cytokines derived from activation of nf-κb and irf-3. in mis-c, such a scenario could lead to a clinical picture similar to sting-associated vasculopathy with onset in infancy (also known as savi) – a condition characterized by fever, lung injury, vascular inflammation, myositis, skin lesions (occasionally acral necrosis), and arterial aneurysms. variations in the presentation and severity of mis-c might at least partially be explained by characteristic differences in polymorphisms of tmem173 found in various populations. epidemiology epidemiological information is limited, and clinical statistics currently derive from review of case series. this emerging condition is considered rare. its incidence is not known. based on available reports, the fatality rate among diagnosed cases appears to have been about 1.7% (notably higher than the rate of 0.07% recorded among children with kawasaki disease in japan). a rapid risk assessment conducted by the european centre for disease prevention and control (ecdc) concluded that the overall risk to children in the european union (eu), european economic area (eea) and the uk "is considered 'low', based on a 'very low' probability of in children and a 'high' impact of such disease." clusters of cases of the newly described condition have been recorded 3–4 weeks after peaks in sars-cov-2 viral transmission through various local communities. such observations have been seen to support the concept that sars-cov-2 infection may be capable of triggering a severe form of a kawasaki-like disease. frequent presentation without prominent respiratory symptoms in children who do not appear to have ongoing sars-cov-2 infection but who have already developed antibodies suggests that the disease may be driven by a delayed, post-infectious mechanism. the median age of onset appears to be at least 7 years (compared with 2 years for kawasaki disease, which primarily affects children under the age of 5). male children seem to be more frequently affected (broadly in line with kawasaki disease, where the male to female ratio is about 1.5 to 1). many affected children appear not to have underlying health conditions, such as asthma or autoimmune disorders, and there have been relatively few reports of known congenital heart disease or preexisting cardiovascular disease. over half (52%) the children with available information had no recorded underlying health condition, including being overweight or obese (among those who did have some comorbidity, 51% were either overweight or obese). regarding ethnicity, reports from france and the uk raised the possibility that children of afro-caribbean descent may be at greater risk, plausibly due to a genetic predisposition. in the us (as of mid-july), the majority of cases were classified as hispanic/latino (38%) or non-hispanic black (33%) people. based on reports confined to europe and the us, the condition seems to affect more children of african, afro-caribbean, and hispanic descent, whereas kawasaki disease affects more of east asian and pacific islander ancestry. the role of socioeconomic and other environmental factors in such discrepancies is unclear. as regards geographical distribution, there has been uncertainty as to whether the initial reports of cases in europe and north america reflected a true pattern, or whether the condition had gone unrecognized elsewhere. in japan and other southeast and east asian countries where kawasaki disease is usually much more prevalent than in europe, no case of kawasaki-like disease linked to covid-19 had been reported during the first wave of transmission. reports of confirmed or suspected cases have since emerged in many different countries around the world. none of the three main provisional case-definitions of the emerging entity is diagnostically specific. concerns have been raised regarding the potential for missed or delayed diagnosis of kawasaki disease due to heightened diagnostic suspicion for the new entity. misclassification of cases of kawasaki disease and of other inflammatory and infectious diseases of childhood whose case definitions overlap with mis-c could skew understanding of the new entity, such as the frequency of coronary artery aneurysms. another concern is that clinically less severe cases of the new entity may be missed, and that the actual spectrum of disease severity could be broader, especially given the reliance on early observations of severe disease for provisional case definition. some statistical modeling has been used to explore possible subdivision of cases satisfying the cdc's case definition into three distinct subgroups based on underlying clinical similarities: class 1, characterized by pronounced multiorgan involvement, with little overlap with kawasaki disease or acute covid-19; class 2, more predominantly characterized by respiratory symptoms typical of acute covid-19; class 3, a clinically less severe grouping, where rashes and mucosal symptoms are prevalent, with less multiorgan involvement, and generally greater overlap with kawasaki disease. a suggestion that research into the biology of the disease might benefit from considering cases of kawasaki disease and of the provisionally defined entity in conjunction is debated. in adults there has been uncertainty as to whether the condition is confined to children, and the appropriateness of excluding adults from case definitions has been questioned. sporadic reports exist of a similar life-threatening condition, denominated 'multisystem inflammatory syndrome in adults' (mis-a), which also usually requires intensive care. history cases of kawasaki disease with concurrent sars-cov-2 infection have been recorded among children in europe and in the united states since 7 april 2020, when a report was published by the american academy of pediatrics regarding a case of 'classic' kawasaki disease in a six-month old girl who tested positive for covid-19 in california. in this case, covid-19 did not appear to have significant clinical implications. on 25 april, concerns were initially raised in the united kingdom regarding a cluster of children of various ages presenting with a multisystem inflammatory state who required intensive care, and who all displayed "overlapping features of toxic shock syndrome and atypical kawasaki disease with blood parameters consistent with severe covid-19 in children." details of the eight cases which helped trigger this alert (not all with confirmed exposure to covid-19) were later reported in the lancet, where the authors summarized the clinical picture as "a hyperinflammatory syndrome with multiorgan involvement similar to kawasaki disease shock syndrome." accounts of analogous cases – including some that appeared less clinically severe – were also being informally shared among clinicians around europe. the eu's early warning and response system flagged suspected cases in austria, germany and portugal that had tested positive for sars-cov-2. in bergamo, at the heart of the covid-19 epidemic in lombardy, a cluster of 20 cases of kawasaki disease appeared to be roughly equivalent to the number commonly recorded there over the course of three years. in france, the government reported on 29 april that around 15 children were in hospital in paris with symptoms of kawasaki disease, an observation which prompted the organization of national surveillance programme for recent cases of kawasaki-like disease. on 1 may, the rcpch published a preliminary case definition based on review of the characteristics of the cases identified in the uk, accompanied by some clinical guidance. two weeks later, on 15 may, two further preliminary case definitions were published separately by the who and by the cdc, while the ecdc released a 'rapid risk assessment' of the condition on behalf of the european union. in the following weeks, further clinical guidance was released by other medical organizations, including the nih, the american college of rheumatology, and the american academy of pediatrics. on 4 may, the new york city department of health and mental hygiene issued an alert to identify children with the condition in new york city hospitals, where 15 such cases were already being treated. on 9 may, the governor of new york, andrew cuomo announced a collaboration with the cdc to help develop national criteria for identifying and responding to the newly identified childhood disease. by 12 may, some 230 suspected cases had been reported across the eu and eea, and in the uk (in the following days, sources were reporting up to 100 in the uk, over 135 in france, 20 in the netherlands, 10 in switzerland and 10 in germany). in the united states, more than 200 cases were suspected by mid-may, including some 145 in new york; 186 confirmed cases were eventually diagnosed between 15 march and 20 may in 26 us states. as of 11 may 2020, five fatalities were reported (1 in france, 1 in the uk, 3 in the us). in peer-reviewed medical journals, case series and related studies of the new condition were rapidly reported from countries including the uk; italy; spain; france and switzerland; france; and across the us, including new york. the emerging observations suggested somewhat greater variety in the severity of symptoms than was originally thought. the proposal of a new clinical entity during a pandemic also prompted scientific discussion about its possible distinction from kawasaki disease, and the potential role of covid-19. by 15 july, 342 confirmed mis-c cases (including 6 deaths) had been recorded in the us across 36 states plus washington dc. most (71%) of the children were hispanic/latino or non-hispanic black people, and the cdc underlined the need to learn the reasons for such a preponderance. by 29 july, a total of 570 cases and 10 deaths had been reported across 40 states, washington dc, and new york city. until late may, no confirmed case had been documented outside the eu/eea/uk and usa. no suspicious case had been observed in east asia or southeast asia (or in australia or new zealand). the absence of documented cases in china and other asian countries that had already experienced a covid-19 epidemic led to conjectures regarding the possibility of a significant evolution of the virus, or variations in susceptibility in different populations. on 2 june, news emerged of a first case of mis-c diagnosed in peru. in brazil, cases of mis-c have been reported in são paulo, and in the context of a prospective study in pará; more children with severe late manifestations of covid-19 were being admitted to paediatric intensive care units in the region. in chile, 42 confirmed cases of mis-c had been recorded nationally by june 28, including 27 in the capital, santiago. in russia, 13 children had been treated (5 with intensive care) by mid-june for a multisystem inflammatory syndrome at the morozov children's hospital in moscow, including a 2-year-old girl with the covid-19 infection who died on 23 may following an initial diagnosis of suspected kawasaki disease. in iran, a case report (first submitted in may) described severe mis-c in a 5-year-old girl who had presented with shock and was initially diagnosed with kawasaki disease, and further cases of the new syndrome have been recorded. in india, a case of suspected mis-c was reported in late may regarding a child who had presented in a covid-19 hotspot in kerala. an editorial commentary urged clinicians to have a high level of diagnostic suspicion and follow who and cdc definitions to facilitate timely identification and treatment of cases. during july, suspected cases were being flagged and reported in mumbai, in delhi, chennai, and elsewhere. in pakistan, at least 24 children were said to have kawasaki-like symptoms in lahore, where 8 cases fulfilling who criteria were prospectively identified by 30 june. in kazakhstan, 14 cases were confirmed by 20 august (among 2,357 children known to have been infected). cases have been recorded in israel, including one of a child who presented with severe central nervous system involvement and complement deficiency. in turkey, four children with a kawasaki-like disease probably associated with covid-19 are reported to have been admitted to the children's hospital of hacettepe university in ankara between 13 april and 11 july. in algeria, a first case was recorded in june. in egypt, on 10 july the authorities denied rumours of the existence of cases of kawasaki-like disease in the country. in south africa, the first 23 affected children were treated in cape town – the initial epicentre of the national covid-19 epidemic – between 4 june and 24 july. in ecuador, the ministry of health announced on 19 july the presence of 46 probable cases. in costa rica, a national public health organization announced towards the end of august that three children had been diagnosed with mis-c. cases of mis-c had also been recorded in many other latin american countries, including argentina, bolivia, colombia, cuba, the dominican republic, el salvador, guatemala, honduras, mexico, nicaragua, panama, uruguay, and venezuela, as well as in puerto rico. news of a