two thirds of the patients and serious complications occurring in only 25% of affected individuals. cardiac complications, including congestive heart failure and ischemic heart disease, have become the most common cause of death in japanese patients with ta. acceleration of atherosclerotic disease emerges as a critical factor in long-term outcome. polyarteritis nodosa (pan) primarily affects mediumsized arteries that supply the skin, gut, nerve, and kidney, but may involve multiple organs. microaneurysms of arteries to or within the kidneys, liver, or gastrointestinal tract are highly characteristic of pan. polyarteritis nodosa is not associated with antineutrophil cytoplasmic antibodies (anca) directed against either proteinase-3 or myeloperoxidase. mononeuritis multiplex, an asymmetric sensory and motor neuropathy due to ischemia and infarction of peripheral nerves, occurs frequently in pan. in mononeuritis multiplex, nerve conduction studies of peripheral nerves reveal a distal, asymmetric, axonal neuropathy involving both motor and sensory nerves. polyarteritis nodosa is characterized pathologically by patchy, transmural infl ammation in medium-and small-sized muscular arteries, sparing large arteries, capillaries, and the venous system. the infl ammation leads to fi brinoid necrosis, but is not associated with granulomatous features. high-dose glucocorticoids are the mainstay of therapy in pan. in cases that are rapidly progressive or life-or organ-threatening, however, cyclophosphamide is added to glucocorticoid treatment. most cases of idiopathic pan do not recur once a sound remission has been achieved with 6 to 12 months of therapy. a minority of pan cases (now >10%) are associated with acute hepatitis b infection. cases associated with hepatitis b are treated with regimens emphasizing antiviral therapy and only short courses of immunosuppression and plasmapheresis. polyarteritis nodosa (pan) is a vasculitis affecting predominantly medium-sized arteries. clinically, pan often presents insidiously with nonspecifi c, constitutional symptoms. the disease has a predilection for mediumsized arteries supplying skin, gut, nerve, and kidney, but may involve multiple organs. the majority of pan cases have no known cause, but cases secondary to hepatitis b virus infection have been reported. described by kussmaul and maier in 1866 (1,2), pan is often regarded as the fi rst reported form of systemic vasculitis. in fact, earlier descriptions of behcet's disease, takayasu's arteritis, henoch-schönlein purpura, and even pan itself exist in the medical literature. for nearly a century after the case reported by kussmaul and maier, however, most forms of systemic vasculitis were termed periarteritis nodosa, and forms of vasculitis recognized later were contrasted and classifi ed in comparison to pan. the patient described by kussmaul and maier was a 27-year-old male with fever, weight loss, abdominal pain, and a polyneuropathy that progressed over the period of 1 month to paralysis. an autopsy revealed microaneurysms ("whitish small tumors up to the size of poppy and hemp seeds") throughout medium-sized arteries, conspicuously sparing both the venous circulation and the lungs. before the delineation of vasculitis subsets and the formulation of defi nitions based principally on vessel size (3), pan was used to describe two now-distinct forms of vasculitis: the classic pan described by kussmaul and maier, and "microscopic pan" (now called microscopic polyangiitis). according to current convention, and as described in this text, pan is a vasculitis affecting medium-sized arteries. pan is also not associated with antineutrophil cytoplasmic antibodies (anca), at least not those directed against proteinase-3 (pr3) or myeloperoxidase (mpo) that are such a distinctive feature of the majority of cases of wegener's granulomatosis, microscopic polyangiitis, and, to a lesser extent, the churg-strauss syndrome. although patients may be p-anca-positive on immunofl uorescence testing, enzyme immunoassays for pr3-and mpo-anca are negative in pan. further, in contrast to the anca-associated vasculitides (see chapter 21c), pan does not involve either the lungs or blood vessels as small as the renal glomeruli (which are essentially capillaries). polyarteritis nodosa affects men and women approximately equally and has a broad age range of patients. although the incidence of pan varies according to the population studied, it is rare in all populations, with annual incidence rates generally ranging from 2 to 9 cases per million. higher rates have been reported in populations with a high burden of hepatitis b virus infection, but with the availability of a vaccine, hepatitis b virus infection now accounts for less than 10% of pan cases in developed countries (4) . pan has also been reported to occur in conjunction with hairy cell leukemia. polyarteritis nodosa can present with nonspecifi c constitutional symptoms such as fever, fatigue, malaise, myalgias, and arthralgias. this phase of the illness can last weeks or months. the more specifi c clinical manifestations of pan are the direct results of infl ammation in medium-and small-sized muscular arteries. pan often has cutaneous involvement, a feature it shares with small vessel vasculitides such as the ancaassociated disorders. this differentiates it from large vessel vasculitis (e.g., giant cell arteritis and takayasu's arteritis), in which skin disease is very rare. however, unlike the anca-associated vasculitides, pan is not associated with glomerulonephritis or pulmonary involvement. common clinical features of pan and their frequency are listed in table 21b -1 (5) . in autopsy studies, the most frequently involved organ in pan is the kidney. involvement of the mediumsized arteries supplying the renal parenchyma can result in hypertension due to renal ischemia; hypertension is mediated by the renin-angiotensin system. renal insuffi ciency, another common manifestation of pan, is due to ischemia resulting from the involvement of arteries the size of renal arteries and smaller. microaneurysms, detectable by angiography [ figure 21b -1(a,b)], are a hallmark of pan. the gastrointestinal (gi) tract is involved in up to 50% of patients. postprandial periumbilical pain, or intestinal angina, is the result of mesenteric ischemia. more severe disease can result in bowel infarction and perforation. other gi symptoms can include nausea, vomiting, diarrhea, and bleeding. while the small intestine is most commonly involved, rare presentations involving ischemia of the gallbladder or appendix have been described (6) . moderately elevated hepatic transaminases often betray liver involvement. asymptomatic mircoaneurysms within the liver are common; these occasionally rupture. involvement of the peripheral nervous system is seen in 50% to 75% of patients, usually as an asymmetric sensory and motor neuropathy due to ischemia of peripheral nerves (7) . infarction of named nerves results in mononeuritis multiplex ( figure 21b -2). progressive sensory neuropathy has been described less frequently. central nervous system involvement is much less common, but has been reported in the form of cerebrovascular accidents. polyarteritis nodosa can have multiple cutaneous manifestations: livedo reticularis, nodules, ulcerations ( figure 21b -3), and frank ischemia of digits (8) . a small group of patients have a form of disease termed cutaneous pan, a variant limited ostensibly to the skin. these patients develop nodules and ulcerations, primarily of the lower legs, which can occur in crops and can be very painful. however, as with any other vasculitis, cutaneous manifestations should prompt a thorough evaluation for evidence of systemic disease. as with kawasaki's disease, the other medium vessel vasculitis described in this text, pan can also involve the coronary arteries. clinical proof of coronary disease during life is diffi cult. myocardial infarction is uncom-mon, and coronary involvement is usually only seen at autopsy. contraction band necrosis, indicative of segmental ischemia, is a common fi nding in the myocardium at autopsy, attesting to the presence of vasculitis below the resolution of conventional angiography. pan can involve other organs, such as the testicle, ovary, breast, and eye. polyarteritis nodosa is characterized pathologically by patchy, transmural infl ammation in medium-and smallsized muscular arteries, sparing large arteries, capillaries, and the venous system. there is a pleomorphic cellular infi ltrate and fi brinoid necrosis in the vessel, but no features of granulomatous infl ammation. disruption of the elastic laminae of the vessel wall can lead to aneurysmal dilatation at the site of the lesion. pan has a predilection for certain organs: arteries to the kidney are estimated to be involved 70% to 80% of the time, the gi tract is involved in 50% of cases, the peripheral nerves are involved in 50% of cases, and the central nervous system is involved in 10% of cases (9) . polyarteritis nodosa is diagnosed based on characteristic symptoms, physical examination fi ndings, and compatible laboratory, angiographic, and pathologic data. because pan is a rare disease and its treatment can result in serious adverse events, the diagnosis should be supported with either abdominal angiography or biopsy whenever possible. pan must be differentiated from other forms of vasculitis, such as the anca-associated disorders, cryoglobulinemia, and buerger's disease. common vasculitis mimics, such as viral hepatitis, bacterial endocarditis, or other embolic diseases, should be excluded. undiagnosed connective tissue diseases, such as systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis, must be ruled out, as such diseases can be associated with systemic vasculitis or widespread vascular dysfunction that involves multiple organs. atrophie blanche, a thrombotic disorder that may lead to lower extremity ulcerations, must be differentiated from pan by skin biopsy. the american college of rheumatology criteria for the classifi cation of pan are listed in table 21b -2 (5). the criteria were developed through the selection of clinical fi ndings that identify pan and distinguish it from other forms of vasculitis. although the criteria are useful for classifying patients in clinical studies, they were not intended for use in diagnosing individual patients (10). routine laboratory studies are often abnormal but nonspecifi c, such as elevated infl ammatory markers (erythrocyte sedimentation rate or c-reactive protein), anemia, and thrombocytosis. the patient may have mild renal insuffi ciency, with an elevated blood urea nitrogen and creatinine. non-nephrotic range proteinuria and mild hematuria are also seen, but active urine sediments are not a feature of pan. as not, pan is not associated with anca. indeed, there is no characteristic autoantibody for pan-a fact that creates one of the diagnostic challenges in this disease. electromyography/nerve conduction velocity (emg/ncv) studies may be very useful in confi rming patterns of nerve dysfunction consistent with mononeuritis multiplex; namely, a distal, asymmetric, axonal neuropathy involving both motor and sensory nerves. imaging in a patient with suspected pan should be guided by symptoms. in patients with abdominal pain, abdominal arteriography often reveals characteristic strictures and aneurysms (beading) of the mesenteric vessels [see figure 21b -1(b)]. similar fi ndings can be seen in the renal vasculature. as with imaging, biopsy should be guided by organ involvement. blind biopsy of an asymptomatic organ, such as muscle or testicle, is not recommended. skin biopsy is often the easiest way to confi rm this diagnosis, with a biopsy from the center of a nodule or the edge of a vasculitic ulcer. routine punch biopsy of involved skin reveals leukocytoclastic vasculitis and fi brinoid necrosis within the blood vessel wall. because punch biopsy samples include only epidermis and superfi cial dermis, they do not capture medium-sized, muscular-walled arteries whose infl ammation is characteristic of pan. when pan is suspected and skin biopsy is indicated, a full thickness skin biopsy that includes some subcutaneous fat should be performed (arteries within the fat lobules of subcutaneous tissue are often involved.) another option for confi rming the diagnosis of pan is a peripheral nerve biopsy. the sural nerve is biopsied most often because it does not mediate motor function. whenever the sural nerve is biopsied, a muscle biopsy (of the gastrocnemius) should be performed simultaneously. because of the highly vascular nature of muscle, biopsies of this organ may yield proof of vasculitis even in the absence of clinical indications of muscle involvement ( figure 21b -4). muscle biopsy showing fi brinoid necrosis within the wall of a medium-sized muscular artery. although the patient had clinical symptoms of a neuropathy and nerve conduction studies were consistent with a mononeuritis multiplex, the nerve biopsy was negative. the diagnosis of polyarteritis was confi rmed by the muscle biopsy. (courtesy of dr. john stone.) untreated pan has a high mortality, with an estimated 5-year survival of 13% prior to the introduction of glucocorticoids. with current treatment, survival is greatly improved, approximately 80% at 5 years. in a population of 278 patients enrolled in prospective trials for pan, mpa, and churg-strauss syndrome, approximately 75% of the deaths occurred during the fi rst 18 months after the diagnosis was made and treatment initiated. of the patients who died, 26% died from progression of their vasculitis, while 13% died of infectious complications related to treatment. no major differences were seen among the three vasculitides studied (11) . not surprisingly, more severe disease is associated with increased mortality. a five factor score has been used to classify disease severity (12) . the fi ve factors are (1) proteinuria >1 g/day, (2) renal insuffi ciency (cr > 1.6 mg/dl), (3) cardiomyopathy, (4) gastrointestinal symptoms, and (5) cns involvement. a five factor score of 0 is associated with a 5-year mortality of only 13% (with not all deaths caused directly by pan). five factor scores of 1 and 2 or more are associated with mortalities of 26% and 46%, respectively (12) . the treatment of pan is guided by both the etiology of the disease (if known) and its severity. pan cases associated with hepatitis b are treated with a short course of prednisone (1 mg/kg/day) to suppress the infl ammation. patients begin 6-week courses of plasma exchange (approximately three exchanges per week) simultaneously with the start of glucocorticoids. the dose of prednisone is tapered rapidly (over approximately 2 weeks), followed by the initiation of antiviral therapy (e.g., lamivudine 100 mg/day). for idiopathic pan, the mainstay of treatment is glucocorticoids, with an initial dose of approximately 1 mg/ kg daily of prednisone. intravenous glucocorticoids can be used in patients with diffi culty taking oral medications due to gi involvement. pulse doses (e.g., methylprednisolone 1 g intravenously each day times three) may be used in severe disease. glucocorticoids alone may be enough to treat milder cases. approximately half of all patients with pan may be cured with glucocorticoids alone. in cases of pan that are rapidly progressive or lifeor organ-threatening, cyclophosphamide is added to glucocorticoid treatment. cyclophosphamide should be considered for any patient with a five factor score of 1 or greater. in addition, severe peripheral neuropathy or mononeuritis multiplex is also a strong indication for cyclophosphamide. although many clinicians still prefer daily oral cyclophosphamide to monthly pulsed intravenous cyclophosphamide, a meta-analysis comparing the two regimens in anca-associated vasculitis showed little difference (13) . therapy should be tailored to the individual patient's circumstances. most cases of idiopathic pan do not recur after remission has been achieved and the patient has received 6 to 12 months of cyclophosphamide. current regimens generally emphasize shorter courses of cyclophosphamide, with durations of therapy closer to 6 months than to 12. after treatment with 6 months of cyclophosphamide, patients in remission-the great majority-should be switched to another immunosuppressive agent for remission maintenance. as with the anca-associated vasculitides, azathioprine or methotrexate is often used. after a total treatment length of approximately 18 months, the remission maintenance agent can often be stopped, with a low relapse rate. patients should continue to be monitored for evidence of recurrence. much potential morbidity in pan relates to adverse events from inappropriate (or overly aggressive) treatment. conversely, poor outcomes also result from undertreatment, for example, failure to employ cyclophosphamide in a patient clearly failing highdose glucocorticoids. an important aspect of treatment is avoiding known side effects of agents used. this includes the use of calcium and vitamin d supplementation in all patients on glucocorticoids, along with use of a bisphosphonate in those at high risk for bone loss and monitoring of bone density. patients on cyclophosphamide should have routine monitoring for cytopenias and hematuria and receive trimethoprim/ sulfamethoxazole for prevention of pneumocystis jiroveci (formerly carinii) pneumonia. patients receiving pulsed intravenous cyclophosphamide are also candidates for mesna (sodium-2-sulfanyl ethanesulfonate) for prevention of hemorrhagic cystitis. premenopausal females on cyclophosphamide are candidates for leuprolide to suppress the gnrh axis and prevent premature ovarian failure; males may opt to bank sperm. finally, as a teratogen, patients should not become pregnant or father children on cyclophosphamide. multiple antibodies may lead to positive immunofl uorescence testing for anca in either perinuclear (p-anca) or cytoplasmic (c-anca) patterns. however, only antibodies to myeloperoxidase (mpo) and proteinase-3 (pr3) are associated with the aav. wegener's granulomatosis may be associated with destructive upper respiratory tract disease, including saddle-nose deformity, erosive sinusitis, and subglottic stenosis. the css is often associated with allergic rhinitis, nasal polyposis, or sinusitis, but is rarely associated with destructive lesions. a host of ocular lesions may occur in the aav, including episcleritis, scleritis, peripheral ulcerative keratitis, and orbital pseudotumor. lung disease is common in the aav and ranges from asthma (in css) to nodular lesions with a tendency to cavitate (in wg) to interstitial lung disease (mpa) to alveolar hemorrhage (all forms of aav). segmental, necrotizing glomerulonephritis commonly accompanies the aav, particularly wg and mpa. eosinophilia is the sine qua non of css. in 1954, godman and churg observed that wegener's granulomatosis (wg), microscopic polyangiitis (mpa), and the churg-strauss syndrome (css) share certain pathological similarities despite their clinical distinctions (1). these diseases, godman and churg noted, "group themselves into a compass, (ranging from) necrotizing and granulomatous processes with angiitis . . . to vasculitis without granulomata." validation of the pathological links between these disorders became clear three decades later with the discovery of antineutrophil cytoplasmic antibodies (anca) and the fi nding that most patients with wg, mpa, and (to a lesser extent) css have anca in their serum. these diseases are commonly termed anca-associated vasculitides (aav), even though not all patients with these diseases have detectable anca (table 21c-1) . anticytoplasmic antibodies directed against neutrophils (i.e., anca) were reported in association with segmental necrotizing glomerulonephritis in the early 1980s. in 1985, the presence of diffuse cytoplasmic staining of neutrophils was reported in patients with wg (2) . in studies of patients with wg, mpa, or renal-limited vasculitis, falk and jennette (3) noted another pattern of immunostaining-perinuclear fl uorescence of alcohol-fi xed neutrophils. the two types of antibodies associated with aav are those directed against (1) proteinase-3 (pr3) and (2) myeloperoxidase (mpo). pr3 and mpo, both serine proteases, are constituents of the primary granules of neutrophils and monocytes. antibodies directed against these antigens are known, respectively, as pr3-anca and mpo-anca. the 1990 american college of rheumatology classification criteria for wg and the css (table 21c-1) (4, 5) were developed to ensure the inclusion of uniform disease populations in research studies (6) . these criteria did not address the utility of anca for classifi cation or the difference between polyarteritis nodosa and mpa. these limitations were addressed by the chapel hill consensus conference (table 21c -2) (7). to date, widely accepted diagnostic criteria for these diseases have not been developed. a population-based study from norfolk, england, reported incidences of 8.5 cases per million for wg, 3.6 cases per million for mpa, and 2.4 cases per million for the css (8). in two large u.s. cohorts of patients with wg (9,10), whites comprised more than 90% of all cases, whereas african americans, hispanics, and asians together represented 1% to 4% of cases. the mean age at diagnosis is about 55 years, but cases involving octogenarians are not unusual. wegener's granulomatosis granulomatous infl ammation involving the respiratory tract, and necrotizing vasculitis affecting small-to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries). necrotizing glomerulonephritis is common. microscopic polyangiitis necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e., capillaries, venules, or arterioles). necrotizing arteritis involving small-and medium-sized arteries may be present. necrotizing glomerulonephritis is very common. pulmonary capillaritis often occurs. churg-strauss syndrome eosinophil-rich and granulomatous infl ammation involving the respiratory tract, and necrotizing vasculitis affecting small-to medium-sized vessels, associated with asthma and eosinophilia. there is substantial overlap in many of the clinical features of the aavs. in some cases, distinguishing among two or more of these diseases on the basis of clinical features alone is diffi cult (table 21c-3) . although patients with the css or mpa may experience substantial ear, nose, or sinus disease, this pattern of involvement is most characteristic of wg. more than 90% of patients with wg eventually develop upper airway or ear abnormalities. the nasal symptoms of wg include nasal pain and stuffi ness, rhinitis, epistaxis, and brown or bloody crusts. nasal infl ammation may lead to septal erosions, septal perforation, or, in many cases, nasal bridge collapse-the "saddle-nose deformity" (figure 21c -1). the distinction between active wg in the sinuses and secondary infections in the sinuses may be challenging (see nonmedical interventions section). in 60% to 70% of patients with the css, allergic rhinitis is the earliest disease manifestation, typically appearing years before the development of full-blown saddle-nose deformity in wegener's granulomatosis. systemic vasculitis. rhinitis may be severe and may require serial polypectomies to relieve obstruction and sinusitis. nasal crusting and conductive hearing loss (due to serous otitis or granulomatous middle ear infl ammation) may also occur in the css. two principal categories of ear disease-conductive and sensorineural hearing loss-are typical of wg. the most common cause of conductive hearing loss may be eustachian tube dysfunction due to nasopharyngeal disease. inner ear disease in wg may be associated with sensorineural hearing loss, vestibular dysfunction, or both. in contrast to middle ear disease, the mechanism of inner ear disturbances in wg is poorly understood. subglottic stenosis and stenotic lesions of the bronchi are potentially serious complications of wg. subglottic involvement, often asymptomatic initially, becomes apparent as hoarseness, pain, cough, wheezing, or stridor. thin-cut computed tomographic scans and often direct laryngoscopy are useful in assessing these airway narrowings. scleritis may lead to necrotizing anterior scleritis (scleromalacia perforans) and blindness. peripheral ulcerative keratitis may cause the corneal melt syndrome. other ocular manifestations of aav include conjunctivitis, episcleritis, and anterior uveitis. in wg, orbital masses termed pseudotumors occur in a retrobulbar location in 10% to 15% of patients, causing proptosis, diplopia, or visual loss. nasolacrimal duct obstruction is most typical of wg. in wg, the pulmonary manifestations range from asymptomatic lung nodules and fl eeting (or fi xed) pulmonary infi ltrates to fulminant alveolar hemorrhage. the nodules are usually multiple, bilateral ( figure 21c-2) , and often cavitary. infi ltrates are often misdiagnosed initially as pneumonia. pulmonary capillaritis, equally likely to occur in wg and mpa, may lead to lung hemorrhage, hemoptysis, and rapidly changing alveolar infi ltrates ( figure 21c-3) . patients with mpa may also develop interstitial fi brosis of the lungs. obstructive airway disease and fl eeting pulmonary infi ltrates are the hallmarks of the css. the majority of patients report the new onset of asthma months to years before the appearance of overt vasculitis. following resolution of the vasculitic phase with treatment, many patients with css suffer from steroid-dependent asthma. the most feared clinical presentation of renal disease among the aavs is rapidly progressive glomerulonephritis. more than 75% of patients with wg will eventually develop renal involvement. the progression of the disease often appears to accelerate once kidney involvement is apparent. in mpa, renal disease may have a more indolent course, and renal biopsies typically demonstrate more sclerosis and fi brosis than do specimens from patients with wg. severe renal disease in css is very rare. "renal-limited" vasculitis is pauci-immune glomerulonephritis (see pathology section) associated with anca, usually directed against mpo, without evidence of disease in other organs. anca-associated renal disease may lead to fi brotic crescents and other scarring within the kidney. subsequent disease fl ares and progression of renal dysfunction through hyperfi ltration may lead to end-stage renal disease. infl ammatory joint complaints, often migratory and oligoarticular in nature, occur in at least 60% of patients with aav. joint problems are frequently the presenting complaint, but the diagnosis is seldom made until other symptoms are manifest. the combination of joint complaints, cutaneous nodules (frequently mistaken for rheumatoid nodules), and the high frequency of rheumatoid factor positivity among patients with aav (approximately one third are rheumatoid factor positive) often lead to the misdiagnosis of rheumatoid arthritis early in the disease course. arthralgias are more common than frank arthritis. the recurrence of musculoskeletal complaints in a patient in remission often marks the start of a disease fl are. in both the css and wg, cutaneous nodules may occur at sites that are also common locations for rheumatoid nodules, particularly the olecranon region ( figure 21c-4) . skin fi ndings in the aavs also include all of the potential manifestations of cutaneous vasculitis: palpable purpura, vesiculobullous lesions, papules, ulcers, digital infarctions, and splinter hemorrhages. vasculitic neuropathy may lead to a devastating mononeuritis multiplex or a disabling sensory polyneuropathy. mononeuritis multiplex occurs more commonly in the css [up to 78% of patients (11) ] and mpa (up to 58%) than in wg. central nervous system abnormalities occur in approximately 8% of patients with wg, usually in the form of cranial neuropathies, mass lesions, or pachymeningitis. the frequency of parenchymal brain involvement in aav, though not yet known with certainty and generally regarded as rare, has been reported. central nervous system disease generally occurs only when more typical disease manifestations are present elsewhere. the css is the type of aav that is most likely to involve the heart, usually in the form of rapid-onset heart failure. cardiac complications in wg and mpa are both less common and more diffi cult to attribute with certainty to the underlying disease. focal cardiac valvular lesions, valvular insuffi ciency, pericarditis, and coronary arteritis have been described in wg. eosinophilic gastroenteritis often precedes the frank vasculitic phase of the css. among patients with either the css or mpa, unexplained abdominal pain occurs in up to one third of patients and may lead to ischemic bowel. gastrointestinal involvement is less common in wg. eosinophilia (before treatment) is a sine qua non of the css. eosinophil counts are usually sensitive markers of disease fl ares, but respond very quickly (within 24 hours) to treatment with high doses of glucocorticoids. tissue infi ltration by eosinophils, however, may remain. mild eosinophilia (rarely more than 15% of the total white blood cell count) may also occur in wg. most patients with css also have elevated serum immunoglobulin e levels. in addition to anca, nonspecifi c autoantibodies, such as antinuclear antibodies and rheumatoid factor, also occur in high percentages of patients with aav. antineutrophil cytoplasmic antibodies-associated vasculitides rarely affect the parotid gland, pulmonary artery, breast, or genitourinary organs. involvement of these organs by aav is usually an unexpected fi nding on biopsies performed to exclude other diseases, particularly cancer and infection. churg-strauss granulomas, that is, cutaneous extravascular necrotizing granulomas, occurring over the elbow. these lesions may occur in both the churg-strauss syndrome and wegener's granulomatosis, mimicking rheumatoid nodules. fibrinoid necrosis, a pathological hallmark of aav, may be found in a variety of vasculitic (and nonvasculitic) conditions, such as polyarteritis nodosa, scleroderma renal crisis, systemic lupus erythematosus, and malignant hypertension. both vasculitic and necrotizing granulomatous features, which do not invariably coexist, may be confi rmed in lung biopsy specimens. in addition, pulmonary wg frequently demonstrates an extensive, nonspecifi c infl ammatory background. coalescence of such neutrophilic microabscesses leads to extensive regions of "geographic" necrosis. palisading granulomas, scattered giant cells, and poorly formed granulomas may also be found in wg. churg-strauss syndrome typically evolves through three phases, with corresponding pathological fi ndings. in the fi rst phase, allergy, asthma, and other atopic symptoms predominate. in the second, eosinophilic infi ltration occurs in the lung and other organs (eosinophilic pneumonia, eosinophilic gastroenteritis; figure 21c -5). in the third phase, vasculitis ensues. curiously, at the time the vasculitic phase begins, patients' asthma often improves signifi cantly. the histopathological fi ndings in css in the lung include eosinophilic infi ltrates; extensive areas of necrosis (reminiscent of the geographic necrosis in wg); a granulomatous vasculitis of small arteries and veins, associated with striking eosinophilic infi ltration. in contrast to wg and mpa, lymphadenopathy (with overwhelming eosinophilic infi ltration into the lymph nodes), is frequently found in css. the interstitial lung disease of mpa resembles usual interstitial pneumonitis (uip), with the exception that necrosis of the alveolar septae and areas of hemorrhage can occur. more characteristic fi ndings in mpa, however, reveal nonspecifi c infi ltrates or alveolar hemorrhage. vasculitis of the pulmonary capillaries may be diffi cult to prove. renal disease in the aavs is associated with focal, segmental lysis of glomerular tufts, disruption of the basement membrane, and accumulation of fi brinoid material (i.e., fi brinoid necrosis). crescents in bowman's space develop as a result of spillage of infl ammatory mediators across the ruptured glomerular capillaries, accumulation of macrophages, and epithelial cell proliferation. thrombotic changes in the glomerular capillary loops are among the earliest histologic changes. acute tubular necrosis and tubulointerstitial nephritis are also seen commonly. immunofl uorescence studies of renal biopsy specimens demonstrate scant deposition of immunoglobulin and complement, hence the term pauci-immune glomerulonephritis. tissue samples from involved areas of the upper respiratory tract (nose, sinuses, and subglottic region) in wg often reveal only acute and chronic infl ammation. nevertheless, these biopsies are easier to obtain than are biopsies of the lung and kidney. moreover, the combination of these pathological fi ndings (nondiagnostic in and of themselves) and compatible clinical features (e.g., pulmonary nodules and pr3-anca) may yield the diagnosis in some cases. upper respiratory tract biopsies are therefore worth undertaking in patients with significant upper respiratory involvement. eosinophilic infi ltration of a salivary gland in a patient with the churg-strauss syndrome. the arrows in panel b indicate the formation of a churg-strauss granuloma, with multinucleated giant cells, palisading histiocytes, and scattered eosinophils. proteinase-3, a 29-kda serine protease, is found in the azurophilic granules of neutrophils and peroxidase-positive lysosomes of monocytes. mpo, which constitutes nearly 5% of the total protein content of the neutrophil, is localized to the same cellular compartments as pr3. the protein is a covalently linked dimer with a molecular weight of 140 kda. the autoantibodies directed against pr3 and mpo are directed against multiple epitopes. sera from different patients may recognize different epitopes. all anca, however, recognize restricted epitopes of pr3 involving its catalytic site. two types of assays for anca-immunofl uorescence and enzyme immunoassay-are now in common use. capture enzyme immunoassays may offer some advantages over the more widely available tests, but are currently performed only in specialty centers. with immunofl uorescence, three principal patterns of fl uorescence are recognized: the cytoplasmic (c-anca), perinuclear (p-anca), and "atypical" patterns. in patients with vasculitis, the c-anca pattern usually corresponds to the detection of pr3-anca by enzyme immunoassay. the combination of a c-anca pattern on immunofl uorescence testing and pr3-anca is associated most strongly with wg. the p-anca pattern, which usually corresponds to the presence of mpo-anca in vasculitis patients, occurs in approximately 10% of patients with wg, but is more typical of mpa, the css, and renal-limited vasculitis. the great majority of patients with drug-induced aavs are p-anca positive, often with very high titers of mpo-anca. regardless of the immunofl uorescence pattern, positive immunofl uorescence assays should be confi rmed by the performance of enzyme immunoassays for the specifi c antibodies associated with vasculitis: pr3-and mpo-anca. even for c-anca, the positive predictive value for wg is only in the range of 45% to 50% (12, 13) . despite advances in anca testing techniques, the cornerstone of diagnosis in wg remains the rigorous interpretation of histopathological specimens within the overall clinical context. when biopsy specimens are nondiagnostic, anca assays provide an important adjunct to diagnosis (table 21c-4 ). in the proper clinical setting, a positive anca assay greatly increases the likelihood that a form of aav is present. most series indicate that up to 10% to 20% of patients with active, untreated wg are anca negative. for patients with limited wg, 30% or more of patients lack anca. approximately 70% of patients with mpa and 50% of those with css (higher in some series) have anca. positive anca serologies are extremely useful in suggesting the diagnosis in the proper clinical setting. positive immunofl uorescence assays without confi rmatory enzyme immunoassays for anti-pr3 or anti-mpo antibodies are of limited utility. histopathology remains the gold standard for diagnosis in most cases. negative anca assays do not exclude anca-associated vasculitis because between 10% and 50% of patients with anca-associated vasculitis (depending on the particular disease) may be anca-negative. persistence of anca in the absence of clinical indications of active disease does not indicate a need for continued treatment. in a patient who was anca-positive during active disease, persistent anca-negativity provides reassurance-but no guarantee-that the disease is not active. if disease fl ares occur in such patients, they are usually limited. a patient who becomes anca-positive again following a period of clinical quiescence associated with negative anca assays may be at an increased risk for a disease fl are. the temporal correlation between the return of anca and a disease fl are, however, is poor. treatment of anca-associated vasculitis should never be predicated upon anca serologies or titers alone. abbreviations: anca, antineutrophil cytoplasmic antibody; mpo, myeloperoxidase; pr3, proteinase 3. in general, anca titers have imperfect correlations with disease activity. in one study, the positive predictive value of a rise in anca titers as measured by immunofl uorescence was only 57% in a prospective study, compared with 71% for enzyme immunoassay (14) . moreover, among patients with an elevation of anca titers measured by enzyme immunoassay, only 39% suffered disease fl ares within 6 months. a more recent prospective study (15) showed that increases in pr3-anca levels did not predict disease relapses. the proportion of patients who relapsed within 1 year following an increase in anca levels was only 40%. although some studies suggest that a rise in anca titer is a risk factor for a fl are, the temporal relationship between a rise in anca titers and the development of disease activity requiring treatment is very poor, with months to years between these two events. thus, the adjustment of immunosuppressive medications based solely on the rise or fall of anca titers is never justifi ed. the aavs are complex disorders mediated by the immune system in which tissue injury results from the interplay between an initiating infl ammatory event and a highly specifi c pathogenic immune response (i.e., the production of anca) to previously shielded epitopes of neutrophil granule proteins. ancas produce tissue damage via interactions with primed neutrophils and endothelial cells. the hypothesis, supported strongly by in vitro evidence, is that the antibodies induce a necrotizing vasculitis by inciting a respiratory burst and degranulation of leukocytes (neutrophils and monocytes), leading to endothelial injury. the initial events in the process require the priming of leukocytes by cytokines and perhaps other stimuli, leading to the expression of pr3 and mpo on the cell surface. the effects of ancas are determined by the state of neutrophil activation. ancas may constitutively activate primed neutrophils and promote binding of the primed neutrophils to the vascular endothelium, degranulation, and the release of neutrophil chemoattractants, hence creating an autoamplifying loop. there is now substantial evidence that ancas are directly involved in the widespread tissue damage that is the hallmark of the aavs. recombinant activating gene 2 (rag-2)-defi cient mice that receive anti-mpo antibodies develop clinical features consistent with aav, including crescentic glomerulonephritis and sys-temic necrotizing vasculitis (16) . in humans, the evidence is indirect. propylthiouracil is known to accumulate within neutrophil granules and may lead to a druginduced aav (17) , possibly by increasing the immunogenicity of mpo (leading to the characteristically high titers of mpo-anca seen in this disease). in addition to anca, multiple other elements of the immune system participate in the pathophysiology of these diseases. if the autoantibody response leading to anca production follows the exposure of a cryptic epitope, epitope spreading may then generalize the antibody response to the rest of the molecule. this hypothesis implies a prominent role for the t cell in the pathogenesis of the aavs. moreover, most patients with aavs produce isotype-switched igg anca, implying a secondary immune response driven by t cells. growing evidence, particularly data from clinical studies (18) , now also implicates b cells as important participants in the infl ammation of aav. as the precursors of plasma cells (which produce anca), b cells now seem a logical therapeutic target in aav. in addition to disrupting anca production, however, interference with b-cell function may also ameliorate aav by disabling critical b cell/t cell interactions, by removing the antigen presenting function of b cells, and perhaps other mechanisms. b-cell depletion is the focus of ongoing randomized trials involving patients with wg and mpa. the pathophysiology of css likely bears many similarities to that of wg and mpa, albeit anca are less common in css. in the css, however, relatively little is currently understood about the special role played by the eosinophil in that disease. because of their multiorgan system nature, the differential diagnosis of aav is lengthy. one frequently challenging task is the differentiation of these diseases from other forms of vasculitis. indeed, clear distinctions are often impossible between wg and mpa, because granulomatous infl ammation is not detected on all biopsy specimens from patients with wg. distinguishing the aavs from other forms of vasculitis is often more critical because the specifi c treatments differ according to diagnosis. in addition, the aavs must be distinguished from a host of other disorders associated with infl ammation and multiorgan system dysfunction. the differential diagnosis of aav is shown in table 21c-5. churg-strauss syndrome has an additional major branch of its differential diagnosis because of the eosinophilia associated with the disease. allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, eosinophilic gastroenteritis, eosinophilic fasciitis, the hypereosinophil syndrome, and eosinophilic leukemias must all be excluded. current choices for treatment in wg are based on the classifi cation of patients into the categories of either severe or limited disease (19) . severe wg constitutes an immediate threat either to the function of a vital organ or to the patient's life. conversely, limited wg consists of disease manifestations that do not pose such threats. the practical distinction between severe and limited disease is that under the current standard of care the diagnosis of severe wg mandates the use of cyclophosphamide, whereas milder therapeutic approaches may be appropriate and should be considered for limited disease. the treatment of mpa parallels very closely that of severe wg. because of the propensity of mpa to involve major organs (lungs, kidneys, peripheral nerves) in a severe fashion, limited forms of the disease are recognized less often. some cases of css can be treated with glucocorticoids alone, but those with vasculitic neuropathy, life-threatening pulmonary involvement, and other sobering organ involvement require cyclophosphamide from the outset of therapy. in treating severe aav, the standard approach now is to employ cyclophosphamide [e.g., 2 mg/kg/day, adjusted for renal dysfunction (20) ] for 3 to 6 months. some experts prefer intermittent (intravenous) regimens of cyclophosphamide (e.g., 500-750 mg/m 2 every month). no data yet available strongly endorse one cyclophosphamide regimen over another. remission induction with cyclophosphamide is usually followed by longer periods of remission maintenance therapy with either azathioprine (11) or methotrexate (21) . for patients who demonstrate propensities to fl are, long-term use of the least toxic drug for the maintenance of remission may be appropriate. this may include methotrexate or azathioprine and, for patients with recurrent disease fl ares, low doses of prednisone (e.g., 5 mg/day). the optimal length of treatment with methotrexate or azathioprine is not clear, but continuation of these medications for at least 1 year after remission is reasonable in most patients. tumor necrosis factor inhibition (or at least etanercept) does not appear to be effective in wg (22) , and its use in combination with cyclophosphamide may heighten the risk of solid malignancies substantially (23) . among patients with limited wg, remission is induced in approximately three fourths of patients with the use of methotrexate (up to 25 mg/week) and glucocorticoids alone. patients treated with methotrexate and glucocorticoids must be observed carefully for breakthrough disease, particularly glomerulonephritis. the use of trimethoprim-sulfamethoxazole as a treatment for wg has fallen increasingly into disfavour. the use of trimethoprim-sulfamethoxazole alone for the treatment of active wg is not appropriate. the medication may have some role in remission maintenance for patients with upper respiratory tract disease, however, its effi cacy is uncertain and its mechanism of action unclear. a wide array of other therapies, such as plasmapheresis, intravenous immunoglobulin, mycophenolate mofetil, and lefl unomide, have been employed in small numbers of patients, but so far there are insuffi cient data to judge their effi cacy. rituximab and other strategies for b-cell depletion are now being tested. interferonalpha has been reported to have some benefi t for css. once scarring and fi brosis are well established in the subglottic region, airway narrowing may be due to the progression of scar tissue rather than to wg-related infl ammation. in such cases, subglottic stenosis responds poorly to immunosuppressive therapy, and the most effective therapeutic approach to this problem is laryngoscopic dilatations of the airway, augmented by intralesional corticosteroid injections (24) . serial procedures are often required. if severe subglottic stenosis precludes a safe dilatation procedure, a patent airway should fi rst be secured by a tracheostomy. wg often leads to chronic nasosinus dysfunction. regardless of disease activity, most patients require multiple daily saline irrigations to minimize the accumulation of secretions and crusts, and to reduce the incidence of secondary infections. persistent or recurrent infections may require surgical drainage. distinguishing between worsening sinus disease caused by active wg and superinfection may be diffi cult. in the absence of a prompt response to antibiotics, surgical drainage and biopsy are often required for a more defi nitive diagnosis. in contrast to the situation in the fi rst 40 years following the descriptions of the aavs, these diseases are now highly treatable. unfortunately, disease relapses are a major threat. mpa and the css are somewhat less likely than wg to fl are after the achievement of remission. the percentages of patients with those diseases who suffer disease fl ares after appropriate courses of treatment have been estimated to be about 25% to 40%. even with therapy, mortality and morbidity are substantial. in a cohort of 158 patients followed at the national institutes of health (nih) from the late 1960s through the early 1990s (9), 12% of deaths were due to either the disease or complications of treatment, and 86% suffered permanent disease-related morbidity, including chronic renal insuffi ciency (42%), end-stage renal disease requiring dialysis (10%), hearing loss (35%), nasal deformity (28%), tracheal stenosis (13%), and visual loss (8%). many patients incurred more than one type of permanent morbidity. in a more recent retrospective study of 246 patients with anca-associated renal vasculitis (25), cumulative patient survival at 5 years was 76%. there was an 18% mortality rate at 1 year, however, with infections as a major cause of death. in this cohort, mortality was associated with age older than 60 years, the development of end-stage renal failure, and an initial serum creatinine level greater than 2.26 mg/dl. in the wegener's granulomatosis etanercept trial (wget) (22) , although >90% of all patients achieved at least a transient disease activity score of zero, fewer than 50% of patients achieved and maintained these disease remissions over the mean 22-month course of follow-up on treatment. thus, although remissions are achieved in most patients with wg, relapse remains a major threat. furthermore, 89% of the patients enrolled in the wget had sustained at least one item of damage from the disease or treatment within 1 year of enrollment (26) . the most common items of damage recorded were hearing loss (26%) and proteinuria (19%). much of the morbidity in the aavs relates to prolonged courses of immunosuppression, particularly the need to re-treat patients who suffer multiple relapses. in the 1229 patient-years of follow-up in the nih series, only 46% of these years were spent in remission. serious infections occurred in 46%. other morbidities included drug-induced cystitis caused by cyclophosphamide (43%), increased risk of malignancy (particularly bladder cancer, leukemia, and lymphoma), infertility (57% of women with childbearing potential), and a host of side effects related to the use of glucocorticoids. pathogenic immune complexes formed between antigen and antibodies tend to occur during periods of antigen excess. when the immune complexes precipitate into the tissues, they fi x complement, leading to an intense immune reaction. in immune complex vasculitis, immune complexes deposit in the vascular endothelium or in capillary beds, such as those found in the skin, kidneys, or lungs. the most common skin manifestation of small vessel vasculitis is palpable purpura. hypersensitivity vasculitis is characterized by immune complex deposition in capillaries, postcapillary venules, and arterioles. the usual causes are either medications (e.g., penicillins, sulfonamides, or cephalosporins) or infections. cryoglobulinemic vasculitis is usually caused by hepatitis c infections. the antigens involved in cryoglobulinemic vasculitis are portions of the hepatitis c virus (hcv) virion. the relevant antibodies are both igg and igm, leading to the designation "mixed" cryoglobulinemia. henoch-schönlein purpura is associated strongly with iga deposition within blood vessel walls. hypocomplementemic urticarial vasculitis has many features that overlap with systemic lupus erythematosus. exposure to a foreign antigen activates an adaptive immune response that leads to the production of antigen-specifi c antibodies. the combination of antibody with antigen creates immune complexes that neutralize the foreign antigen, and allow it to be cleared safely by the reticuloendothelial system. this complex system, however, contains within it the potential for failure. if the antibody response is just right, these immune complexes may escape early detection, and instead imbed themselves into joints and blood vessels. these immune complexes can then activate complement, leading to local infl ammation. immune complexes deposited in the kidneys, for example, create glomerulonephritis (1). those deposited in the synovium lead to arthritis. if the immune complexes are found in the blood vessels, vasculitis is the result. in pathology, the word vasculitis describes infl ammation within blood vessel walls. this process frequently leads to cellular destruction, damage to the vascular structures, and compromise of blood fl ow to organs supplied by the involved vessels, resulting in organ compromise. several forms of vasculitis are the direct result of immune complex deposition. this chapter outlines several examples of immune complex-mediated vasculitis and highlights some common themes. in 1903, maurice arthus noted that intradermal injection of a rabbit with horse serum resulted in a cutaneous infl ammatory reaction that evolved into localized tissue necrosis (2). the reaction was faster, he observed, if the animal had been previously exposed to horse serum. this response, now known as the arthus reaction, forms the basis of our understanding of immune complexmediated diseases. in the arthus model, injection of the horse serum leads to immune complex formation that initiates complement activation and an infl ux of infl ammatory cells. in the areas of most intense infl ammation, in situ thrombosis formation can lead to tissue ischemia and hemorrhagic infarction. in general, immune complexes are not pathogenic. their immunogenicity is governed by a large number of factors, including antigen load, antibody response, the effi ciency of the reticuloendothelial system in the clear-ance of immune complexes, physical properties of the blood vessels (including fl ow dynamics and previous endothelial damage), and the solubility of the immune complexes themselves. immune complex solubility is determined by the ratio of antibody to antigen. when antibody and antigen are present in equal proportion, large immune complexes are formed, which are identifi ed easily and removed by the reticuloendothelial system. when there is an excess of antibody, small immune complexes are formed, which remain in solution, and do not elicit an immune response. when there is a slight excess of antigen, however, the immune complexes precipitate from solution, and become trapped in characteristic areas-either the capillary beds (such as those found in the skin, kidneys, or lungs), or the endothelium of medium-sized blood vessels previously damaged by turbulent blood fl ow. when the immune complexes precipitate into the tissues, they fi x complement, leading to an intense immune reaction. complement fi xation and local infl ammation recruit neutrophils, which attempt to engulf the immune complexes. during this process, the neutrophils degranulate, releasing lysosomal enzymes and oxygen free radicals that cause tissue necrosis. the inciting antigen can be from numerous sources. in infective endocarditis, the antibody response, formed against bacterial antigens, can lead to painful cutaneous lesions known as osler nodes. in systemic lupus erythematosus (sle), antibodies form against nuclear components (e.g., dna and histones) that are released during tissue injury. certain forms of malignancy can be associated with immune complex formation, with antibodies directed against tumor-associated antigens. immune complexes may also form in response to a large number of drugs, including penicillin and sulfonamides. hypersensitivity reactions were fi rst noted in patients who were treated with antitoxin derived from horse serum. such patients developed an antibody response to the horse antigens, which led to a characteristic syndrome of fever, joint pain, and rash now known as serum sickness. hypersensitivity vasculitis refers to a heterogeneous group of syndromes (including serum sickness and druginduced vasculitis) characterized by immune complex deposition in capillaries, postcapillary venules, and arterioles. this is the most common form of vasculitis. although multiple agents have been implicated, including penicillins, sulfonamides, and cephalosporins, the inciting agent cannot always be identifi ed. the presence of three or more criteria has a sensitivity of 71% and specifi city of 84% for the diagnosis of hypersensitivity vasculitis. hypersensitivity vasculitis that occurs without systemic manifestations is sometimes referred to as cutaneous vasculitis or cutaneous leukocytoclastic angiitis. the term serum sickness, on the other hand, is reserved to describe a systemic illness, including rash and arthralgias, which occurs 1 to 2 weeks after exposure to a drug or foreign antigen. most patients with hypersensitivity vasculitis will develop cutaneous manifestations, the most common of which is purpura ( figure 21d-1) . these lesions are distributed usually in a symmetric fashion over dependent regions of the body, particularly the lower legs (and, in recumbent patients, over the buttocks) because of the increased hydrostatic pressure in such areas. purpuric lesions are not always palpable to the touch. the term palpable purpura is essentially synonymous with small vessel vasculitis, but does not necessarily imply an immune complex-mediated pathophysiology; pauciimmune forms of vasculitis, such as wegener's granulomatosis, microscopic polyangiitis, and the churg-strauss syndrome, for example, may present with identical skin fi ndings (see chapter 21c). biopsy is the diagnostic method of choice. cutaneous biopsies are associated with low morbidity, and are generally suffi cient to confi rm one's clinical suspicion. light microscopy examination of a hematoxylin and eosin (h&e) preparation will demonstrate an infl ammatory infi ltrate primarily composed of mononuclear or polymorphonuclear cells, as well as telltale signs of small vessel vasculitis: leukocyte diapedesis, karyorrhexis, and leukocytoclasis. although h&e preparations are adequate for confi rming the presence of vasculitis, they often provide insuffi cient data for a precise diagnosis. in cases of immune complex-mediated vasculitis, direct immunofl uorescence (dif) studies on the biopsy demonstrate the types of immunoreactants (i.e., immunoglobulin and complement proteins) present at the site of disease. although direct immunofl uorescence requires a biopsy of a second cutaneous site, this procedure is critical in many cases to differentiating the array of conditions associated with cutaneous vasculitis. biopsy is especially useful to exclude other causes of vascular injury, including embolism and hypercoagulability states, which may demonstrate evidence of erythrocyte extravasation but not immune complex deposition. of course, the presence of small vessel vasculitis does not always confi rm the presence of a primary autoimmune disease; malignancy, for example, can also be associated with leukocytoclastic vasculitis. all biopsies, therefore, must be evaluated in the appropriate clinical context. removal of the inciting agent is the only reliable therapy. in patients who have been exposed to multiple medications, determining the inciting agent may be diffi cult, and may require withdrawal of multiple agents simultaneously until the syndrome clears, typically in 1 to 2 weeks. immunosuppression with glucocorticoids should be reserved for patients with particularly fulminant disease, and may be discontinued usually within several weeks. the prognosis for patients with hypersensitivity vasculitis depends on the nature of the inciting agent. in the case of drug-induced vasculitis, multiple agents may need to be discontinued and re-introduced gradually. approximately half of cases of isolated cutaneous angiitis do not have an obvious cause. many such cases are associated with a relapsing and remitting course, but remain restricted to the skin and do not mandate aggressive immunosuppressive therapy. in 1933, wintrobe and buell noted that when serum from a patient with a hyperviscosity syndrome due to multiple myeloma was held at temperatures less than 37°c, a protein precipitate formed (4). in 1947, this "cold precipitable serum globulin" was referred to for the fi rst time as a "cryoglobulin." cryoglobulins are immune complexes that are characterized by their tendency to precipitate from serum under conditions of cold. cryoglobulins, detectable to a varying degree in a wide array of infl ammatory conditions, are not invariably pathogenic. in some patients, however, cryoglobulins deposit in the small-and medium-sized blood vessels and activate complement, leading to cryoglobulinemic vasculitis (5) . three major types of cryoglobulinemia are recognized, defi ned by the specifi c kinds of immunoglobulins with which they are associated. type i cryoglobulinemia, characterized by a monoclonal gammopathy (generally igg or igm), can be associated with waldenström's macroglobulinemia or, less frequently, multiple myeloma. type i iga cryoglobulinemia has also been described, although this is quite rare. in contrast to the monoclonal nature of type i cryoglobulinemia, type ii and type iii cryoglobulinemias are known as "mixed" cryoglobulinemias because they are comprised of both igg and igm. in most cases of type ii cryoglobulinemia, more than 90% of which are caused by hepatitis c infections, the cryoproteins consist of monoclonal igm and polyclonal igg. cases of type ii cryoglobulinemia not associated with hepatitis c infections are sometimes termed "mixed essential" cryoglobulinemia. such cases may be associated with a still undefi ned viral infection. type iii cryoglobulinemia, typically associated with polyclonal igg and polyclonal igm, is associated with many forms of chronic infl ammation, including infection and autoimmune disease. not every form of cryoglobulinemia fi ts neatly into this classifi cation system; cryoglobulins can, for example, have an oligoclonal antibody component. type i cryoglobulinemia rarely presents with signs and symptoms of vasculitis. when symptomatic, type i cryoglobulinemia may be associated with a hyperviscosity syndrome that can lead to serious neurologic manifestations, including dizziness, confusion, headache, and stroke. type i cryoglobulinemia can also be associated with other evidence of vascular stasis, including livedo reticularis, acrocyanosis, and digital gangrene ( figure 21d-2) . type ii and type iii cryoglobulinemias often present with a triad of signs and symptoms: purpura, arthralgias, and myalgias. the purpura may be extensive and confl uent, and sometimes involves the trunk, upper extremities, and even the face (albeit in most cases the rash is confi ned to the lower extremities). other common organ system involvement, more common in type ii than in type iii cryoglobulinemia, includes membranoproliferative glomerulonephritis ( figure 21d-3) , peripheral neuropathy, and cutaneous ulcerations (the result of medium vessel vasculitis, in contrast to the smallsized vessel involvement that leads to purpura). biopsy of an affected organ (such as the skin or kidney) may be the most straightforward method of confi rming the diagnosis. light microscopy of purpuric lesions demonstrates leukocytoclastic vasculitis. direct immuno fl uorescence studies reveal various types of immunoglobulin and complement deposition, depending on cryoglobulinemia type. in type ii cryoglobulinemia, for example, direct immunofl uorescence reveals igg and igm deposition, as well as complement components. renal biopsies from patients with glomerulonephritis caused by cryoglobulinemia reveal a membranoproliferative glomerulonephritis that must be distinguished from lupus nephritis (another disorder in which immune complexes play a major role). if biopsy is impractical or impossible, serologic testing may be helpful. the most directly relevant test is a serum cryoglobulin assay, which can give a direct sense of the burden of disease. the serum is allowed to remain at 4°c for several days before interpretation. the percentage of the serum occupied by the cryoprecipitate is commonly referred to as the cryocrit, and may be useful for following such patients longitudinally. serum cryoglobulin tests are, unfortunately, notoriously diffi cult to obtain, largely because the collection apparatus must be prewarmed and the blood must be allowed to clot at 37°c before processing. falsenegative assays for cryoglobulins are common, particularly in laboratories not experienced in the collection and processing of samples. for patients with type ii and type iii cryoglobulinemia, nonspecifi c serologic testing may also heighten suspicion. first, a strong clue to the presence of mixed cryoglobulinemia is an extremely low (to almost undetectable) level of c4. for reasons that are not entirely clear, c4 levels are lowered out of proportion to the decrease observed in c3. second, the monoclonal component of type ii cryoglobulins almost invariably has rheumatoid factor activity (i.e., binds to the fc portion of igg). thus, essentially all patients with type ii cryoglobulinemia are rheumatoid factor-positive-usually strikingly so. in many cases, rheumatoid factor tests are a more reliable screening test for type ii cryoglobulinemia than are assays for cryoglobulins themselves. although rheumatoid factor titers correlate with immunoglobulin burden in such patients and can be used in longitudinal follow-up in a manner similar to the cryocrit, the level of clinical symptomatology often correlates poorly with both rheumatoid factor level and cryocrit. once patients have achieved a state of disease quiescence following treatment, both rheumatoid factor levels and cryocrit often remain elevated. neither should be used as a gauge of therapy for most patients. finally, acute-phase reactants such as the erythrocyte sedimentation rate and the c-reactive protein are elevated in many patients with cryoglobulinemia. in patients with type i cryoglobulinemia, for example, the erythrocyte sedimentation rate may be even higher than anticipated because of the excess circulating immunoglobulin. treatment of the underlying cause of the cryoglobulins is the only approach that may lead to long-term response. immunosuppression alone will not be suffi cient to treat a cryoglobulinemic vasculitis that is driven by malignancy or chronic infection. in the case of hepatitis cassociated cryoglobulinemic vasculitis, for example, the optimal therapy consists of the effective control of the underlying viral infection (typically with interferonalpha and ribavirin). in patients who experience severe consequences of cryoglobulinemia (such as mononeuritis multiplex, glomerulonephritis, or other forms of tissue necrosis), immunosuppression with high dose glucocorticoids and cyclophosphamide may be necessary to prevent further damage. in patients with rampant systemic vasculitis, anecdotal evidence suggests that the systemic infl ammation should be controlled fi rst with glucocorticoids and other immunosuppressive agents, as appropriate, before the institution of antiviral therapy. in some cases of fl agrantly active vasculitis, the introduction of antiviral therapy fi rst is believed to have triggered disease exacerbation through an unfavorable alteration of the antigen/antibody ratio. the prognosis of patients with cryoglobulinemia generally depends on the underlying cause. the outcome of type i cryoglobulinemia relates closely to the effi cacy in treating the cause of the cryoglobulin. type ii cryoglobulinemia secondary to hepatitis c may be treated effectively if the viral infection is responsive to therapy. if patients do not tolerate antiviral therapy well or if the treatment is ineffective, however, some patients may require low-to-moderate doses of prednisone to control the disease. type iii cryoglobulinemia is frequently a response to an infl ammatory event (such as infection), and may not require specifi c therapy. henoch-schönlein purpura (hsp) is an immune complex-mediated form of small vessel vasculitis that is associated strongly with iga deposition within blood vessel walls. many cases of hsp are reported to occur after upper respiratory tract infections. group a streptococci, mycoplasma, epstein-barr virus, varicella, and other infectious agents have all been implicated in the pathogenesis of this disease, but the true etiology remains unknown. in 1990, the american college of rheumatology proposed the following criteria for the classifi cation of hsp (6): • palpable purpura • age ≤ 20 years at disease onset • bowel angina • granulocytes in arteriole or venule walls on biopsy meeting two of four criteria is associated with a sensitivity of 87% and a specifi city of 88% for this diagnosis. the hallmarks of hsp include an upper respiratory tract infection followed by a syndrome characterized by a purpuric rash, arthralgias, abdominal pain, and renal disease. hsp is usually viewed as a disease of childhood and, indeed, the majority of cases affect children younger than 5 years of age. adults, however, can also be affected by hsp, and have a greater tendency toward prolonged disease courses (with recurrent bouts of purpura) than do children (7) . colicky abdominal pain, presumably secondary to gastrointestinal vasculitis, is a common characteristic of hsp, and frequently occurs within a week after the onset of rash. occasionally the abdominal pain in hsp occurs before the onset of purpura, and may be diffi cult to distinguish from an acute abdomen. endoscopy may demonstrate purpura in the upper or lower intestinal tract. mild glomerulonephritis is common and generally self-limited, although some patients will develop end-stage renal disease. in children with mild manifestations, the clinical history alone may be suffi cient to confi rm the diagnosis. in more serious cases or when there is suffi cient doubt about the diagnosis, biopsy of an involved organ is essential. unlike other forms of immune complex-mediated disease, however, direct immunofl uorescence will reveal fl orid iga deposition. in the proper clinical setting, this fi nding is diagnostic of hsp. other forms of small vessel vasculitis may have small quantities of iga within blood vessels, but iga is not the predominant immunoreactant in such cases. in mild cases of hsp, no specifi c therapy is necessary. even for patients with glomerulonephritis, it has been diffi cult to demonstrate that treatment with glucocorticoids or immunosuppressive agents signifi cantly alters outcomes. despite this, it may be prudent to treat aggressive renal involvement with an immunosuppressive regimen, including high-dose glucocorticoids and another immunosuppressive agent such as cyclophosphamide, azathioprine, or mycophenolate mofetil, depending on disease severity (8) . in patients with renal involvement, anecdotal evidence suggests that plasmapheresis and intravenous immunoglobulin may also be benefi cial, particularly in patients who are refractory to standard immunosuppressive regimens. recurrences of skin disease, often comprised of multiple episodes occurring over many months, are not unusual. generally, however, even in patients with recurrent disease, the rule is for the disorder to subside and to resolve completely over a few months to a year. in a minority of patients, some evidence of permanent renal damage persists in the form of proteinuria and hematuria. only a small minority, probably well under 5%, develop renal failure as a result of hsp. the study of urticaria is hampered by multiple terms that sound similar but describe different types of diseases. the word urticaria is most frequently used to describe acute urticaria, an ige-mediated hypersensitivity reaction to a variety of stimuli, including medications, infection, and other triggers. acute urticaria manifests as pruritic wheals that resolve days after the allergen is removed. chronic urticaria is an autoimmune condition that is probably driven by an autoantigen. this form of urticaria may require immunosuppressive therapy in addition to antihistamines to prevent recurrence (9) . urticarial vasculitis describes a form of small vessel vasculitis that is characterized by the appearance of urticarial wheals. normocomplementemic urticarial vasculitis is most often simply an example of hypersensitiv-ity vasculitis in which the principal skin manifestation is urticaria. normocomplementemic urticarial vasculitis tends to be self-limited, as is the case with hypersensitivity vasculitis. in contrast, urticarial vasculitis associated with hypocomplementemia is much more likely to constitute a signifi cant and persistent clinical problem. two categories of urticarial vasculitis associated with hypocomplementemia are recognized. the distinctions between these two categories are not always sharp, and both categories also share a number of features with systemic lupus erythematosus. the fi rst category, known simply as hypocomplementemic urticarial vasculitis, refers to cutaneous vasculitis associated with low levels of serum complement (c3 and c4). the diagnosis of hypocomplementemic urticarial vasculitis is predicated upon the exclusion of other disorders that may present in a similar fashion, particularly cryoglobulinemia and sle. the second category-a more specifi c but still loosely defi ned entity known as the hypocomplementemic urticarial vasculitis syndrome (huvs)-consists of the constellation of low complement levels and urticaria for a period of at least 6 months, as well as some or all of the following: arthritis, glomerulonephritis, uveitis, angioedema, chronic obstructive pulmonary disease, pleurisy, or pericarditis. although the lesions associated with chronic urticaria and urticarial vasculitis are similar in appearance, certain differences help differentiate these two conditions. in urticarial vasculitis, the urticaria typically have a purpuric quality, indicative of small blood vessel damage and red blood cell extravasation ( figure 21d-4) . unlike common urticaria, the lesions of urticarial vasculitis are frequently associated with moderate pain, burning, and tenderness, in addition to pruritus. whereas common urticaria typically resolve completely within 24 to 48 hours, the lesions of urticarial vasculitis may take days to resolve completely and often worsen without therapy. arthralgias and myalgias are common in urticarial vasculitis. as noted above, patients with huvs may also develop glomerulonephritis, pulmonary manifestations (particularly obstructive airway disease), and other fi ndings. gastrointestinal, cardiovascular, and neurologic manifestations are uncommon, but have been reported. there is striking overlap between huvs and sle, and patients will frequently have characteristics of both, although angioedema and copd are more common in huvs. biopsy of an urticarial wheal in uv will demonstrate evidence of leukocytoclastic vasculitis, including injury to the endothelial cells of the postcapillary venules, erythrocyte extravasation, leukocytoclasis, fi brin deposition, and a perivascular neutrophilic (or less commonly, lymphocytic) infi ltrate. direct immunofl uorescence demonstrates immune complex deposition around blood vessels in the superfi cial dermis and striking deposition of immunoglobulins and complement along the dermal-epidermal junction ( figure 21d-5) . the "interface dermatitis" is identical to that observed in lupus-a histopathological fi nding termed the lupus band test. in the proper setting, these fi ndings (interface dermatitis as well as immunoreactant deposition within blood vessels) are diagnostic of hypocomplementemic urticarial vasculitis. huvs, in contrast, is a clinical diag-nosis based not only on the presence of urticarial vasculitis but also the occurrence of typical features in extracutaneous organ systems. some cases of hypocomplementemic urticarial vasculitis respond to therapies commonly used for the treatment of sle, including low-dose prednisone, hydroxychloroquine, dapsone, or other immunomodulatory agents. there is anecdotal evidence that antihistamines, calcium channel antagonists, doxepin, methotrexate, indomethacin, colchicine, and pentoxifylline are effective in some cases. serious cases, particularly those presenting with glomerulonephritis or other forms of serious organ involvement, may require treatment with high doses of glucocorticoids and cytotoxic agents. both chronic obstructive pulmonary disease (copd) and cardiac valvular abnormalities are associated with huvs, and may require specifi c treatment as well. the prognosis of huvs is frequently linked to the disorder with which it is associated. sle, copd, angioedema, and valvular abnormalities are all known to occur in association with this disorder, and in such cases, may strongly infl uence both quality and quantity of life. the immune complex-mediated vasculitides are a clinically heterogeneous group of disorders linked by ineffi cient, defective, or dysregulated clearance of immune complexes by the reticuloendothelial system. biopsy of an involved organ is frequently helpful in establishing the diagnosis. direct immunofl uorescence studies of involved blood vessels demonstrate characteristic patterns of immunoglobulin and complement deposition, which may be particularly useful in distinguishing these diseases. the prognosis of patients with immune complex-mediated vasculitis is tied closely to the ability to identify and to treat the underlying cause of the immune response. the prevalence of behçet's disease is highest in countries of the eastern mediterranean, the middle east, and east asia. aphthous oral ulcers are usually the fi rst and most persistent clinical feature of behçet's disease. aphthous ulcers also occur frequently on the genitals (e.g., the scrotum or vulva). uveitis-either anterior or posterior-is common in behçet's disease and a source of major morbidity. many forms of central nervous system disease may occur in behçet's disease. these include aseptic meningitis and white matter lesions in the brainstem. human leukocyte antigen (hla)-b51 is a strong risk factor for behçet's disease. the diagnosis of primary angiitis of the central nervous system is predicated upon either biopsy evidence of vasculitis or angiographic fi ndings suggestive of vasculitis in the setting of other compelling features, for example, strokes demonstrated by magnetic resonance imaging or the fi ndings of a cerebrospinal fl uid pleocytosis. the diagnosis of primary angiitis of the central nervous system should never be made on the basis of an angiogram alone. patients with benign angiopathy of the central nervous system are predominantly female, tend to present acutely with headache (with or without focal symptoms), and have normal or near normal cerebrospinal fl uid. cogan's syndrome refers to the association of infl ammation in both the eyes and ears: specifi cally, the occurrence of nonsyphilitic interstitial keratitis and immune-mediated inner ear disease, resulting in audiovestibular dysfunction. any type of ocular infl ammation may occur in cogan's syndrome (e.g., scleritis, uveitis, orbital pseudotumor). the inner ear disease associated with this condition often leads to deafness. in erythema elevatum diutinum, skin lesions consist of purple, red, or brown plaques and often have an annular or nodular appearance. the skin lesions have a predilection for the extensor surfaces of the distal extremities and often overlie joints, but may be generalized. behçet's disease (bd) is a chronic infl ammatory disorder of unknown cause. its manifestations are thought to be caused by an underlying vasculitis. although this disease is recognized worldwide, the prevalence is highest in countries of the eastern mediterranean, the middle east, and east asia, thus the name silk road disease. the disease tends to be more severe in areas where it is more common. prevalence rates in all areas of the world are increasing, probably because of improved recognition and reporting. behçet's disease occurs primarily in young adults. the mean age at onset is between 25 and 30 years. the incidence of disease in males and females with the disease is approximately equal along the silk road, but in japan, korea, and western countries the disease occurs more frequently in women. familial aggregation and juvenile cases are not common. case confi rmation can be challenging because many patients labeled as having behçet's disease have oral ulcers as the primary or sole manifestation. aphthous oral ulcers are usually the fi rst and most persistent clinical feature of bd. lesions occur in crops and some patients may have them during most of the course of the disease. aphthae occur as ulcers that are 2 to 12 mm or larger. these are discrete, painful, round or oval red-rimmed lesions that affect mainly the nonkeratinized mucosa of the cheeks, the border of the tongue, the soft palate, and the pharynx ( figure 21e-1) . oral ulcers are identical to the lesions of recurrent aphthous stomatitis. the severity and behavior of the oral ulcers in bd often fi t the description of complex aphthosis, in which multiple, recurrent, or persisting lesions result in a severe syndrome that may include perianal or genital ulceration. genital ulcers resemble oral aphthae but occur less frequently. they occur as single or multiple lesions of the vulva and in the vagina, or on the scrotum or penile shaft ( figure 21e-2) . genital lesions are usually painful and may result in scarring, but vaginal ulcers may be asymptomatic or only produce a discharge. perianal ulcers may occur. skin lesions are common in bd. the international study group (isg) criteria for the diagnosis of bd (table 21ebd. a neutrophilic infi ltrate is typical of other dermatoses occasionally seen with the disorder, including pyoderma gangrenosum and sweet's syndrome. pathergy is an excessive skin response to trauma, refl ecting neutrophil hyperreactivity, and is highly specifi c for bd. pathergy is suggested if there is a history of red papules, pustules, or sterile abscesses after therapeutic injections, at intravenous catheter sites, or after minor skin trauma. testing for pathergy can be done with a sterile 20-gauge needle, used to penetrate the cleansed skin perpendicularly to a depth of approximately one quarter of an inch, rotated briefl y on its axis, and then removed. after 48 hours, the appearance of an erythematous papule or pustule at the puncture site constitutes a positive test. the volar forearm is usually chosen for the test and sensitivity is greater when three needle punctures are made. the positivity of the test may vary during the course of the disease and is more likely to be positive at times of active disease. the sensitivity of the test is lower in western countries than in silk road countries, but a positive test adds great support for the diagnosis of bd. ocular infl ammation typically follows mucocutaneous symptoms by a few years, but it often progresses with a chronic, relapsing course affecting both eyes. the ocular fi nding in behçet's original patients was anterior uveitis associated with a hypopyon [the accumulation of an infl ammatory cell infi ltrate-essentially pus-in the anterior chamber ( figure 21e-3) ]. anterior uveitis that is not treated promptly with a mydriatic agent may result in synechiae formation between the iris and the lens and permanent papillary distortion. the ocular manifestations of behçet's disease may also include a panuveitis, however, with posterior chamber involvement and retinal vasculitis, the complications of which may extend to visual loss. retinal vasculitis, which leads to episodes of retinal occlusion and areas of ischemia, may be followed by neovascularization, vitreous hemorrhage and contraction, glaucoma, and retinal detachment. the earliest fi ndings of retinal vasculitis may be detected with fl uorescein angiography. isolated optic disk edema in bd suggests cerebral venous thrombosis rather than ocular disease, but papillitis may occur with ocular infl ammation and central nervous system disease. cranial nerve palsies may result from brain stem lesions, and visual fi eld defects may also be caused by intracranial disease involving the optic pathways. with cerebral venous thrombosis, patients usually present with symptoms of intracranial pressure: headache, visual obscurations, and papilledema. magnetic resonance imaging may be used to demonstrate acute or recent clot in the larger dural sinuses, but magnetic resonance venography is more reliable for recognizing clot in the cerebral venous system, especially in the smaller veins and older thromboses. central nervous system symptoms in bd may be due to aseptic meningitis or parenchymal lesions, resulting in focal or diffuse brain dysfunction. an increased protein concentration and lymphocytic pleocytosis in the cerebrospinal fl uid (csf) is supportive of the diagnosis. the clinical combination of stroke, aseptic meningitis with csf pleocytosis, and mucocutaneous lesions can be diagnostic of bd. focal or multifocal nervous system involvement refl ects the predilection of the disease for diencephalon, midbrain, and brainstem ( figure 21e-4) . in contrast to multiple sclerosis, there is hypopyon in the anterior chamber of a patient with behçet's disease, caused by anterior uveitis. brainstem involvement in a patient with behçet's disease. no preference for the periventricular structures (2) . isolated headaches in bd are common but the cause is not well understood. these may represent secondary migraine or may not be related to the disease. large vessel involvement, which occurs in about one fourth of patients with bd, is a major cause of morbidity and mortality (3) . patients with vascular disease often have multiple lesions and involvement of both the arterial and venous systems (4) . deep venous thrombosis (dvt) is the most common large vascular lesion. patients with recurrent dvts are at risk for chronic stasis changes in the legs. occlusions of the vena cava, hepatic, and portal veins, other recognized thrombotic complications in bd, are associated with an increased risk of mortality. chest wall, abdominal, and esophageal varices may occur from deep-seated venous thrombosis. right ventricular thrombi have been reported, usually in association with pulmonary vasculitis. no primary abnormality of the coagulation, anticoagulation, or fi brinolytic system explaining the thrombotic tendency in bd has been identifi ed consistently. arterial complications occur in up to 7% of patients with bd (5). stenoses, occlusions, and aneurysms occur in the systemic circulation or the pulmonary arterial bed. arterial aneurysms, caused by vasculitis of the vasa vasorum, involve the aorta or its branches. the risk of rupture is high. pulmonary artery aneurysms (6) may lead to fi stulae between the pulmonary artery and bronchi, presenting with hemoptysis. anticoagulant treatment for presumed pulmonary emboli can result in massive hemorrhage and death. clinically apparent cardiac vascular involvement is unusual, but may result in myocardial infarction. gastrointestinal symptoms in bd include melena and abdominal pain. colonoscopic lesions appear as single or multiple ulcerations involving primarily the distal ileum and cecum. gastrointestinal lesions have a tendency to perforate or to bleed. the lesions in bd should be differentiated from those of crohn's disease and those due to the use of nonsteroidal antiinfl ammatory drugs. an intermittent, symmetric oligoarthritis of the knees, ankles, hands, or wrists affects one half of the patients with bd; arthralgia is also common. an erosive or destructive arthropathy is unusual. infl ammatory cells of the synovium and synovial fl uid are primarily polymorphonuclear leukocytes. epididymitis occurs in about 5% of affected patients. glomerulonephritis and peripheral neuropathy occur much less frequently in bd than in other forms of systemic vasculitis. aa-type amyloidosis, presenting as nephrotic syndrome, can accompany bd. the occasional association of the disorder with ankylosing spondylitis [in human leukocyte antigen (hla)-b27-positive patients] or relapsing polychondritis (magic syn-drome [mouth and genital ulcers with infl amed cartilage]) likely represents the simultaneous occurrence of two disorders. no laboratory abnormality is diagnostic of bd. acute-phase reactants may be increased, especially in patients with large vessel vasculitis, but they may be normal in other patients, even those with active eye disease. the histocompatibility antigen hla-b51 is associated with bd in areas of high prevalence and in patients with ocular disease. the multiple manifestations of bd in the same patient may be separated in time, occasionally by several years. for defi nitive diagnosis, the manifestations must be documented or witnessed by a physician. the isg criteria for the classifi cation of bd (table 21einfl ammatory bowel disease, sprue, cyclic neutropenia or other hematologic disorders, herpes simplex infection, and acquired immune defi ciency syndrome may cause similar lesions. other disorders responsible for orogenital/ocular syndromes include erythema multiforme, mucous membrane pemphigoid, and the vulvovaginal-gingival form of erosive lichen planus. the differential diagnosis can be clarifi ed with the aid of an experienced dermatologist and biopsy fi ndings. in reiter's disease, mucocutaneous lesions are nonulcerative and painless, and the uveitis is usually limited to the anterior chamber. similarities between bd and crohn's disease include gastrointestinal lesions, fever, anemia, oral ulcers, uveitis, arthritis, thrombophlebitis, and erythema nodosum. granuloma formation in intestinal lesions is not typical in bd, and in crohn's disease the iritis is typically confi ned to the anterior chamber. genital ulcerations and central nervous system disease are rare in crohn's disease. frequent ophthalmologic examinations are essential for patients with ocular disease, and periodic monitoring of the eyes is recommended for all patients. a careful history and examination, with attention to the vascular and neurologic systems, should be part of the physician's assessment. standardized forms for scoring disease activity and ocular infl ammation have been developed for use in clinical trials and the care of individual patients (8) . aphthous lesions are treated with topical or intralesional corticosteroids. an empiric trial of dapsone or methotrexate may be appropriate in diffi cult cases. colchicine is used in the treatment of mucocutaneous manifestations and as an adjunct in the treatment of more serious manifestations (0.6 mg three times daily may be required to achieve a therapeutic effect; many patients suffer gastrointestinal intolerance of the drug at that dose). the effectiveness of colchicine has been demonstrated for genital ulcers and erythema nodosum in females and for arthritis in both sexes (9) . thalidomide has been used for the treatment of mucosal and follicular lesions, but toxicity is a major concern. short courses of prednisone are useful in the management of mucocutaneous disease in some patients. in others, low-dose prednisone as maintenance therapy is required. cyclosporine can be effective for the control of uveitis. a controlled study has demonstrated the value of azathioprine at a dose of 2.5 mg/kg per day in limiting the progression of ocular disease and preventing new eye disease in males. combination treatment with cyclosporine and azathioprine can been used when singleagent treatment has failed. azathioprine can have a benefi cial effect on mucosal ulcers, arthritis, deep venous thrombosis, and long-term prognosis (10) . because young males are at the greatest risk for severe disease, especially uveitis, aggressive treatment is warranted in this disease subset. in open trials, interferon-alpha has been found useful for treating mucocutaneous lesions and arthritis and is emerging as an effective treatment for ocular disease (11) . etanercept, a tumor necrosis factor inhibitor, was shown to be benefi cial for mucocutaneous manifestations in a controlled study (12) . reports of uncontrolled experience with infl iximab for eye infl ammation have been positive, but controlled data are lacking. immunosuppression with chlorambucil or cyclophosphamide is used for uncontrolled ocular disease, central nervous system disease, and large vessel vasculitis, including recurrent deep venous thrombosis. glucocorticoids are useful in suppression of infl ammation in acute phases of the disease, but these agents are insuffi cient by themselves to treat such severe disease manifestations as posterior uveitis or parenchymal brain disease. because of the high risk of rupture, surgical treatment is indicated for systemic arterial aneurysms. glucocorticoids and alkylating agents should also be used to minimize the high risk of anastomotic recurrences or continued disease. pulmonary arterial aneurysms may respond to these same medications, but uncontrolled bleeding requires percutaneous embolization or surgical treatment. cerebral venous thrombosis is treated with anticoagulation and corticosteroids. the treatment of budd-chiari syndrome has included anticoagulants or antiaggregants, colchicine, and glucocorticoids. portocaval shunting should be considered if the inferior vena cava is patent. in many geographic areas, genetic studies have shown a strong association with hla-b51, but the exact role of this gene in the development of bd is uncertain. neutrophilic hyperfunction is recognized in bd, in normal subjects with hla-b51, and in hla-b51 transgenic mice (13) . evidence also exists for antigen-driven immune mechanisms in the pathogenesis of bd. cytokine analysis and cellular characterization suggest a thelper cell (th1) response by lymphocytes in bd. molecular techniques have identifi ed herpes simplex viral rna and dna in cells from patients with bd, and streptococcal antigens have been proposed as triggers of active disease. activated gamma-delta t cells are increased in the circulation and in mucosal lesions, but the precise role of these cells in the pathogenesis of bd is uncertain. peptides from mycobacterial heat shock protein (hsp) and homologous human peptides have been found to stimulate gd+ t cells from patients with bd in a specifi c fashion (14) . cross-reactivity and molecular mimicry between peptides from streptococcal or viral hsp, homologous human hsp, and mucosal antigens may result in selection of autoreactive t cells (15) . more recently, similarities between bd and infl ammatory disorders associated with autoimmunity have been recognized (16) . primary angiitis of the central nervous system (pacns) is a rare form of vasculitis limited to the brain and spinal cord. the term granulomatosis angiitis of the central nervous system was previously applied because of the histopathologic fi ndings observed in arteries from early reported cases. however, an analysis of a larger number of cases supports varied mononuclear cell infi ltrates, with fewer than 50% of cases showing granulomatous infl ammation (17) . anatomically, the angiitis is multifocal and segmental in distribution and involves the small leptomeningeal and intracerebral arteries. in general, the arteries are involved much more frequently than the veins. the disease predominantly affects males. most patients are young or middle-aged, although patients of a broad age range are affected. cases of pacns in children have also been described. the clinical manifestations of pacns are not distinctive. the most common symptom is headache. because virtually every anatomic area of the central nervous system may be affected by the vasculitis, a wide range of neurologic presentations and defi cits may be seen, including transient ischemic attacks (tias), cerebral infarction, paraparesis, quadriparesis, hemiparesis, ataxia, seizures, aphasia, and visual fi eld defects, among others. decreased cognitive function or fl uctuating levels of consciousness are not uncommon. progressive multifocal symptoms over time in a younger patient should suggest the possibility of pacns, particularly in the absence of other risk factors. the spinal cord may occasionally be involved. presentations with subarachnoid or intracerebral hemorrhage are rare. timely diagnosis of pacns is critical, before the occurrence of massive brain damage. preliminary diagnostic criteria for pacns have been proposed (18) but never validated. the diagnosis of pacns is usually predicated upon either biopsy evidence of vasculitis or angiographic fi ndings suggestive of vasculitis in the setting of other compelling features, for example, strokes demonstrated by magnetic resonance imaging or the fi ndings of a cerebrospinal fl uid pleocytosis (17) . histologic confi rmation remains the most specifi c diagnostic procedure for pacns, but the sensitivity of brain biopsy is limited because of the focal segmental distribution of the disease. a negative biopsy does not exclude the diagnosis of pacns, but may be essential to excluding other disorders that mimic pacns clinically. in the absence of histologic confi rmation, a cerebral angiogram typical of vasculitis in the appropriate clinical settings is frequently used to establish the diagnosis of pacns. suggestive angiographic fi ndings include segmental narrowing, dilatation, or occlusion affecting multiple cerebral arteries in the absence of proximal atherosclerotic changes ( figure 21e-5) . the fi ndings of narrowing are, however, highly nonspecifi c, and can be caused by a host of nonvasculitic causes. angiographic fi ndings compatible with vasculitis are commonly encountered in conditions such as vasospasm, central nervous system infection, cerebral arterial emboli, intravascular lymphomatosis, and atherosclerosis. furthermore, the sensitivity of angiography is limited if small vessels beyond its resolution are primarily involved. cerebral angiography has been normal in some biopsy-proven cases. general laboratory tests, including acute-phase reactants such as c-reactive protein and the erythrocyte sedimentation rate, are not useful in the diagnosis of pacns. in addition to being nonspecifi c, in fact, acutephase reactants are known often to be normal even in the setting of biopsy-proven active disease. cerebrospinal fl uid (csf) analysis, however, is an essential part of the diagnostic workup of pacns. the csf fi ndings are abnormal in 80% to 90% of cases documented pathologically. csf fi ndings are characterized by a modest pleocytosis and elevated protein levels. csf analysis should include appropriate stains, cultures, and serologic tests to exclude for cns infections. magnetic resonance imaging (mri) is the most sensitive imaging study in the evaluation of pacns. only rare cases have no mri abnormalities. the most common fi ndings are multiple, bilateral, supratentorial infarcts distributed in the cortex, deep white matter, and/or leptomeninges, but the fi ndings lack specifi city. magnetic resonance angiography (mra) is limited in sensitivity in most cases of pacns. angiographically demonstrable lesions are often beyond the resolution of current mra technology. thus, a normal mra does not rule out the disorder. primary angiitis of the central nervous system is considered a progressive disorder with a fatal course unless treated vigorously with a combination of high-dose glucocorticoids and a cytotoxic agent (usually cyclophoscerebral angiogram in a patient with central nervous system vasculitis. the angiogram reveals multiple segmental stenoses of the a1 and a2 segments of the anterior cerebral artery and the distal segments of the middle cerebral artery. phamide). there are no controlled treatment trials on which to base this standard. the optimal duration of therapy is unknown, but in view of the substantial side effects associated with cyclophosphamide and the successful use of shorter courses of therapy in other forms of vasculitis, a 6-month course of cyclophosphamide followed by an additional 1 year of azathioprine appears reasonable. prednisone should be discontinued in a tapering fashion over 6 to 9 months. the presence of a subset of patients with some features suggesting pacns but demonstrating a more benign course has been suggested (19) . this subset of patients is considered to have a disease entity known as benign angiopathy of the central nervous system (bacns). bacns patients are predominantly female, primarily present acutely with headache, with or without focal symptoms, and have normal or near normal csf analysis. the diagnosis in these cases has been established angiographically and appeared to have a monophasic course with a favorable neurologic outcome. most of these patients recover after only short-term glucocorticoid treatment, often supplemented by a calcium channel blocker to mitigate against vasospasm. cytotoxic agents are not required for patients with bacns. the etiology of the vascular disease in this benign form has not been defi ned clearly, but could be the result of arteritis or reversible vasospasm. the existence of a benign, angiographically defi ned subset, however, remains controversial (20) . recently, we identifi ed a subset of patients presenting with evidence of prominent leptomeningeal enhancement on mri (21) . these patients were characterized by normal cerebral angiography, brain biopsy evidence of vasculitis predominantly affecting the small leptomeningeal vessels, and a good response to corticosteroids and/or immunosuppressive therapy with a favorable neurologic course. cogan's syndrome refers to the association of nonsyphilitic interstitial keratitis ( figure 21e-6 ) and immunemediated inner ear disease, resulting in audiovestibular dysfunction. the disorder affects men and women equally at any age, but typically in their third and fourth decade. presenting manifestations include sudden hearing loss, ménière's-like vertigo and tinnitus, and ocular infl ammation, alone or in any combination (22) . other features of the disease, if not present initially, usually follow within several months. hearing loss is bilateral, shows a downsloping pattern on audiograms, and is often progressive and profound. vestibular testing shows bilateral cochlear dysfunction, helping to distinguish this disorder from ménière's syndrome. in comparison to ménière's syndrome, the damage to hearing from cogan's syndrome is typically more unremitting. scleritis, uveitis, or other infl ammatory conditions of the eye ( figure 21e -7) may be present initially but often patients will subsequently develop interstitial keratitis if not present initially. systemic manifestations include headache, fever, arthralgia, and vasculitis, with or without aortitis. the critical evaluation and monitoring of cogan's patients requires the expertise and collaboration of the treating rheumatologist, otolaryngologist, and ophthalmologist (23) . there are no controlled studies on the treatment of cogan's syndrome. glucocorticoids are used topically for anterior eye disease and systemically for audiovestibular manifestations, unremitting ocular disease, or when the disorder is complicated by vasculitis or significant systemic manifestations. these agents should be started as soon as the disorder is recognized, in adequate doses (at least 1 mg/kg/day), and for a suffi cient duration to initially control the disease or for relapse. documented improvement in 2 to 3 weeks supports a therapeutic response and can be followed by gradual tapering of the dose and use of immunosuppressive agents if necessary for maintenance. the prognosis for hearing in these patients has been poor (22) , but cochlear implants are used successfully in these patients with bilateral deafness. erythema elevatum diutinum (eed) is an extremely rare, chronic, recurrent vasculitis with distinctive clinical and histopathologic features (24,25). the disorder affects both men and women in middle age. individual lesions consist of purple, red, or brown plaques that often have an annular or nodular appearance. the skin lesions of eed have a predilection for the extensor surfaces of the distal extremities and often overlie joints, but may be generalized. older lesions may be dense and coalesce ( figure 21e-8) . erupting lesions may be associated with stinging, burning, or tenderness, and may be accompanied by systemic symptoms. in early lesions, the pathology of eed is one of a leukocytoclastic vasculitis with a perivascular neutrophilic infi ltrate. more mature lesions demonstrate perivascular or onion-skinlike fi brosis. capillary proliferation and cholesterolcontaining histiocytes may also be seen. the differential diagnosis includes other neutrophilic dermatoses, primarily sweet's syndrome. erythema elevatum diutinum has been recognized to occur in association with infections diseases, including human immunodecifi ency virus infection, hematologic disorders (particularly iga gammopathies), and several immune-mediated infl ammatory diseases, including rheumatoid arthritis. treatment of any associated disorder may benefi t eed. dapsone (100 mg/day) has been reported to be successful in some patients. kawasaki's disease (kd), once known as mucocutaneous lymph node syndrome, is a systemic infl ammatory disorder occurring in children that is accompanied by vasculitis and a risk of coronary artery aneurysms. other typical features of kd include spiking fevers, cervical lymphadenopathy, conjunctivitis, erythematous changes on the lips and in the oral cavity, dryness and cracking of the lips, a strawberry appearance to the tongue, and a polymorphous rash. eighty percent of kd cases occur in children less than 5 years of age. attempts to link kd defi nitively to some types of infection, particularly ones associated with superantigens, have thus far been unsuccessful. high dose aspirin and intravenous immune globulin (ivig) are the cornerstones of therapy in kd. ivig is essential to the prevention of coronary aneurysms. years after kd has occurred during childhood years, some cases of myocardial infarction caused by thrombosis of coronary aneurysms have been reported. kawasaki's disease (kd) is a form of systemic vasculitis that occurs in young children and may be associated with the development of coronary arteritis and aneurysm formation ( figure 21f-1) . kd is the leading cause of acquired heart disease of children in the united states. this illness, fi rst recognized to be a new entity by tomasaku kawasaki in japan in 1967 (1,2), was termed for mucocutaneous lymph node syndrome (mclns) until kd became the accepted designation for this disorder (3). although the disorder was named after kawasaki, at least one previous case exists in the medical literature (4) . this case, recounted in detail below, is classic in its clinical features of kd. a 5-year-old girl presented with a sore throat, a fever to 105°f, and an erythematous rash over her trunk, appearing "desperately and acutely ill" (4). oropharyngeal lesions included an aphthous stomatitis, erythematous lesions of the hard palate, and prominent lingual papillae. on the fi fth hospital day the hectic fevers ceased, but low-grade fevers and tachycardia to 140 beats per minute persisted. the skin of her fi ngers desquamated, but over the ensuing weeks she improved steadily. one month after admission, however, she developed acute chest pain, shortness of breath, and expired. a postmortem examination revealed blood and clots in the pericardial space, and several large aneurysms along the epicardial vessels. one aneurysm, the size of a large ripe cherry in the left coronary artery, was the site of hemorrhage into the pericardium. although the microscopic appearance of the disease was typical of periarteritis nodosa (i.e., pan; see chapter 21b), no hepatic or renal infarctions were present. indeed, among the internal organs the heart alone was involved. the child's death was attributed to an atypical case of "infantile periarteritis nodosa," now recognized as kd. kawasaki's disease strikes quickly, runs a furious course over a few weeks, and then apparently resolves. in all 50 of the patients described initially by kawasaki, the symptoms resolved without sequelae within 1 month. in subsequent years, however, mortality from cardiac complications (usually coronary artery thrombosis) was reported (5, 6) . cardiac complications of kd result from a severe panvasculitis, leading to narrowing of the coronary lumina by the migration of myointimal cells from the media through the fragmented internal elastic lamina. although catastrophic heart complications occur in only a small minority of patients (<5%), the preponderance of patients with kd appear to have at least some cardiac involvement. heart lesions may include myocarditis, pericarditis, aneurysmal dilatation and thrombosis of the coronary arteries ( figure 21f-2) , and myocardial infarction. the tropism of the vascular infl ammation for coronary arteries and its unusual propensity to cause aneurysm formation remain unexplained. in addition to the cardiac fi ndings, kd is associated with a number of other dramatic clinical fi ndings (table 21f-1) . spiking fevers may last for 5 days or more. the conjunctivae, generally infl amed in a nonpurulent manner, are accompanied by erythematous changes on the lips and in the oral cavity [ figure 21f-3(a) ]. the lips become dry and cracked [ figure 21f-3(b) ], with a diffuse reddening of the oropharyngeal area and a strawberry appearance to the tongue ( figure 21f-4) . a polymorphous rash typically involves the trunk [ figure 21f -3(a)], and there may be extensive lymphadenopathy in the neck region. the palms and soles become erythematous and indurated, followed by desquamation in the skin of these areas during the healing phase (7-9). the term atypical kd has been used to describe both older children and young infants presenting outside the typical age range of 2 to 5 years, as well as those presenting with features other than the classical criteria. incomcoronary and peripheral aneurysms in kawasaki's disease (kd). magnetic resonance angiogram in an infant with kd, revealing irregularities of the subclavian, axillary, and proximal brachial arteries, as well as fusiform dilatation of the right common iliac and right proximal internal iliac arteries. there is also a focal aneurysm of the left internal iliac artery. plete kd has been applied to any patient felt to have kd but who did not fulfi ll classical criteria. these are often diagnosed by echocardiogram fi ndings of coronary aneurysms and often occur in the older children or young infants (10, 11) . coronary aneurysms, in fact, are most likely to occur in infants <6 months of age. because the epidemiology of kd is consistent with an infectious cause: clinical features that resemble infection (fever, lymphadenopathy), time/space clusters, epidemic occurrences, and alleged proximity of case foci to bodies of water. to date, however, no infectious etiology has been proven. there has been no culture or serologic evidence for conventional viral agents, mycoplasmae, rickettsiae, or bacterial agents (streptococcus, staphylococcus). molecular biologic techniques have provided support, however, for a propionibacterium acnes variant, retroviruses, rickettsiae, parvovirus b19, epstein-barr virus, and coronavirus, as well as for the participation of the s. aureus toxin tsst-1 and other superantigens (e.g., yersinia pseudotuberulosis). support exists for a superantigen-mediated process both from clinical studies (18) (19) (20) (21) (22) and from a murine model for coronary arteritis stimulated by lactobacillus casei cell wall extracts (23) . this hypothesis proposes that the etiologic agents-which may differ across geographic sites throughout the world-are capable of evoking immunologic responses via t-cell receptor v beta restriction. an oligoclonal response is supported by the discovery of iga-secreting plasma cells within gia and arthritis, aseptic meningitis, diarrhea, abdominal pain, pericardial effusion, obstructive jaundice, and hydrops of the gallbladder. intravenous immune globulin (ivig), a critical medication in the treatment of kd, is a limited resource in many parts of the world because of its expense. the american heart association (aha), concerned about both the potential for overuse of ivig as well as the failure to employ this medication in a timely manner in appropriate patients, issued guidelines on the diagnosis and treatment of kd (tables 21f-2 through 21f-4) (12, 13) . in these guidelines, the epidemiologic case defi nition of kd included fever of at least 4 days and four or more principal criteria (table 21f -1) without other explanation; or fever and less than four principal criteria if coronary artery abnormalities are detected by echocardiogram or coronary angiography. in japan, the illness appears in late winter and spring. the peak age is 6 to 12 months, with 80% of cases occurring in patients younger than 5 years of age. the male: female ratio is 1.5:1. except for three major pandemics (1979, 1982, 1985/6) , the cases have reached a plateau of 5000 to 6000 per year. the endemic annual incidence is 67/100,000 children <5 years old, with a recurrence rate of 6%. in the united states, there is also a seasonal variation in most places. the peak age is 18 to 24 months, and the illness accounts for 3000 hospitalizations/year. the recurrence rate is 1% to 3%. data from hawaii from 1971-1980 show ethnic incidence rate/100,000 children <8 years old per year of 33.6 in japanese, 11.1 in chinese, 9.2 in hawaiians, 2.9 in filipinos, 2.8 in caucasians. in los angeles from 1980-1983, rates per 100,000 children the walls of the affected arteries. this fi nding lends credence to the hypothesis that the respiratory or gastrointestinal tract may be the portal of entry for the inciting organism, and that the process is antigen-driven (24, 25) . the pathogenesis is characterized by immune activation. a host of immunologic irregularities have been described in kd, not all of which have been confi rmed consistently: endothelial cell activation [particularly human leukocyte antigen (hla)-dr expression on coronary endothelial cells]; autoantibody formation (e.g., anti-endothelial cell antibodies); complement activation and immune complex formation; abnormalities of immunoregulation (lymphocyte infi ltration, activated cd4+ and b cells, activated monocyte/macrophages, t lymphopenia, polyclonal b-cell activation); adhesion molecule upregulation (soluble p-, e-, and l-selectins); increased vascular endothelial growth factor; and marked cytokine production with high levels of interferon-gamma, interleukins-1, -4, -6, and -10, and tumor necrosis factor (tnf)-alpha (18, (26) (27) (28) . in severe cases, this "cytokine storm" results in a macrophage activation syndrome (mas). following the initial recognition of kd, this illness was treated with salicylates, using the same doses of aspirin employed in the treatment of rheumatic fever. because of the potential for impedance of aspirin absorption caused by vasculitic involvement of the gastrointestinal tract, however, the use of aspirin must be monitored carefully in this setting. if aspirin doses are too high (e.g., 100-150 mg/kg/day), improvement of intestinal absorption with therapy may lead to symptoms of toxicity. in japan, doses of 30 to 50 mg/kg/day have been employed because of the high incidence of the slowacetylator gene in the japanese population. a combined us and japanese multicenter study demonstrated that 30 to 50 mg/kg of aspirin plus ivig (see below) was effective at preventing aneurysm formation in most cases (29) . current aha guidelines, however, endorse aspirin doses of 80 to 100 mg/kg/day, in four divided doses (table 21f-4) . furusho studied the use of aspirin alone versus the combination of aspirin plus ivig (0.4 mg/kg/day × 4 days), using a protocol then in use for immune thrombocytopenic purpura (30) . a multicenter study demonstrated a decrease in the incidence of coronary artery abnormalities: only 4% (3 of 68) in the ivig group, compared with 33% (38 of 119) in the aspirin-only arm (31) . no patients in the ivig arm developed giant coronary artery aneurysms. in contrast, 6% of the aspirinonly group suffered this occurrence. this study established ivig as the standard of care. several years later, a follow-up trial compared a single dose of ivig (2 g/kg) to the traditional 0.4 mg/kg/day × 4 schedule, confi rming the superiority (a further lowering of the coronary aneurysm rate) of the single-dose regimen (32) . thereafter, the single-dose regimen became the standard of care recommendation by the aha (table 21f -4) (9,33). the use of glucocorticoids in kd is, surprisingly, controversial. one retrospective study assessed the outcomes of fi ve different treatment regimens, including aspirin alone, aspirin plus prednisolone, prednisolone alone, prednisolone plus warfarin, and no treatment aside from background antibiotic therapy (which all other treatment groups received, as well). although aspirin alone reduced the aneurysm rate from 20% to 11% compared with the no-treatment group, treatment with prednisolone was associated with an increase in the percentages of patients who developed aneurysm to 67% (34) . of note, the seven patients treated with aspirin plus prednisolone-none of whom developed aneurysm-were not emphasized in the discussion. in addition, the patients in the prednisolone-only group were perhaps the most ill at baseline (and hence were treated with glucocorticoids, presumed empirically to be the most powerful therapy). after the publication of this study's results, glucocorticoids for the treatment of kd fell into disfavor among pediatricians and in fact were viewed as contraindicated for this disease. more recent case series, evaluating the use of pulse methylprednisolone as rescue therapy for ivig nonresponders, have been more encouraging with regard to the potential for a benefi cial effect of glucocorticoids (35) (36) (37) . initial results from a multicenter trial (38) indicate no worsening in the coronary aneurysm rate among patients treated with glucocorticoids, and a decrease in fever, infl ammatory markers, length of hospital stay, and ivig side effects. a consensus conference at the national institutes of health (18) was prompted by the recognition of an ongoing immune activation at microvascular levels in patients treated adequately by the current therapies. outcome data from japan with long-term (10-15 year) follow-up demonstrated persistence of disease in some cases, with intravascular ultrasound and ultrafast computed tomography studies demonstrating lingering coronary aneurysms and/or wall fi brosis. of greatest alarm was the fi nding of such abnormalities in areas of the vasculature previously documented as normal by echocardiogram and even coronary angiography. electron microscopy studies of endomyocardial biopsies up to 23 years after the kd episode showed ongoing microaneurysms and small vessel coagulopathy. in a small number of young adults who have experienced myocardial infarctions in the absence of known cardiac risk factors, angiograms have revealed giant coronary artery aneurysms compatible with old kd. the extent of active kd in such patients, if any, as opposed to the clinical sequelae occurring in arteries damaged years before, is not clear. newer treatment modalities have been utilized in selected patients and patient populations. small studies and anecdotal reports of treatment with the antiglycoprotein iib/iiia monoclonal antibody (abciximab) or with low-molecular-weight heparin have suggested more rapid regression of aneurysms and perhaps endothelial cell remodeling. noninvasive imaging modalities, such as magnetic resonance imaging studies of the chest and abdomen, have identifi ed the extracardiac arterial aneurysms and dilatation ( figure 21f-1) . the knowledge of the more widespread nature of the vasculitic involvement has prompted more aggressive and combination therapies (39) . pentoxifylline, a phosphodiesterase inhibitor, has antiplatelet activity, vasodilatory effects, effects on red blood cell rheology, and the ability to inhibit tnf synthesis. a regimen of 20 mg/kg/day of pentoxifylline in three divided doses demonstrated an improvement in clinical features and the rate of aneurysm formation in kd (40) . further pharmacokinetic studies of a commercial liquid preparation of pentoxifylline demonstrated safety and a reduction in tnf levels in kd patients of 28% with doses up to 25 mg/kg/day (41) . anecdotal reports indicate tolerability of doses of 40 to 60 mg/kg/day in infants with kd. a multicenter trial of infl iximab in kd is currently under way (42, 43) . giant cell arteritis and polymyalgia rheumatica medium-and large-vessel vasculitis activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis correlation of the topographical arrangement and the functional pattern of tissue-infi ltrating macrophages in giant cell arteritis tissue-destructive macrophages in giant cell arteritis disease patterns 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(granulomatous) angiitis of the central nervous system: a clinicopathologic analysis of 15 new cases and a review of the literature report of 8 new cases, review of the literature, and proposal for diagnostic criteria benign angiopathy: a distinct subset of angiographically defi ned primary angiitis of the central nervous system angiographically defi ned primary angiitis of the cns: is it really benign primary central nervous system vasculitis (pcnsv): clinical features and outcome syndrome: a retrospective review of 60 patients throughout a half century cogan's syndrome erythema elevatum diutinum: clinical, histopathologic, and immunohistochemical characteristics of six patients erythema elevatum diutinum japanese ministry of health criteria (coronary artery diameter >3 mm in children <5 year or >4 mm in children ≥5 years, lumen diameter ≥1.5× an adjacent segment ≥3 suggestive features: (perivascular brightness, lack of tapering, ↓ left venticular function, mitral regurgitation, 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