Multisystem inflammatory syndrome in children

{{Short description|Disease of children; pediatric comorbidity from COVID-19}} {{Update|reason=The content was largely intended to provide timely information (in 2020–2021) about an ongoing event|date=January 2023}} {{Use dmy dates|date=May 2020}} {{Use British English|date=May 2020}} {{Infobox medical condition | name = Paediatric multisystem inflammatory syndrome (PMIS/PIMS/PIMS-TS) | synonyms = * Multisystem inflammatory syndrome in children (MIS-C)<ref name=CDC2020/> * Multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19<ref name="WHO-CRP">{{cite web |title=Case Report Form for suspected cases of multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19 |url=https://www.who.int/publications/i/item/case-report-form-for-suspected-cases-of-multisystem-inflammatory-syndrome-(mis)-in-children-and-adolescents-temporally-related-to-covid-19 |website=www.who.int |publisher=World Health Organization |archive-url=https://web.archive.org/web/20200624222731/https://www.who.int/publications/i/item/case-report-form-for-suspected-cases-of-multisystem-inflammatory-syndrome-(mis)-in-children-and-adolescents-temporally-related-to-covid-19 |archive-date=24 June 2020 |url-status=live |language=en}}</ref> * Paediatric inflammatory multisystem syndrome (PIMS), temporally associated with SARS-CoV-2 infection (PIMS-TS)<ref name="ECDC-2020"/> * Kawa-COVID-19<ref name=Pouletty2020/> * Systemic Inflammatory Syndrome in COVID-19 (SISCoV)<ref name="Dhar2021">{{cite journal |vauthors=Dhar D, Dey T, Samim MM, et al. |title=Systemic inflammatory syndrome in COVID-19-SISCoV study: systematic review and meta-analysis |journal=Pediatric Research |volume= 91|issue= 6|pages= 1334–1349|date=2021 |pmid=34006982 |pmc=8128982 |doi=10.1038/s41390-021-01545-z |url=}}</ref> | image = File:Novel Coronavirus SARS-CoV-2.jpg | image_size = 250px | caption = {{longitem|TEM image of SARS-CoV-2, the coronavirus responsible for COVID-19: PMIS / MIS-C is thought to be caused by an unusual biological response to infection in certain children}} | pronounce = | specialty = Pediatrics | symptoms = Fever, abdominal pain, diarrhea, vomiting, low blood pressure, insufficient blood supply (shock), pink eye, "strawberry tongue", rash, large lymph nodes, swollen hands or feet, neurological disturbances, among others | complications = Cardiac dysfunction; coronary artery abnormalities, including aneurysms; acute kidney injury; coagulopathy | onset = 2–6 weeks<ref name=ACR1/> after COVID-19 exposure | duration = | types = | causes = Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) | risks = | diagnosis = Clinical evaluation by specialists | differential = Alternative infectious/non-infectious causes, Kawasaki disease | prevention = | treatment = Intravenous immunoglobulin (IVIG); corticosteroids; oxygen; supportive care | management = | medication = | prognosis = Generally good with treatment; long-term prognosis, unclear<ref name=Ahmed2020/> | frequency = Rare | deaths = <2% of reported cases | alt = }}

'''Multisystem inflammatory syndrome in children''' ('''MIS-C'''), or '''paediatric inflammatory multisystem syndrome''' ('''PIMS''' / '''PIMS-TS'''), or '''systemic inflammatory syndrome in COVID-19''' ('''SISCoV'''), is a rare systemic illness involving persistent fever and extreme inflammation following exposure to SARS-CoV-2, the virus responsible for COVID-19.<ref name=Ahmed2020/> Studies suggest that MIS-C occurred in 31.6 out of 100,000 people under 21 who were infected with COVID-19.<ref name="CDC2023">{{cite web |title=Multisystem Inflammatory Syndrome in Children (MIS-C): Information for Healthcare Providers About Talking with Families and Caregivers |url=https://www.cdc.gov/mis/mis-c/hcp/provider-families.html#:~:text=Studies%20have%20reported%20that%20early,decreased%20from%202020%20to%202023. |website=Centers for Disease Control | date=3 June 2024 |access-date=3 June 2024}}</ref><ref name="Payne2021">{{cite journal |last1=Payne |first1=Amanda B. |last2=Gilani |first2=Zunera |last3=Godfred-Cato |first3=Shana |title=Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2 |journal=JAMA Netw Open |date=2021 |volume=4 |issue=6 |pages=e2116420 |doi=10.1001/jamanetworkopen.2021.16420|pmid=34110391 |pmc=8193431 }}</ref> MIS-C has also been monitored as a potential, rare<ref name=Zhang2022>{{cite journal |vauthors=Zhang M, Zhang P, Liang Y, et al. |title=A systematic review of current status and challenges of vaccinating children against SARS-CoV-2 |journal=Journal of Infection and Public Health |volume=15 |issue=11 |pages=1212–1224 |date=2022 |pmid=36257126 |pmc=9557115 |doi=10.1016/j.jiph.2022.10.006 |url=}}</ref> pediatric adverse event following COVID-19 vaccination.<ref>{{cite web |title=Adverse Events Following Immunization (AEFIs) for COVID-19 in Ontario: December 13, 2020 to January 30, 2022 |url=https://www.publichealthontario.ca/-/media/documents/ncov/epi/covid-19-aefi-report.pdf |publisher=Public Health Ontario |access-date=11 February 2022}}</ref> Research suggests that COVID-19 vaccination lowers the risk of MIS-C, and in cases where symptoms develop after vaccine, is likely extremely rare or related to factors like recent exposure to COVID-19.<ref name="Jain2022">{{cite journal |last1=Jain |first1=Eisha |last2=Donowitz |first2=Jeffrey R. |last3=Aarons |first3=Elizabeth |last4=Marshall |first4=Beth C. |last5=Miller |first5=Michael P. |title=Multisystem Inflammatory Syndrome in Children after SARS-CoV-2 Vaccination |journal=Emerging Infectious Diseases |date=May 2022 |volume=28 |issue=5 |pages=990–993 |doi=10.3201/eid2805.212418 |pmid=35275051 |pmc=9045439 }}</ref> It can rapidly lead to medical emergencies such as insufficient blood flow around the body (a condition known as shock).<ref name=Ahmed2020/> Failure of one or more organs can occur.<ref name=RCP/> A warning sign is unexplained persistent fever with severe symptoms following exposure to COVID-19.<ref name="AAP-interim"/> Prompt referral to pediatric specialists is essential, and families need to seek urgent medical assistance.<ref name=Ahmed2020/> Most affected children will need intensive care.<ref name=Ahmed2020/>

All affected children have persistent fever.<ref name=Ahmed2020/> Other clinical features vary.<ref name="AAP-interim"/> The first symptoms often include acute abdominal pain with diarrhea or vomiting.<ref name=Ahmed2020/> Muscle pain and general fatigue are frequent,<ref name=Ahmed2020/> and low blood pressure is also common.<ref name=Sperotto2020/> Symptoms can also include pink eye, rashes, enlarged lymph nodes, swollen hands and feet, and "strawberry tongue".<ref name=ACR1/> Various mental disturbances are possible.<ref name=ACR1/> A cytokine storm may take place,<ref name=Rowley2020/> in which the child's innate immune system stages an excessive and uncontrolled inflammatory response.<ref name=Alunno2020/> Heart failure is common.<ref name=Sperotto2020/> Clinical complications can include damage to the heart muscle, respiratory distress, acute kidney injury, and increased blood coagulation.<ref name=Aronoff2020/> Coronary artery abnormalities can develop (ranging from dilatation to aneurysms).<ref name=ACR1/>

This life-threatening disease has proved fatal in under 2% of reported cases.<ref name=Ahmed2020/> Early recognition and prompt specialist attention are essential.<ref name="ACRdraft"/> Anti-inflammatory treatments have been used, with good responses being recorded for intravenous immunoglobulin (IVIG), with or without corticosteroids.<ref name=Rajapakse2020/> Oxygen is often needed.<ref name=Ahmed2020/> Supportive care is key for treating clinical complications.<ref name=Aronoff2020/> Most children who receive expert hospital care survive.<ref name=Ahmed2020/>

Knowledge of this newly described syndrome is evolving rapidly.<ref name=WNY2020/> Its clinical features may appear somewhat similar to Kawasaki disease, a rare disease of unknown origin that typically affects young children, in which blood vessels become inflamed throughout the body.<ref name=Sperotto2020/> It can also show features of other serious inflammatory conditions of childhood, including toxic shock and macrophage activation syndromes.<ref name=Sperotto2020/> Nevertheless, it appears to be a separate syndrome.<ref name=Abrams2020/> Older children tend to be affected.<ref name=NIHchildren/>

This emerging condition has been defined slightly differently (using different names), by the World Health Organization (WHO),<ref name=WHO2020/> the Royal College of Paediatrics and Child Health (RCPCH),<ref name=RCP>{{cite web |title=Guidance - Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS) |url=https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims |website=RCPCH |publisher=Royal College of Paediatrics and Child Health |archive-url=https://web.archive.org/web/20200616123145/https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims |archive-date=16 June 2020 |language=en |date=May 2020 |url-status=live}}</ref> and the Centers for Disease Control and Prevention (CDC).<ref name=CDC2020/> Although the condition is thought to follow SARS-CoV-2 viral infection, antigen or antibody tests are not always positive.<ref name="ECDC-2020"/> Exclusion of alternative causes, including bacterial and other infections, is essential for differential diagnosis.<ref name="ECDC-2020"/> Some general clinical guidance has been provided by the RCPCH,<ref name=RCP/> the National Institutes of Health,<ref name=NIHchildren/> the American College of Rheumatology,<ref name="Pond2020"/> and the American Academy of Pediatrics.<ref name="Hester2020">{{cite web |last1=Hester |first1=M |title=AAP issues interim guidance for MIS-C |url=https://www.contemporarypediatrics.com/view/aap-issues-interim-guidance-for-mis-c |website=Contemporary Pediatrics |archive-url=https://web.archive.org/web/20200721163846/https://www.contemporarypediatrics.com/view/aap-issues-interim-guidance-for-mis-c |archive-date=21 July 2020 |date=21 July 2020 |url-status=live}}</ref>

Clusters of new cases have been reported two to six weeks after local peaks in viral transmission.<ref name=ACR1/> The disease is thought to be driven by a delayed biological mechanism in certain predisposed children.<ref name=Rajapakse2020/> The European Centre for Disease Prevention and Control (ECDC) has rated risk to children in Europe as being 'low' overall, based on a 'very low' likelihood of a child developing this 'high impact' disease.<ref name="ECDC-2020">{{cite web |title=Rapid risk assessment: Paediatric inflammatory multisystem syndrome and SARS-CoV-2 infection in children |url=https://www.ecdc.europa.eu/en/publications-data/paediatric-inflammatory-multisystem-syndrome-and-sars-cov-2-rapid-risk-assessment |publisher=European Centre for Disease Prevention and Control |archive-url=https://web.archive.org/web/20200515100600/https://www.ecdc.europa.eu/en/publications-data/paediatric-inflammatory-multisystem-syndrome-and-sars-cov-2-rapid-risk-assessment |archive-date=15 May 2020 |url-status=live |language=en |format=PDF |date=15 May 2020}}</ref> Regarding ethnicity, the condition seems to affect more children of African, Afro-Caribbean, and Hispanic descent, whereas Kawasaki disease affects more of East Asian ancestry.<ref name="ACRdraft"/> Initial reports regarded children in various parts of Europe and the United States, and it was unclear to what extent the condition had gone unrecognized elsewhere.<ref name=WHO2020/> Reports have since emerged of cases in various other countries around the world.<ref name=Jiang2020/><ref name=Ulloa2020/> In adults, a similar condition has occasionally been reported, which has been called '''multisystem inflammatory syndrome in adults''' ('''MIS-A''').<ref name=Morris2020/>

==Name== The disorder has been called by various names, including: * Multisystem inflammatory syndrome in children (MIS-C)<ref name=CDC2020/> * Multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19<ref name="WHO-CRP"/> * Paediatric inflammatory multisystem syndrome (PIMS)<ref name=RCP/> * Paediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2 infection (PIMS-TS)<ref name="ECDC-2020"/><ref name=Ahmed2020/> * Paediatric multisystem inflammatory syndrome (PMIS)<ref name=Sperotto2020/> * Kawa-COVID-19<ref name=Pouletty2020/> * Systemic inflammatory syndrome in COVID-19 (SISCoV)<ref name="Dhar2021"/>

== Background == thumb|X-ray showing aneurysmal enlargement of the coronary arteries, which is a complication in a Kawasaki syndrome

Symptomatic cases of COVID-19 in children have been relatively uncommon,<ref name=Lu2020>{{cite journal |vauthors=Lu X, Zhang L, Du H, et al. |title=SARS-CoV-2 infection in children |journal=The New England Journal of Medicine |volume=382 |issue=17 |pages=1663–1665 |date=April 2020 |pmid=32187458 |pmc=7121177 |doi=10.1056/NEJMc2005073 }}</ref> possibly because they generally experience milder disease.<ref name=Zimmermann2020>{{cite journal |vauthors=Zimmermann P, Curtis N |title=Coronavirus infections in children including COVID-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children |journal=The Pediatric Infectious Disease Journal |volume=39 |issue=5 |pages=355–368 |date=May 2020 |pmid=32310621 |pmc=7158880 |doi=10.1097/INF.0000000000002660 }}</ref> Early infection tends to be associated with mild or no symptoms, while the later pulmonary phase, which can be life-threatening in adults, is usually mild or absent.<ref name=Nakra2020/><ref name=Hoang2020>{{cite journal |vauthors=Hoang A, Chorath K, Moreira A, et al. |title=COVID-19 in 7780 pediatric patients: a systematic review |journal=eClinicalMedicine |volume=24 |article-number=100433 |date=July 2020 |pmid=32766542 |doi=10.1016/j.eclinm.2020.100433 |pmc=7318942 |doi-access=free |language=en}}</ref> While cases of children with severe symptoms are exceptional, they can occasionally require intensive care.<ref name=Yasuhara2020/><ref name=Jeng2020>{{cite journal |vauthors=Jeng MJ |title=Coronavirus disease 2019 in children: current status |journal=Journal of the Chinese Medical Association |volume=83 |issue=6 |pages=527–533 |date=June 2020 |pmid=32502117 |doi=10.1097/JCMA.0000000000000323 |pmc=7199766 |doi-access=free }}</ref><ref name=Choi2020>{{cite journal |vauthors=Choi SH, Kim HW, Kang JM, et al. |title=Epidemiology and clinical features of coronavirus disease 2019 in children |journal=Clinical and Experimental Pediatrics |volume=63 |issue=4 |pages=125–132 |date=April 2020 |pmid=32252139 |pmc=7170785 |doi=10.3345/cep.2020.00535 }}</ref> Fatalities have been rare.<ref name=Hoang2020/><ref name=Castagnoli2020>{{cite journal |vauthors=Castagnoli R, Votto M, Licari A, et al. |title=Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review |journal=JAMA Pediatrics |date=April 2020 |volume=174 |issue=9 |pages=882–889 |pmid=32320004 |doi=10.1001/jamapediatrics.2020.1467 |doi-access=free }}</ref>

In April 2020, a small group of children with evidence of SARS-CoV-2 infection or exposure to COVID-19 were found to display clinical features corresponding to the diagnostic criteria of Kawasaki disease, sometimes accompanied by shock.<ref name=Yasuhara2020>{{cite journal |vauthors=Yasuhara J, Kuno T, Takagi H, Sumitomo N |title=Clinical characteristics of COVID-19 in children: a systematic review |journal=Pediatric Pulmonology |volume= 55|issue= 10|pages= 2565–2575|date=July 2020 |pmid=32725955 |doi=10.1002/ppul.24991 |doi-access=free }}</ref><ref name=Viner2020/> Kawasaki disease is a rare syndrome which mainly affects young children (adult onset has occasionally been reported<ref name=Wolff2007>{{cite journal | vauthors = Wolff AE, Hansen KE, Zakowski L | title = Acute Kawasaki disease: not just for kids | journal = Journal of General Internal Medicine | volume = 22 | issue = 5 | pages = 681–4 | date = May 2007 | pmid = 17443379 | pmc = 1852903 | doi = 10.1007/s11606-006-0100-5 }}</ref>).<ref name="ECDC-2020"/><ref name=Dietz2017>{{cite journal |vauthors=Dietz SM, van Stijn D, Burgner D, et al. |title=Dissecting Kawasaki disease: a state-of-the-art review |journal=European Journal of Pediatrics |volume=176 |issue=8 |pages=995–1009 |date=2017 |pmid=28656474 |pmc=5511310 |doi=10.1007/s00431-017-2937-5 |doi-access=free}}</ref><ref name=PubMedHealth2014>{{cite web|title=Kawasaki Disease|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0062985/|website=PubMed Health|publisher=NHLBI Health Topics|access-date=26 August 2016|language=en|date=11 June 2014|archive-url=https://web.archive.org/web/20170911003355/https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0062985/|archive-date=11 September 2017}}</ref> It is a form of vasculitis, where blood vessels become inflamed throughout the body, and it results in a persistent fever.<ref name="ECDC-2020"/> Recovery typically occurs spontaneously, though some children later develop mid-sized or giant coronary artery aneurysms in the heart – a potentially fatal complication.<ref name="ECDC-2020"/><ref name=Brogan2020>{{cite journal |vauthors=Brogan P, Burns JC, Cornish J, et al. |title=Lifetime cardiovascular management of patients with previous Kawasaki disease |journal=Heart |volume=106 |issue=6 |pages=411–420 |date=2020 |pmid=31843876 |pmc=7057818 |doi=10.1136/heartjnl-2019-315925 }}</ref> Symptoms of toxic shock (a syndrome caused by bacterial toxins) occasionally occur – an association sometimes referred to as 'Kawasaki shock syndrome',<ref name=Walker2020/> which is characterized by systolic hypotension or signs of poor perfusion.<ref name="ECDC-2020"/><ref name=Taddio2017>{{cite journal |vauthors=Taddio A, Rossi ED, Monasta L, et al. |s2cid=1104479 |title=Describing Kawasaki shock syndrome: results from a retrospective study and literature review |journal=Clinical Rheumatology |volume=36 |issue=1 |pages=223–228 |date=2017 |pmid=27230223 |doi=10.1007/s10067-016-3316-8 }}</ref> While the exact cause of Kawasaki disease is unknown, one plausible explanation is that it may stem from an infection triggering an autoimmune and/or autoinflammatory response in children who are genetically predisposed.<ref name=McCrindle2020/><ref name=Marrani2018>{{cite journal |vauthors=Marrani E, Burns JC, Cimaz R |title=How should we classify Kawasaki disease? |journal=Frontiers in Immunology |volume=9 |date=2018 |page=2974 |pmid=30619331 |pmc=6302019 |doi=10.3389/fimmu.2018.02974 |doi-access=free }}</ref> No specific diagnostic test exists for Kawasaki disease, and its recognition is based on various combinations of clinical and laboratory findings (including persistent fever, widespread rashes, enlarged lymph nodes, conjunctivitis, changes to the mucous membranes, and swollen hands and feet).<ref name="ECDC-2020"/><ref name=Dietz2017/><ref name=McCrindle2017>{{cite journal |vauthors=McCrindle BW, Rowley AH, Newburger JW, et al. |title=Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association |journal=Circulation |volume=135 |issue=17 |pages=e927–e999 |date=2017 |pmid=28356445 |doi=10.1161/CIR.0000000000000484 |doi-access=free }}</ref>

== Characteristics == MIS-C / PIMS-TS is a systemic disorder involving persistent fever, extreme<ref name=Ahmed2020/> inflammation (hyperinflammation), and organ dysfunction, which is temporally associated with exposure to COVID-19.<ref name=CDC2020/><ref name=RCP/> Onset may be delayed or contemporary with ongoing SARS-CoV-2 infection,<ref name=Galeotti2020>{{cite journal |vauthors=Galeotti C, Bayry J |title=Autoimmune and inflammatory diseases following COVID-19 |journal=Nature Reviews. Rheumatology |volume= 16|issue= 8|pages= 413–414|date=2020 |pmid=32499548 |doi=10.1038/s41584-020-0448-7 |pmc=7271827 |doi-access=free }}</ref> which may pass without symptoms.<ref name=Ahmed2020/> The time the syndrome takes to appear following the initial viral infection is debated, though it may develop between the first and second week.<ref name=Junior2020/> Epidemiological data suggest that recognition of the disease may typically be delayed by 2–6 weeks,<ref name=ACR1/> and usually by 3–4 weeks.<ref name="Multisystem inflammatory syndrome i">{{cite journal |vauthors=Sharma C, Ganigara M, Galeotti C, Burns J, Berganza FM, Hayes DA, Singh-Grewal D, Bharath S, Sajjan S, Bayry J |title=Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison |journal=Nat Rev Rheumatol |date=29 October 2021 |volume=17 |issue=12 |pages=731–748 |doi=10.1038/s41584-021-00709-9 |pmid=34716418 |pmc=8554518 }}</ref><ref name=Ahmed2020/> By the time of presentation, children have often developed antibodies to SARS-CoV-2, but test negative for the virus at RT-PCR.<ref name=Ahmed2020/>

The condition may match some or all of the diagnostic criteria for Kawasaki disease (i.e. the 'complete' or 'incomplete'/'atypical' subtypes<ref name=Ahmed2020/><ref name=McCrindle2017/>),<ref name=RCP/> or for Kawasaki disease shock syndrome.<ref name=Walker2020/> It tends to affect all paediatric age groups, ranging from infancy to adolescence.<ref name=ACR1/><ref name=Rajapakse2020/> It can also share clinical features with other paediatric inflammatory conditions, including toxic shock syndrome, and secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome.<ref name=RCP/><ref name=Nakra2020/> Coinfections with other pathogens have been recorded.<ref name="ECDC-2020"/>

Affected children always present with persistent fever.<ref name=Ahmed2020/> Other clinical features at presentation vary.<ref name="Multisystem inflammatory syndrome i"/><ref name="AAP-interim"/> In contrast to acute COVID-19, most children have gastrointestinal symptoms, such as diarrhoea, vomiting, and intense abdominal pain (sometimes severe enough to suggest appendicitis).<ref name=Ahmed2020/> Muscle pain and feelings of tiredness and general physical weakness are also very common.<ref name=Ahmed2020/><ref name=Sperotto2020/> Some Kawasaki-like symptoms that may be present (especially in children under the age of 5)<ref name=Junior2020/> include mucosal changes around the mouth ("strawberry tongue", cracked lips, etc.), red eyes (conjunctivitis without pus), widespread rash (consistent with leukocytoclastic vasculitis<ref name=Kaya2020>{{cite journal |vauthors=Kaya G, Kaya A, Saurat JH |title=Clinical and histopathological features and potential pathological mechanisms of skin lesions in COVID-19: review of the literature |journal= Dermatopathology|volume=7 |issue=1 |pages=3–16 |date=June 2020 |pmid=32608380 |doi=10.3390/dermatopathology7010002 |pmc=7583593 |doi-access=free }}</ref>), red or swollen hands and feet, and enlarged lymph nodes.<ref name=ACR1/><ref name="AAP-interim"/><ref name=Sperotto2020/> Chest or neck pain may also be present.<ref name=PICU2020>{{cite journal |vauthors=Kache S, Chisti MJ, Gumbo F, et al. |title=COVID-19 PICU guidelines: for high- and limited-resource settings |journal=Pediatric Research |volume= 88|issue= 5|pages= 705–716|date=July 2020 |pmid=32634818 |doi=10.1038/s41390-020-1053-9 |pmc=7577838 |doi-access=free }}</ref> Severe headache and altered mental state have been reported, along with various neurological disturbances.<ref name=ACR1/><ref name=Abrams2020/><ref name=Chen2020>{{cite journal |vauthors=Chen TH |title=Neurological involvement associated with COVID-19 infection in children |journal=Journal of the Neurological Sciences |volume=418 |article-number=117096 |date=August 2020 |pmid=32823135 |doi=10.1016/j.jns.2020.117096 |pmc=7423535 |doi-access=free }}</ref> Features of meningitis have been reported<ref name="AAP-interim"/><ref name=Rajapakse2020/> as well as septic encephalopathy,<ref name=Divani2020>{{cite journal |vauthors=Divani AA, Andalib S, Biller J, et al. |title=Central Nervous System Manifestations Associated with COVID-19 |journal=Current Neurology and Neuroscience Reports |volume=20 |issue=12 |page=60 |date=2020 |pmid=33128130 |pmc=7599061 |doi=10.1007/s11910-020-01079-7}}</ref> stroke,<ref name=Divani2020/> and Guillain-Barre Syndrome.<ref name=Rodriguez2020/> Some patients present with very low blood pressure and shock, and they may require urgent admission to a paediatric intensive care unit.<ref name=Sperotto2020/>

Cardiovascular involvement is very frequent.<ref name=Ahmed2020/><ref name=Abrams2020/><ref name=Junior2020/> Acute heart failure is common in the form of left ventricular dysfunction,<ref name=Sperotto2020/><ref name=Alsaied2020/> and a left ventricular ejection fraction under 60% is frequent.<ref name=Aronoff2020/> Shock is often of myocardial – mainly left ventricular – origin.<ref name=Rajapakse2020/> Respiratory symptoms are less common,<ref name=Abrams2020/> and are not usually a prominent feature.<ref name=Rajapakse2020/><ref name="AAP-interim"/><ref name=Alsaied2020/> When present, breathing difficulties are often linked to shock,<ref name="ECDC-2020"/> and are suggestive of heart failure.<ref name="AAP-interim"/> Some children display features of a cytokine storm,<ref name="AAP-interim"/> including extremely high serum interleukin-6 (IL-6) levels,<ref name=Abrams2020/> and need inotropic support to maintain cardiac output.<ref name=Rowley2020/> Coronary artery abnormalities, such as dilatation, are frequent.<ref name=Sperotto2020/> Some children have developed coronary artery aneurysms.<ref name="AAP-interim"/> Electrocardiographic (ECG) abnormalities are common.<ref name=Sperotto2020/> Other cardiological features sometimes include inflammation of the heart valves (valvulitis) and of the fibrous sac surrounding the heart (pericarditis).<ref name=ACR1/><ref name=Alsaied2020/> Echocardiographic features of myocarditis (inflammation of the heart muscle) have been recorded.<ref name=ACR1/><ref name=Ahmed2020/>

Affected children consistently show laboratory evidence of hyperinflammation.<ref name=Sperotto2020/> Pronounced biological markers of inflammation generally include strongly raised erythrocyte sedimentation rate (ESR), C-reactive protein (CRP),<ref name="Tonge2023">{{cite journal |vauthors=Tonge J, Stevens O, et al. |title=Assessing the Response of Biomarkers to Anti-Inflammatory Medications in PIMS-TS by Longitudinal Multilevel Modeling: Real-World Data from a UK Tertiary Center |journal=Pediatric Allergy, Immunology, and Pulmonology |date=2021 |volume=36 |issue=3 |pages=94–103 |doi=10.1089/ped.2023.0024 |pmid=37433192 |s2cid=259832603 |url=}}</ref> procalcitonin, ferritin, and IL6.<ref name=Sperotto2020/> Low platelet counts and impaired blood clotting (coagulopathy) are also common,<ref name=Rajapakse2020/> with increased levels of D-dimer and fibrinogen.<ref name=Sperotto2020/> Other haematological features include raised numbers of white blood cells (leukocytosis), characterized by high numbers of neutrophils,<ref name=Tonge2023/> with many immature forms, and low numbers of lymphocytes (lymphopaenia).<ref name=Sperotto2020/> Numbers of red blood cells and platelets may be either normal or decreased.<ref name=Sperotto2020/> Acute kidney injury and low albumin levels in the blood (hypoalbuminaemia) are common.<ref name=Nakra2020/> Low blood sodium levels and raised liver enzymes have been reported.<ref name=Rajapakse2020/> Accumulations of fluid in the lungs (pleural effusion), around the heart (pericardial effusion), and in the abdomen (ascites) have also been reported, consistent with generalized inflammation.<ref name=Nakra2020/>

Differences with respect to Kawasaki disease include frequent presentation with gastrointestinal symptoms such as vomiting, diarrhoea, and abdominal pain.<ref name=ACR1/><ref name=Ahmed2020>{{cite journal |vauthors=Ahmed M, Advani S, Moreira A, et al. |title=Multisystem inflammatory syndrome in children: a systematic review |journal=eClinicalMedicine |date=September 2020 |volume= 26|article-number=100527 |doi=10.1016/j.eclinm.2020.100527 |pmid=32923992 |pmc=7473262 |s2cid=221494176 |url=|issn=2589-5370}}</ref> Neurological involvement also appears to be relatively frequent.<ref name="AAP-interim"/> It often affects older children, whereas Kawasaki disease usually occurs before the age of five.<ref name=Ahmed2020/><ref name=Rajapakse2020/> Multiorgan disease appears to be more frequent.<ref name=Abrams2020/> Myocarditis and cardiogenic shock seem to be relatively common.<ref name=Abrams2020/> Myocarditis may be more evident in older children and adolescents.<ref name=Junior2020>{{cite journal |vauthors=Junior HS, Sakano TM, Rodrigues RM, et al. |title=Multisystem inflammatory syndrome associated with COVID-19 from the pediatric emergency physician's point of view |journal=Jornal de Pediatria |date=September 2020 |volume=97 |issue=2 |pages=140–159 |pmid=32946801 |doi=10.1016/j.jped.2020.08.004 |pmc=7486073 |doi-access=free }}</ref> Preschool children tend to display more Kawasaki-like characteristics.<ref name=Junior2020/> Features of macrophage activation syndrome appear to be more frequent than in Kawasaki disease.<ref name=NIHchildren>{{cite web |title=Special Considerations in Children |url=https://www.covid19treatmentguidelines.nih.gov/special-populations/children/ |website=NIH - COVID-19 Treatment Guidelines |publisher=National Institutes of Health |archive-url=https://web.archive.org/web/20200719133952/https://www.covid19treatmentguidelines.nih.gov/special-populations/children/ |archive-date=19 July 2020 |language=en |date=11 June 2020 }}</ref><ref name=Rodriguez2020>{{cite journal |vauthors=Rodríguez Y, Novelli L, Rojas M, et al. |title=Autoinflammatory and autoimmune conditions at the crossroad of COVID-19 |journal=Journal of Autoimmunity |volume= 114|date=June 2020 |article-number=102506 |pmid=32563547 |doi=10.1016/j.jaut.2020.102506 |pmc=7296326 |doi-access=free }}</ref> Characteristic laboratory findings that are not usually encountered in Kawasaki disease include very high levels of ventricular natriuretic peptide (a marker of heart failure),<ref name=Rowley2020/> as well as somewhat lower platelet counts, lower absolute lymphocyte counts, and higher CRP levels.<ref name="ACRdraft"/> Very high troponin levels (suggestive of myocardial damage) are also common.<ref name=Rajapakse2020/><ref name=Nakra2020/><ref name=Abrams2020/>

=== Clinical course === Clinical course tends to be more severe than with Kawasaki disease.<ref name=Galeotti2020/> A child's condition can deteriorate rapidly, even in the presence of reassuring laboratory findings.<ref name=WNY2020/> Many children develop shock and heart failure.<ref name=Ahmed2020/> Most require paediatric intensive care.<ref name=Ahmed2020/> Supplemental oxygen is often needed, and mechanical ventilation is sometimes used.<ref name=Ahmed2020/> Most children who receive expert multidisciplinary care survive.<ref name=Ahmed2020/> In addition to respiratory distress, major complications that may need aggressive supportive care can include myocardial damage, acute kidney injury, and coagulopathy (thrombophilia).<ref name=Aronoff2020>{{cite journal |vauthors=Aronoff SC, Hall A, Del Vecchio MT |title=The natural history of SARS-Cov-2 related multisystem inflammatory syndrome in children (MIS-C): a systematic review |journal=Journal of the Pediatric Infectious Diseases Society |date=September 2020 |volume=9 |issue=6 |pages=746–751 |pmid=32924059 |doi=10.1093/jpids/piaa112 |pmc=7797745 |doi-access=free }}</ref> In some cases, sustained cardiac arrhythmias have led to haemodynamic collapse and need for extracorporeal membrane oxygenation (ECMO).<ref name=Sperotto2020/> Deaths have been recorded in a small minority (under 2%) of the cases reported.<ref name=Ahmed2020/><ref name=Cato2020/> Occasionally, fatalities have followed complications of ECMO.<ref name=Rowley2020>{{cite journal |vauthors=Rowley AH |title=Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children |journal=Nature Reviews. Immunology |volume= 20|issue= 8|pages= 453–454|date=June 2020 |pmid=32546853 |doi=10.1038/s41577-020-0367-5 |pmc=7296515 |doi-access=free }}</ref> Some children exposed to COVID-19 also appear to have a less severe Kawasaki-like disease.<ref name=Viner2020/> Ventricular function often recovers before discharge from hospital (often after 6–10 days).<ref name=Ahmed2020/> Coronary artery aneurysms can develop even in the absence of Kawasaki-like features.<ref name=ACR1/> Their frequency and severity is uncertain.<ref name="ACRdraft"/> So far, they have been recorded in 7% of reported cases.<ref name=Ahmed2020/> Long-term prognosis is unclear.<ref name=Sperotto2020/>

== Diagnosis == {{quote box | border=2px | align=right | bgcolor = white | title=Preliminary WHO case definition<ref name=WHO2020/> | halign=left | quote= Children and adolescents * 0–19 years of age with fever >3 days ;And * Two of the following: # Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet) # Hypotension or shock # Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP) # Evidence of coagulopathy (by PT, PTT, elevated d-Dimers) # Acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain) ;And * Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin ;And * No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes ;And * Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19 (''Note:'' Consider this syndrome in children with features of typical or atypical Kawasaki disease or toxic shock syndrome.) }}

Diagnosis is by specialist clinical evaluation.<ref name="CHOPpathway"/> Diagnostic suspicion may be raised by unexplained persistent fever and clinically concerning symptoms following exposure to COVID-19.<ref name="AAP-interim"/> Families need to seek immediate medical care, as the child's condition can deteriorate rapidly.<ref name=Ahmed2020/> Paediatricians' first involvement is often in the emergency department.<ref name=Junior2020/> Early recognition and multidisciplinary referral to paediatric specialists (in intensive care, infectious diseases, cardiology, haematology, rheumatology, etc.) is essential.<ref name=RCP/><ref name=NIHchildren/><ref name="AAP-interim"/><ref name="ACRdraft"/> Examinations may include blood tests, chest x-ray, heart ultrasound (echocardiography), and abdominal ultrasound.<ref name=CDCparents>{{cite web |title=For parents: multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 |url=https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/children/mis-c.html |website=cdc.com |publisher=Centers for Disease Control and Prevention |archive-url=https://web.archive.org/web/20200901133129/https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/children/mis-c.html |archive-date=1 September 2020 |language=en-us |date=20 May 2020}}</ref> Clinicians worldwide have been urged to consider this condition in children who display some or all the features of Kawasaki disease or toxic shock syndrome.<ref name=WHO2020/>

=== Case definitions and guidance === A universally accepted case definition for this newly described syndrome has still not been agreed.<ref name=Jiang2020/><ref name=Kanthimathinathan2020/> In the meantime, different names and provisional case definitions are being used around the world.<ref name=Jiang2020/><ref name=Kanthimathinathan2020/> The initial case definitions released by the World Health Organization (WHO), the Royal College of Paediatrics and Child Health (RCPCH) and Centers for Disease Control and Prevention (CDC) all include involvement of more than one organ system, along with fever and elevated inflammatory markers.<ref name=Walker2020>{{cite journal |vauthors=Walker DM, Tolentino VR |title=COVID-19: The impact on pediatric emergency care |journal=Pediatric Emergency Medicine Practice |volume=17 |issue=Suppl 6-1 |pages=1–27 |date=June 2020 |pmid=32496723 |url=https://www.ebmedicine.net/topics/infectious-disease/COVID-19-Peds}}</ref> Criteria that vary among these three definitions include the ways in which involvement of different organs is defined, the duration of fever, and how exposure to COVID-19 is assessed.<ref name=Sperotto2020/> * The preliminary WHO case definition is for "multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19"<ref name=WHO-CRP/> (box).<ref name=WHO2020>{{cite web |title=Multisystem inflammatory syndrome in children and adolescents with COVID-19: scientific brief |url=https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19 |website=www.who.int |publisher=World Health Organization |archive-url=https://web.archive.org/web/20200515220732/https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19 |archive-date=15 May 2020 |url-status=live |language=en }}</ref> The WHO has established a platform for standardized, anonymized clinical data, along with a dedicated case report form, and underlines the "urgent need for collection of standardized data describing clinical presentations, severity, outcomes, and epidemiology."<ref name=WHO2020/> * Diagnostic guidance by the RCPCH proposes a broader case definition (for PIMS-TS),<ref name=Jiang2020/> which was also endorsed by an expert panel convened by the American College of Cardiology.<ref name="ACC2020">{{cite web |last1=Newburger |first1=JW |title=Pediatric hyperinflammatory syndrome and COVID-19: statement and recommendations from a pediatric intensive care international collaborative conference call |url=https://www.acc.org/latest-in-cardiology/articles/2020/05/01/01/42/pediatric-hyperinflammatory-syndrome-and-covid-19-statement-and-recommendations-from-a-pediatric-intensive-care-coronavirus-disease-2019-international-collaborative-conference-call |website=www.acc.org |publisher=American College of Cardiology |archive-url=https://web.archive.org/web/20200519202816/https://www.acc.org/latest-in-cardiology/articles/2020/05/01/01/42/pediatric-hyperinflammatory-syndrome-and-covid-19-statement-and-recommendations-from-a-pediatric-intensive-care-coronavirus-disease-2019-international-collaborative-conference-call |archive-date=19 May 2020 |url-status=live |date=15 May 2020}}</ref> Key clinical criteria set out in the RCPHC case definition are: persistent fever, inflammation (indicated by neutrophilia, high CRP levels and low lymphocyte count), and evidence of organ dysfunction (shock; cardiac, respiratory, renal, gastrointestinal, or neurological disorder), coupled with additional clinical features, including laboratory, imaging and ECG findings.<ref name="ECDC-2020"/><ref name=RCP/> Coronary artery abnormalities, such as dilatation, may be apparent at echocardiography and ECG (or contrast CT of the chest).<ref name=RCP/> Biomarkers supporting the diagnosis include abnormal fibrinogen levels, high D-dimers (possible coagulopathy), high troponin, low albumin, and high ferritin.<ref name="RCP" /> According to the RCPCH definition, the child may test positive or negative for SARS-CoV-2, but other possible microbial causes need to be excluded.<ref name="ECDC-2020"/><ref name=RCP/> * The CDC case definition for MIS-C comprises individuals "aged <21 years 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 neurological)."<ref name=CDC2020/> It also requires that there should either be a positive antigen/antibody SARS-CoV-2 test or COVID-19 exposure in the 4 weeks before onset of symptoms, along with exclusion of other plausible diagnoses.<ref name=CDC2020>{{cite web |title=Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) |url=https://emergency.cdc.gov/han/2020/han00432.asp |website=emergency.cdc.gov |publisher=Centers for Disease Control and Prevention |date=14 May 2020 |archive-url=https://web.archive.org/web/20200515005515/https://emergency.cdc.gov/han/2020/han00432.asp |archive-date=15 May 2020 |url-status=live}}</ref> This case definition is quite broad (it overlaps not only with Kawasaki disease, but also with juvenile rheumatoid arthritis, and various infectious/inflammatory conditions of childhood, including other viral diseases),<ref name=Rowley2020/> but not as broad as the RCPCH definition.<ref name=Jiang2020/> The CDC advises health providers in the United States to inform their public health authorities of suspected cases, even if they also meet full or partial criteria for Kawasaki disease, and to consider MIS-C after any childhood fatality in which there is evidence of SARS-CoV-2 infection.<ref name=CDC2020/>

Further case definitions have been formulated by the British Paediatric Surveillance Unit (BPSU) and the Canadian Paediatric Surveillance Program (CPSP).<ref name=Kanthimathinathan2020>{{cite journal |vauthors=Kanthimathinathan HK, Scholefield BR |title=Pediatric inflammatory multisystem syndrome: time to collaborate |journal=Journal of the Pediatric Infectious Diseases Society |date=September 2020 |volume=10 |issue=3 |pages=227–229 |pmid=32945863 |doi=10.1093/jpids/piaa105 |pmc=7543404 |doi-access=free }}</ref> Some provisional diagnostic guidance has been provided by both the American College of Rheumatology<ref name="ACRdraft"/> and the American Academy of Pediatrics.<ref name="AAP-interim"/> In the UK, consensus has been reached for diagnostic investigation of children with suspected PIMS-TS.<ref name=Harwood2020>{{cite journal |vauthors=Harwood R, Allin B, Jones CE, et al. |title=A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process |journal=The Lancet Child & Adolescent Health |date=September 2020 |volume=5 |issue=2 |pages=133–141 |pmid=32956615 |doi=10.1016/S2352-4642(20)30304-7 |pmc=7500943 |doi-access=free |language=en |issn=2352-4642}}</ref> A clinical pathway for diagnostic evaluation of suspected MIS-C has also been proposed by the Children's Hospital of Philadelphia.<ref name="CHOPpathway">{{cite web |title=Multisystem inflammatory syndrome (MIS-C) clinical pathway – emergency, ICU and inpatient |url=https://www.chop.edu/clinical-pathway/multisystem-inflammatory-syndrome-mis-c-clinical-pathway |website=www.chop.edu |publisher=The Children's Hospital of Philadelphia |archive-url=https://web.archive.org/web/20200626183744/https://www.chop.edu/clinical-pathway/multisystem-inflammatory-syndrome-mis-c-clinical-pathway |archive-date=26 June 2020 |language=en |date=20 May 2020 |url-status=live}}</ref> A set of guidelines proposed by Western New York recommends also evaluating children with clinical features that overlap with the MIS-C case definition, but who have been screened with mild illness and laboratory abnormalities, and who do not have an alternative diagnosis.<ref name=WNY2020>{{cite journal |vauthors=Hennon TR, Penque MD, Abdul-Aziz R, et al. |title=COVID-19 associated multisystem inflammatory syndrome in children (MIS-C) guidelines; a Western New York approach |journal=Progress in Pediatric Cardiology |volume= 57|article-number=101232 |date=May 2020 |pmid=32837142 |doi=10.1016/j.ppedcard.2020.101232 |pmc=7244417 |doi-access=free }}</ref>

=== Differential diagnosis === It is essential to exclude alternative non-infectious<ref name="AAP-interim"/> and infectious causes of the inflammatory condition, including bacterial sepsis, staphylococcal and streptococcal shock, and infections associated with myocarditis, such as enterovirus.<ref name=RCP/><ref name="ECDC-2020"/> (Coinfection with additional pathogens, including human metapneumovirus and various other microbes, may sometimes occur.)<ref name="ECDC-2020"/> Other potentially unrelated sources of abdominal pain include appendicitis and mesenteric adenitis.<ref name=Harwood2020a>{{cite journal |vauthors=Harwood R, Partridge R, Minford J, Almond S |title=Paediatric abdominal pain in the time of COVID-19: a new diagnostic dilemma |journal=Journal of Surgical Case Reports |volume=2020 |issue=9 |article-number=rjaa337 |date=September 2020 |pmid=32994918 |pmc=7505408 |doi=10.1093/jscr/rjaa337 |doi-access=free }}</ref>

Differential diagnosis with Kawasaki disease can be challenging, given the lack of a diagnostic test for either condition.<ref name=Rowley2020/> It is not currently known whether the newly described condition is superimposable with Kawasaki disease shock syndrome.<ref name=Walker2020/> Since prompt diagnosis and timely treatment of actual Kawasaki disease is important to prevent complications, a call has been made to "Keep a high suspicion for Kawasaki disease in all children with prolonged fever, but especially in those younger than 1 year of age."<ref name=Harahsheh2020/>

== Treatment == Due to the limited information available on this rare new diagnosis, clinical management has been largely based on expert opinion, including knowledge acquired from treating Kawasaki disease and other systemic inflammatory disorders of childhood, in addition to experience with COVID-19 in adults.<ref name=Sperotto2020/> Treatment is tailored for each individual child, with input from the various consulting specialists.<ref name=WNY2020/> Approaches vary.<ref name=Elias2020>{{cite journal |vauthors=Elias MD, McCrindle BW, Larios G, et al. |title=Management of multisystem inflammatory syndrome in children associated with COVID-19: a survey from the International Kawasaki Disease Registry |journal=CJC Open |date=September 2020 |volume=2 |issue=6 |pages=632–640 |pmid=32935083 |doi=10.1016/j.cjco.2020.09.004 |doi-access=free|pmc=7484693 }}</ref> The RCPCH initially outlined a provisional approach to clinical management, including guidance on early medical management, monitoring and some general principles of treatment;<ref name=RCP/> for the UK, consensus has since been reached regarding a recommended pathway for clinical management (including access to registered clinical trials).<ref name=Harwood2020/> The National Institutes of Health provides some general considerations.<ref name=NIHchildren/> The American College of Rheumatology provides guidance for clinical management of MIS-C.<ref name="ACRdraft">{{cite web |last1=ACR MIS-C and COVID-19 Related Hyperinflammation Task Force |title=Clinical guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19 |url=https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-MIS-C-Hyperinflammation.pdf |website=rheumatology.org |publisher=American College of Rheumatology |archive-url=https://web.archive.org/web/20200625141131/https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-MIS-C-Hyperinflammation.pdf |archive-date=25 June 2020 |date=17 June 2020 |url-status=live}}</ref><ref name=ACR1>{{cite journal |vauthors=Henderson LA, Canna SW, Friedman KG, et al. |title=American College of Rheumatology clinical guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19. Version 1 |journal=Arthritis & Rheumatology |date=July 2020 |volume=72 |issue=11 |pages=1791–1805 |pmid=32705809 |doi=10.1002/art.41454 |pmc=7405113 |doi-access=free }}</ref> The American Academy of Pediatrics has also provided some interim guidance.<ref name="AAP-interim">{{cite web |title=Multisystem inflammatory syndrome in children (MIS-C) interim guidance |url=https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/ |website=services.aap.org |publisher=American Academy of Pediatrics |archive-url=https://web.archive.org/web/20200717130345/https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interim-guidance/ |archive-date=17 July 2020 |language=en |date=July 2020 |url-status=live}}</ref> Other proposals have also been made.<ref name=Sperotto2020/><ref name=WNY2020/><ref name=PICU2020/><ref name=Elias2020/><ref name=Garcia2020>{{cite journal |vauthors=García-Salido A, Antón J, Martínez-Pajares JD, et al. |title=[Spanish consensus document on diagnosis, stabilisation and treatment of pediatric multisystem inflammatory syndrome related to SARS-CoV-2 (SIM-PedS)] |language=es-es |journal=Anales de Pediatria |date=October 2020 |volume=94 |issue=2 |pages=116.e1–116.e11 |pmid=33132066 |doi=10.1016/j.anpedi.2020.09.005 |pmc=7604157 |doi-access=free }}</ref> RCPCH guidance recommends that all affected children should be treated as having suspected COVID-19.<ref name=RCP/>

Little specific information is available regarding therapeutic effectiveness.<ref name=NIHchildren/> Most children who have been treated as for Kawasaki disease have recovered.<ref name=Ahmed2020/> Supportive care is a mainstay of therapy,<ref name=NIHchildren/> and for mild or moderate disease it may be sufficient.<ref name=RCP/><ref name=Rajapakse2020/> Major complications may respond well to more aggressive supportive care.<ref name=Aronoff2020/> Cardiac and respiratory support may benefit children who present predominantly with shock.<ref name=WNY2020/>

Strategies for clinical management tend to be broadly based on anti-inflammatory medications, treatment of shock, and prevention of thrombosis.<ref name=Elias2020/> Most children have received immunomodulatory treatment with intravenous immunoglobulin (IVIG).<ref>{{cite journal |vauthors=Zhu YP, Shamie I, Lee JC, Nowell CJ, Peng W, Angulo S, Le LN, Liu Y, Miao H, Xiong H, Pena CJ, Moreno E, Griffis E, Labou SG, Franco A, Broderick L, Hoffman HM, Shimizu C, Lewis NE, Kanegaye JT, Tremoulet AH, Burns JC, Croker BA |collaboration=Pediatric Emergency Medicine Kawasaki Disease Research Group Consortium |title=Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C |journal=J Clin Invest |date=15 October 2021 |volume=131 |issue=20 |article-number=e147076 |doi=10.1172/JCI147076 |pmc=8516453 |pmid=34464357 }}</ref><ref name="Multisystem inflammatory syndrome i"/><ref name=Sperotto2020/> IVIG has been reported target IL-1β+ neutrophils and their activation in the affected children.<ref>{{cite journal |vauthors=Ganigara M, Sharma C, Bayry J |title=Unraveling the mechanisms of IVIG immunotherapy in MIS-C |journal=Cell Rep Med |date=October 2021 |volume=2 |issue=10 |article-number=100431 |doi=10.1016/j.xcrm.2021.100431 |pmc=8481087 |pmid=34608458 }}</ref> Other anti-inflammatory treatments have been used, including corticosteroids at various doses.<ref name=Sperotto2020/> Good responses have been recorded for IVIG, with or without corticosteroids.<ref name=Ahmed2020/><ref name=Rajapakse2020>{{cite journal |vauthors=Rajapakse N, Dixit D |title=Human and novel coronavirus infections in children: a review |journal=Paediatrics and International Child Health |pages=36–55 |date=June 2020 |volume=41 |issue=1 |pmid=32584199 |doi=10.1080/20469047.2020.1781356 |s2cid=220061129 |doi-access= }}</ref><ref name=Nakra2020/> Cases requiring steroids due to resistance to IVIG may be more common than in Kawasaki disease.<ref name=Galeotti2020/> In a minority of cases,<ref name=Ahmed2020/> cytokine blockers have been used as a supplemental therapy to inhibit production of IL-6 (tocilizumab) or IL-1 (anakinra); TNF-α-inhibitors (infliximab) have also been used.<ref name=Sperotto2020/> Inotropic or vasoactive agents are often used for children with cardiac dysfunction and hypotension.<ref name=Jiang2020/> Anticoagulants have been used.<ref name=Jiang2020/> Low-dose aspirin has been used as an antiplatelet drug.<ref name=Sperotto2020/><ref name="AAP-interim"/><ref name=Rajapakse2020/>

Treatment strategies are being considered to prevent serious long-term complications such as coronary artery aneurysms (the main complication of Kawasaki disease).<ref name=Viner2020>{{cite journal |vauthors=Viner RM, Whittaker E |title=Kawasaki-like disease: emerging complication during the COVID-19 pandemic |journal=The Lancet |volume= 395|issue= 10239|pages= 1741–1743|date=2020 |pmid=32410759 |doi=10.1016/S0140-6736(20)31129-6 |pmc=7220168 |doi-access=free }}</ref> Close outpatient follow-up by a paediatric cardiology team has been recommended.<ref name=Sperotto2020/><ref name="AAP-interim"/>

== Causes == While it has been hypothesized that the condition is related to COVID-19,<ref name=WHO2020/> it has also been emphasized that the potential link "is neither established nor well understood."<ref name="ECDC-2020"/> A temporal association between SARS-CoV-2 infection and clinical presentation of the syndrome is plausible.<ref name="ECDC-2020"/> A causality assessment found that 'temporality' was among the five (out of nine) Bradford Hill criteria that supported a causal relationship between SARS-CoV-2 infection and the development of the syndrome.<ref name="ECDC-2020"/> Further characterization of the syndrome is essential to identify risk factors and help understand causality.<ref name=WHO2020/> It is unclear to what extent this emerging syndrome has a similar aetiology to Kawasaki disease (a condition predating the emergence of SARS-CoV-2, which is currently thought to be triggered by a distinct viral agent).<ref name=Rowley2020/> Although some cases resemble toxic shock syndrome, there is no evidence that staphylococcal or streptococcal toxins are involved.<ref name=Jiang2020/> The role of comorbidities is unclear.<ref name=Sperotto2020>{{cite journal| vauthors=Sperotto F, Friedman KG, Son MB, et al.| title=Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach. | journal=European Journal of Pediatrics |year= 2020 | volume=180 | issue=2 | pages=307–322 |pmid=32803422 |doi=10.1007/s00431-020-03766-6 | pmc=7429125 |doi-access=free }}</ref> Improved understanding will have potential implications for clinical management.<ref name=Schroeder2020>{{cite journal |vauthors=Schroeder AR, Wilson KM, Ralston SL |title=COVID-19 and Kawasaki disease: finding the signal in the noise |journal=Hospital Pediatrics |volume= 10|issue= 10|pages= e1–e3|date=2020 |pmid=32404331 |doi=10.1542/hpeds.2020-000356 |s2cid=218634534 |url=https://hosppeds.aappublications.org/content/hosppeds/early/2020/05/11/hpeds.2020-000356.full-text.pdf }}</ref> Genome-wide association studies are expected to provide insights on susceptibility and potential biological mechanisms.<ref name=Galeotti2020/>

== Mechanism == {{Update|section|updated=October 2021|date=January 2023}} The pathogenesis is not completely known and could implicate several factors.<ref name="Multisystem inflammatory syndrome i"/><ref name=CDC2020/><ref name="ECDC-2020"/> SARS-CoV-2 could have one of several roles; it could act as an environmental trigger for the condition either directly or indirectly (by somehow paving the way for a different trigger).<ref name=McCrindle2020/>

As with Kawasaki disease, antibody-dependent enhancement, whereby development of antibodies could facilitate viral entry into host cells, has been proposed as a potential mechanism.<ref name="ECDC-2020"/><ref name=Tanner2020>{{cite journal |vauthors=Tanner T, Wahezi DM |title=Hyperinflammation and the utility of immunomodulatory medications in children with COVID-19 |journal=Paediatric Respiratory Reviews |volume= 35|pages= 81–87|date=July 2020 |pmid=32792288 |doi=10.1016/j.prrv.2020.07.003 |pmc=7387280 |doi-access=free }}</ref> Epidemiological considerations make a post-infectious mechanism seem likely,<ref name="Multisystem inflammatory syndrome i"/><ref name=Rajapakse2020/><ref name=Abrams2020/><ref name=Rowley2020/><ref name=Fialkowski2020>{{cite journal |vauthors=Fialkowski A, Gernez Y, Arya P, et al. |title=Insight into the pediatric and adult dichotomy of COVID-19: age-related differences in the immune response to SARS-CoV-2 infection |journal=Pediatric Pulmonology |volume= 55|issue= 10|pages= 2556–2564|date=July 2020 |pmid=32710693 |doi=10.1002/ppul.24981 |doi-access=free }}</ref> possibly coinciding with the development of acquired immune responses to the virus.<ref name=Jiang2020/> It has been suggested that the condition may be caused by the cytokine storms induced by COVID-19.<ref name=Alunno2020>{{cite journal |vauthors=Alunno A, Carubbi F, Rodríguez-Carrio J |title=Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm that has a different origin |journal=RMD Open |volume=6 |issue=1 |article-number= e001295|date=2020 |pmid=32423970 |doi=10.1136/rmdopen-2020-001295 |pmc=7299508 |doi-access=free}}</ref><ref name=Fialkowski2020/> The characteristic ability of coronaviruses to block type I and type III interferon responses could help explain a delayed cytokine storm in children whose immune systems struggle to control SARS-CoV-2 viral replication, or are overwhelmed by a high initial viral load.<ref name=Rowley2020/> One plausible chain of events leading up to a hyperimmune response could involve early viral triggering of macrophage activation, followed by T helper cell stimulation, in turn leading to cytokine release, stimulation of macrophages, neutrophils, and monocytes, in conjunction with B cell and plasma cell activation, and autoantibody production.<ref name="Multisystem inflammatory syndrome i"/><ref name=Nakra2020>{{cite journal |vauthors=Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S |title=Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management |journal= Children|volume=7 |issue=7 |date=July 2020 |page=69 |pmid=32630212 |doi=10.3390/children7070069 |pmc=7401880 |doi-access=free }}</ref>

It is unknown to what extent the pathophysiology resembles that of other paediatric inflammatory syndromes that share similar clinical features.<ref name=Tanner2020/> Clinical overlaps with syndromes that have different causes (Kawasaki disease, toxic shock, macrophage activation syndrome, and secondary haemophagocytic lymphohistiocytosis) may be explained by immunological activation and dysregulation of similar inflammatory pathways.<ref name="Multisystem inflammatory syndrome i"/><ref name=Radia2020>{{cite journal |vauthors=Radia T, Williams N, Agrawal P, et al. |title=Multi-system inflammatory syndrome in children & adolescents (MIS-C): a systematic review of clinical features and presentation |journal=Paediatric Respiratory Reviews |date=August 2020 |volume=38 |pages=51–57 |pmid=32891582 |doi=10.1016/j.prrv.2020.08.001 |pmc=7417920 |doi-access=free }}</ref> In each of these syndromes, a cytokine storm leads to failure of multiple organs.<ref name=Junior2020/> They also share with MIS-C and severe cases of COVID-19 high levels both of ferritin (released by neutrophils) and of haemophagocytosis.<ref name=Junior2020/>

The frequent gastrointestinal presentation and mesenteric lymph node inflammation are in keeping with the known liking of SARS-CoV-2 to replicate in enterocytes.<ref name=Rowley2020/> Association of Kawasaki-like disease with COVID-19 could support the view that SARS-CoV-2 can cause systemic vasculitis by targeting endothelial tissue via angiotensin-converting enzyme 2 (ACE2), the protein which the virus uses to gain access to cells.<ref name=Sardu2020>{{cite journal |vauthors=Sardu C, Gambardella J, Morelli MB, et al. |title=Hypertension, thrombosis, kidney failure, and diabetes: is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence |journal= Journal of Clinical Medicine|volume=9 |issue=5 |date=2020 |page=1417 |pmid=32403217 |doi=10.3390/jcm9051417 |pmc=7290769 |doi-access=free}}</ref> While the initial infection is known to be capable of causing acute myocardial damage, occurrence of myocarditis could also plausibly be linked to systemic hyperinflammation triggered by a disorderly post-infectious immune response.<ref name=Sperotto2020/> It has been suggested that SARS-CoV-2 might lead to immune-mediated damage to the heart and coronary arteries via immune complexes or increased T-cell responses.<ref name=Jiang2020/>

Understanding the pathophysiology is a key research priority.<ref name="IPA-UNICEF2020">{{cite web |institution=International Pediatric Association, UNICEF |vauthors=Irfan O, Tang K, Arii M, Bhutta ZA |title=Epidemiology, spectrum, and impact of COVID-19 on children, adolescents, and pregnant women |url=https://ipa-world.org/society-resources/code/images/x5f7u8p3T41e.pdf |website=ipa-world.org |type=Joint IPA-UNICEF COVID-19 information brief |access-date=25 November 2020 |language=en |date=June 2020 }}</ref> Questions regarding the underlying molecular mechanisms that lead to the disorder following exposure to SARS-CoV-2 include identification of: any genetic predisposition factors; any associations with particular viral variant/s; any molecular patterns capable of triggering the autoimmune/autoinflammatory responses.<ref name=Galeotti2020/> Another key question is whether the molecular mechanisms that trigger autoimmune/autoinflammatory responses in children with PMIS and adults with severe COVID-19 (including the induction of high concentrations of IL-6) are similar or distinct.<ref name=Galeotti2020/>

A potential link with Kawasaki disease is under discussion.<ref name=Loke2020>{{cite journal |vauthors=Loke YH, Berul CI, Harahsheh AS |title=Multisystem inflammatory syndrome in children: is there a linkage to Kawasaki Disease? |journal=Trends in Cardiovascular Medicine |volume= 30|issue= 7|pages= 389–396|date=July 2020 |pmid=32702413 |doi=10.1016/j.tcm.2020.07.004 |pmc=7370900 |doi-access=free }}</ref> It has been noted that a leading hypothesis for the pathogenesis of Kawasaki disease also involves a hyperinflammatory response to viral infection (such as by a novel RNA virus<ref name=McCrindle2017/><ref name=Kam2020/>) in some genetically predisposed children, and that SARS-CoV-2 is now "added to the list" of implicated viral triggers.<ref name=Galeotti2020/> Hopes have been expressed that study of the new condition may help understand the hidden mechanisms behind Kawasaki disease.<ref name=Viner2020/> But current evidence suggest that MIS-C and Kawasaki disease represent two distinct disease entities<ref name="Multisystem inflammatory syndrome i"/>

===Proposed role of the STING pathway=== A possible role of the stimulator of interferon genes known as STING has been proposed.<ref name=Dhar2021/> SARS-CoV-2 is capable of upregulating the STING protein (encoded by TMEM173 transmembrane protein, and expressed in alveoli, endothelial cells, and the spleen), resulting in massive release of interferon-beta and cytokines derived from activation of NF-κB and IRF-3.<ref name=Dhar2021/> 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.<ref name=Dhar2021/> 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.<ref name="Dhar2021"/>

=== Potential role of TGFβ and Epstein-Barr Virus === A study suggests that the suppression of T cell surveillance of latent viruses, especially Epstein-Barr virus (EBV), through the cytokine TGFβ, is a potential contributor to the pathogenesis of MIS-C. The study demonstrated that TCRVβ21.3-expressing T cells expanded in MIS-C are reactive against EBV but possess reduced cytotoxicity and are unable to effectively eliminate EBV-infected B cells. This suppression was dependent on the cytokine TGFβ and led to EBV reactivation in MIS-C patients. The study further revealed that approximately 80% of children with MIS-C had antibodies against EBV, compared to about 50% of age-matched children who had experienced a SARS-CoV-2 infection but did not develop MIS-C 4–6 weeks later. This suggests that prior EBV infection may increase the risk of developing MIS-C.<ref>{{Cite journal |last1=Goetzke |first1=Carl Christoph |last2=Massoud |first2=Mona |last3=Frischbutter |first3=Stefan |last4=Guerra |first4=Gabriela Maria |last5=Ferreira-Gomes |first5=Marta |last6=Heinrich |first6=Frederik |last7=von Stuckrad |first7=Anne Sae Lim |last8=Wisniewski |first8=Sebastian |last9=Licha |first9=Jan Robin |last10=Bondareva |first10=Marina |last11=Ehlers |first11=Lisa |last12=Khaldi-Plassart |first12=Samira |last13=Javouhey |first13=Etienne |last14=Pons |first14=Sylvie |last15=Trouillet-Assant |first15=Sophie |date=2025-03-12 |title=TGFβ links EBV to multisystem inflammatory syndrome in children |journal=Nature |volume=640 |issue=8059 |language=en |pages=762–771 |doi=10.1038/s41586-025-08697-6 |issn=1476-4687|doi-access=free |pmid=40074901 |pmc=12003184 |bibcode=2025Natur.640..762G }}</ref>

== Epidemiology == {{Update|section|updated=December 2020|date=January 2023}} Epidemiological information is limited, and clinical statistics currently derive from review of case series.<ref name=ACR1/><ref name=Abrams2020/>{{efn|Given that hospital case series can be selected on the basis of clinical factors such as presence of heart failure or admission to intensive care units, available statistical information regarding the frequencies of different clinical features may be skewed by selection bias.<ref name=Alsaied2020>{{cite journal |vauthors=Alsaied T, Tremoulet AH, Burns JC, et al. |title=Review of cardiac involvement in multisystem inflammatory syndrome in children |journal=Circulation |date=November 2020 |volume=143 |issue=1 |pages=78–88 |pmid=33166178 |doi=10.1161/CIRCULATIONAHA.120.049836 |doi-access=free }}</ref> |name=|group=}} This emerging condition is considered rare.<ref name="ECDC-2020"/> Its incidence is not known.<ref name=ACR1/><ref name=Alsaied2020/>{{efn| In the state of New York, about 2 out of 100,000 individuals under 21 years of age are thought to have been affected in conjunction with the COVID-19 epidemic there (with the numbers of new cases peaking 31 days after the local peak in viral infection).<ref name=ACR1/><ref name=Dufort2020/> |name=|group=}} 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).<ref name=Ahmed2020/> 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 [the disease] in children and a 'high' impact of such disease."<ref name="ECDC-2020"/>

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.<ref name=Rajapakse2020/>{{efn|A nationwide surveillance programme in France, set up to investigate the temporal relationship between SARS-CoV-2 infection and PMIS, revealed that 95 of the 156 cases of Kawasaki-like disease notified between 1 March and 17 May 2020 were "confirmed or probable post-COVID-19 cases", with a peak in incidence 4–5 weeks after the peak of the COVID-19 epidemic in the country.<ref name=Belot2020/> Clinicians in Bergamo, Italy, reported an apparent (not seasonally adjusted<ref name=Sperotto2020/>) 30-fold increase in the incidence of Kawasaki-like disease during the first six weeks after the arrival there of SARS-CoV-2 virus infection, at a time when Bergamo was experiencing the highest rates of infections and deaths in Italy.<ref name=Viner2020/><ref name=Verdoni2020>{{cite journal |vauthors=Verdoni L, Mazza A, Gervasoni A, et al. |title=An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study |journal=The Lancet |volume= 395|issue= 10239|pages= 1771–1778|date=2020 |pmid=32410760 |pmc=7220177 |doi=10.1016/S0140-6736(20)31103-X }}</ref> In the UK, the number of intensive care admissions for children fulfilling the RCPCH case definition of PMIS during 40 days through April and early May, following the first national surge in COVID-19 cases, was at least 11-fold higher than historical trends for paediatric inflammatory conditions.<ref name=Davies2020>{{cite journal |vauthors=Davies P, Evans C, Kanthimathinathan HK, et al. |title=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 |journal=The Lancet. Child & Adolescent Health |volume= 4|issue= 9|pages= 669–677|date=July 2020 |pmid=32653054 |doi=10.1016/S2352-4642(20)30215-7 |pmc=7347350 |doi-access=free }}</ref> Time series analysis of cases of Kawasaki disease admitted to a paediatric centre in Paris, France, revealed a spike that started 2 weeks after the first peak of the COVID-19 epidemic there, corresponding to a roughly 5-fold increase in incidence.<ref name=Ouldali2020/> These cases from Paris had a similarly severe clinical profile to those reported in Bergamo (and differed from the more typical Kawasaki disease profile observed in a newly uncovered spike following the peak of the 2009 H1N1 swine flu epidemic in Paris).<ref name=Ouldali2020>{{cite journal |vauthors=Ouldali N, Pouletty M, Mariani P, et al. |title=Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a time-series analysis |journal=The Lancet. Child & Adolescent Health |volume= 4|issue= 9|pages= 662–668|date=July 2020 |pmid=32622376 |doi=10.1016/S2352-4642(20)30175-9 |pmc=7332278 |doi-access=free }}</ref> |name=|group=}} 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.<ref name=Kam2020>{{cite journal |vauthors=Kam KQ, Ong JS, Lee JH |title=Kawasaki disease in the COVID-19 era: a distinct clinical phenotype? |journal=The Lancet. Child & Adolescent Health |volume= 4|issue= 9|pages= 642–643|date=July 2020 |pmid=32622377 |doi=10.1016/S2352-4642(20)30207-8 |pmc=7833489 |doi-access=free }}</ref> 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.<ref name=Rajapakse2020/>

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).<ref name=Abrams2020/> 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).<ref name=Abrams2020>{{cite journal |vauthors=Abrams JY, Godfred-Cato SE, Oster ME, et al. |title=Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: a systematic review |journal=The Journal of Pediatrics |date=August 2020 |volume=226 |pages=45–54.e1 |pmid=32768466 |doi=10.1016/j.jpeds.2020.08.003 |pmc=7403869 |doi-access=free }}</ref> 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.<ref name=Ahmed2020/><ref name=Sperotto2020/> 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).<ref name=Ahmed2020/>

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.<ref name=Galeotti2020/> In the US (as of mid-July), the majority of cases were classified as Hispanic/Latino (38%) or non-Hispanic Black (33%) people.<ref name=CDC-15July/> 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.<ref name="ACRdraft"/><ref name=Loke2020/> The role of socioeconomic and other environmental factors in such discrepancies is unclear.<ref name=McCrindle2020>{{cite journal |vauthors=McCrindle BW, Manlhiot C |title=SARS-CoV-2-related inflammatory multisystem syndrome in children: different or shared etiology and pathophysiology as Kawasaki disease? |journal=JAMA |volume= 324|issue= 3|pages= 246–248|date=2020 |pmid=32511667 |doi=10.1001/jama.2020.10370 |s2cid=219553490 | doi-access= }}</ref> One study suggested that rates of children with COVID-19 who do not get MIS-C may be underrepresented in some communities and lack diversity, making it difficult to determine the rates of MIS-C among children who were infected with COVID-19 in these communities.<ref name="Hogan2024">{{cite journal |last1=Hogan |first1=Alexander H. |last2=Herbst |first2=Katherine W. |last3=Defelice |first3=Carlie |last4=Schulman |first4=Noah |last5=Adams |first5=Aaron M. |last6=Carroll |first6=Christopher L. |last7=Salazar |first7=Juan C. |title=Going Viral: Assessing the Impact of Social Media on Enrollment in a Coronavirus Disease 2019 (COVID-19) Cohort Study |journal=Cureus |date=13 March 2024 |volume=13 |issue=3 |article-number=e56096 |doi=10.7759/cureus.56096 |doi-access=free |pmid=38618422 |pmc=11009901 }}</ref>

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.<ref name="ECDC-2020"/><ref name=WHO2020/> 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.<ref name="ECDC-2020"/><ref name=Rowley2020/><ref name=Kam2020/><ref name=Wiwanitkit2020>{{cite journal |vauthors=Wiwanitkit V |title=COVID-19 and Kawasaki syndrome |journal=Cardiology in the Young |volume= 30|issue= 9|date=June 2020 |page=1372 |pmid=32618551 |doi=10.1017/S1047951120001894 |pmc=7322145 |doi-access=free }}</ref>{{efn|No apparent rise in new cases of Kawasaki disease was noted in these countries,<ref name=Galeotti2020/> including in South Korea<ref name=Kim2020>{{cite journal |vauthors=Kim YJ, Park H, Choi YY, et al. |title=Defining association between COVID-19 and the multisystem inflammatory syndrome in children through the pandemic |journal=Journal of Korean Medical Science |volume=35 |issue=22 |article-number=e204 |date=June 2020 |pmid=32508068 |pmc=7279946 |doi=10.3346/jkms.2020.35.e204 }}</ref> (where one diagnosis was subsequently reclassified as MIS-C<ref name=Kim2020a>{{cite journal |vauthors=Kim H, Shim JY, Ko JH, et al. |title=Multisystem inflammatory syndrome in children related to COVID-19: the first case in Korea |journal=Journal of Korean Medical Science |volume=35 |issue=43 |article-number=e391 |date=November 2020 |pmid=33169560 |doi=10.3346/jkms.2020.35.e391 |pmc=7653165 |doi-access=free }}</ref>), and in Singapore.<ref name=Yung2020>{{cite journal |vauthors=Yung CF, Nadua KD, Oh BK, Thoon KC |title=Epidemiological trends in Kawasaki disease during COVID-19 in Singapore |journal=The Journal of Pediatrics |date=July 2020 |volume=226 |pages=314–315 |pmid=32717229 |doi=10.1016/j.jpeds.2020.07.063 |pmc=7380241 |doi-access=free }}</ref> There had been no report of Kawasaki disease or Kawasaki-like symptoms in mainland China.<ref name=Xu2020>{{cite journal |vauthors=Xu S, Chen M, Weng J |title=COVID-19 and Kawasaki disease in children |journal=Pharmacological Research |volume=159 |article-number=104951 |date=May 2020 |pmid=32464327 |pmc=7247462 |doi=10.1016/j.phrs.2020.104951 |doi-access=free }}</ref> |name=|group=}} Reports of confirmed or suspected cases have since emerged in many different countries around the world.<ref name=Jiang2020>{{cite journal |vauthors=Jiang L, Tang K, Levin M, et al. |title=COVID-19 and multisystem inflammatory syndrome in children and adolescents |journal=Lancet Infectious Diseases |volume= 20|issue= 11|pages= e276–e288|date=August 2020 |pmid=32818434 |doi=10.1016/S1473-3099(20)30651-4 |pmc=7431129 |doi-access=free }}</ref>{{efn|An extensive Latin-American Kawasaki disease surveillance network (REKAM-LATINA) has recorded cases of MIS-C across all its participating countries.<ref name=Ulloa2020>{{cite journal |vauthors=Ulloa-Gutierrez R, Ivankovich-Escoto G, Yock-Corrales A, Tremoulet AH |title=Multisystem inflammatory syndrome (MIS-C) surveillance and COVID-19 in Latin America |journal=The Pediatric Infectious Disease Journal |date=September 2020 |volume=39 |issue=12 |pages=e473–e474 |pmid=32947601 |doi=10.1097/INF.0000000000002901 |doi-access=free }}</ref> Some other countries where cases have been reported include Russia,<ref name=Семенова2020/> India,<ref name=Dhanalakshmi2020/><ref name=Rauf2020/> Pakistan,<ref name=Sadiq2020/> Kazakhstan,<ref name=Ali2020/> South Korea,<ref name=Kim2020a/><ref name=Yonhap2020/> Turkey,<ref name=Akca2020/> Iran,<ref name=Bahrami2020/><ref name=Mamishi2020/> Saudi Arabia,<ref name=Ameer2020>{{cite journal |vauthors=Al Ameer HH, AlKadhem SM, Busaleh F, et al. |title=Multisystem inflammatory syndrome in children temporally related to COVID-19: a case report from Saudi Arabia |journal=Cureus |date=September 2020 |volume=12 |issue=9 |article-number=e10589 |doi=10.7759/cureus.10589 |doi-access=free |pmid=33110725 |pmc=7580961}}</ref> Israel,<ref name=Sheba2020/><ref name=Regev2020/> Algeria,<ref name=Saada2020/> South Africa,<ref name=Webb2020/> and Australia.<ref name=Australia25>{{cite journal |author=COVID-19 National Incident Room Surveillance Team |title=COVID-19, Australia: Epidemiology Report 25 (Fortnightly reporting period ending 13 September 2020) |journal=Communicable Diseases Intelligence |volume=44 |date=September 2020 |pmid=32981492 |doi=10.33321/cdi.2020.44.77 |doi-access=free }}</ref> |name=|group=}}

None of the three main provisional case-definitions of the emerging entity is diagnostically specific.<ref name=Loke2020/> Concerns have been raised regarding the potential for missed or delayed diagnosis of Kawasaki disease due to heightened diagnostic suspicion for the new entity.<ref name=Harahsheh2020>{{cite journal |vauthors=Harahsheh AS, Dahdah N, Newburger JW, et al. |title=Missed or delayed diagnosis of Kawasaki disease during the 2019 novel coronavirus disease (COVID-19) pandemic |journal=The Journal of Pediatrics |volume= 222|pages= 261–262|date=May 2020 |pmid=32370951 |pmc=7196408 |doi=10.1016/j.jpeds.2020.04.052 }}</ref> 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.<ref name=Rowley2020a>{{cite journal |vauthors=Rowley AH |title=Diagnosing SARS-CoV-2 related multisystem inflammatory syndrome in children (MIS-C): focus on the gastrointestinal tract and the myocardium |journal=Clinical Infectious Diseases |date=July 2020 |volume=72 |issue=9 |pages=e402–e403 |pmid=32717055 |doi=10.1093/cid/ciaa1080 |pmc=7454389 |doi-access=free }}</ref><ref name=Rowley2020b>{{cite journal |vauthors=Rowley AH |title=Multisystem inflammatory syndrome in children and Kawasaki disease: two different illnesses with overlapping clinical features |journal=The Journal of Pediatrics |volume= 224|pages= 129–132|date=June 2020 |pmid=32585239 |pmc=7308002 |doi=10.1016/j.jpeds.2020.06.057 |doi-access=free }}</ref> 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,<ref name=Jiang2020/><ref name=Levin2020>{{cite journal |vauthors=Levin M |title=Childhood multisystem inflammatory syndrome - a new challenge in the pandemic |journal=The New England Journal of Medicine |volume= 383|issue= 4|pages= 393–395|date=June 2020 |pmid=32598829 |doi=10.1056/NEJMe2023158 |pmc=7346677 |doi-access=free }}</ref> especially given the reliance on early observations of severe disease for provisional case definition.<ref name=Yeung2020/> 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.<ref name=Rowley2020c/><ref name=Cato2020>{{cite journal |vauthors=Godfred-Cato S, Bryant B, Leung J, et al. |title=COVID-19-associated multisystem inflammatory syndrome in children - United States, March-July 2020 |journal=MMWR. Morbidity and Mortality Weekly Report |volume=69 |issue=32 |pages=1074–1080 |date=August 2020 |pmid=32790663 |pmc=7440126 |doi=10.15585/mmwr.mm6932e2 |doi-access=free }}</ref> A suggestion<ref name=Yeung2020>{{cite journal |vauthors=Yeung RS, Ferguson PJ |title=Is multisystem inflammatory syndrome in children on the Kawasaki syndrome spectrum? |journal=The Journal of Clinical Investigation |volume= 130|issue= 11|pages= 5681–5684|date=July 2020 |pmid=32730226 |doi=10.1172/JCI141718 |pmc=7598074 |doi-access=free }}</ref> 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.<ref name=Rowley2020c>{{cite journal |vauthors=Rowley AH, Shulman ST, Arditi M |title=Immune pathogenesis of COVID-19-related multisystem inflammatory syndrome in children (MIS-C) |journal=The Journal of Clinical Investigation |volume= 130|issue= 11|pages= 5619–5621|date=September 2020 |pmid=32870815 |doi=10.1172/JCI143840 |pmc=7598032 |doi-access=free}}</ref>

=== In adults === There has been uncertainty as to whether the condition is confined to children,<ref name=WNY2020/> and the appropriateness of excluding adults from case definitions has been questioned.<ref name=Most2020>{{cite journal |vauthors=Most ZM, Hendren N, Drazner MH, Perl TM |title=The striking similarities of multisystem inflammatory syndrome in children and a myocarditis-like syndrome in adults: overlapping manifestations of COVID-19 |journal=Circulation |date=August 2020 |volume=143 |issue=1 |pages=4–6 |pmid=32787714 |doi=10.1161/CIRCULATIONAHA.120.050166 |doi-access=free }}</ref> Sporadic reports exist of a similar life-threatening condition, denominated 'multisystem inflammatory syndrome in adults' (MIS-A), which also usually requires intensive care.<ref name=Morris2020>{{cite journal |vauthors=Morris SB, Schwartz NG, Patel P, et al. |title=Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - United Kingdom and United States, March-August 2020 |journal=MMWR. Morbidity and Mortality Weekly Report |volume=69 |issue=40 |pages=1450–1456 |date=October 2020 |pmid=33031361 |doi=10.15585/mmwr.mm6940e1 |pmc=7561225 |doi-access=free }}</ref>

== History == {{Update|section|updated=April 2021|date=January 2023}}

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.<ref name="ECDC-2020"/><ref name=Jones2020>{{cite journal |vauthors=Jones VG, Mills M, Suarez D, et al. |s2cid=215406465 |title=COVID-19 and Kawasaki disease: novel virus and novel case |journal=Hospital Pediatrics |volume= 10|issue= 6|pages= 537–540|date=2020 |pmid=32265235 |doi= 10.1542/hpeds.2020-0123|url=https://hosppeds.aappublications.org/content/hosppeds/early/2020/04/06/hpeds.2020-0123.full-text.pdf }}</ref> In this case, COVID-19 did not appear to have significant clinical implications.<ref name=Schroeder2020/><ref name=Jones2020/>

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."<ref name=Viner2020/><ref name=Mahase2020>{{cite journal |vauthors=Mahase E |title=COVID-19: concerns grow over inflammatory syndrome emerging in children |journal=BMJ |volume=369 |article-number=m1710 |date=2020 |pmid=32345602 |doi=10.1136/bmj.m1710 |doi-access=free |url=https://www.bmj.com/content/369/bmj.m1710.full |quote=The alert, which relayed information from NHS England, said, 'It has been reported that over the past three weeks there has been an apparent rise in the number of children of all ages presenting with a multisystem inflammatory state requiring intensive care across London and other regions of the UK.'|url-access=subscription }}</ref> 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."<ref name=Schroeder2020/><ref name=Riphagen2020>{{cite journal |vauthors=Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P |title=Hyperinflammatory shock in children during COVID-19 pandemic |journal=The Lancet |volume= 395|issue= 10237|pages= 1607–1608|date=7 May 2020 |pmid=32386565 |pmc=7204765 |doi=10.1016/S0140-6736(20)31094-1 |quote=During a period of 10 days in mid-April, 2020, we noted an unprecedented cluster of eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome (typical number is one or two children per week). This case cluster formed the basis of a national alert.}}</ref> Accounts of analogous cases – including some that appeared less clinically severe – were also being informally shared among clinicians around Europe.<ref name=Viner2020/> The EU's Early Warning and Response System flagged suspected cases in Austria, Germany and Portugal that had tested positive for SARS-CoV-2.<ref name="ECDC-2020"/> 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.<ref name=Schroeder2020/> In France, the government reported on 29 April that around 15 children were in hospital in Paris with symptoms of Kawasaki disease,<ref name=Schroeder2020/><ref name="Kyodo">{{cite news |title=Rising cases of kids with Kawasaki disease possibly linked to coronavirus |url=https://english.kyodonews.net/news/2020/04/05476c47050f-rising-cases-of-kids-with-kawasaki-disease-possibly-linked-to-virus.html |agency=Kyodo News |date=30 April 2020 |archive-url=https://web.archive.org/web/20200513132001/https://english.kyodonews.net/news/2020/04/05476c47050f-rising-cases-of-kids-with-kawasaki-disease-possibly-linked-to-virus.html |archive-date=13 May 2020 |access-date=22 May 2020 |url-status=live}}</ref> an observation which prompted the organization of national surveillance programme for recent cases of Kawasaki-like disease.<ref name=Belot2020>{{cite journal |vauthors=Belot A, Antona D, Renolleau S, et al. |title=SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020 |journal=Eurosurveillance |volume=25 |issue=22 |date=2020 |pmid=32524957 |doi=10.2807/1560-7917.ES.2020.25.22.2001010 |pmc=7336112 |doi-access=free }}</ref>

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.<ref name=RCP/><ref name=Viner2020/> Two weeks later, on 15 May, two further preliminary case definitions were published separately by the WHO<ref name=WHO2020/> and by the CDC,<ref name=CDC2020/> while the ECDC released a 'rapid risk assessment' of the condition on behalf of the European Union.<ref name="ECDC-2020"/> In the following weeks, further clinical guidance was released by other medical organizations, including the NIH,<ref name=NIHchildren/> the American College of Rheumatology,<ref name="Pond2020">{{cite web |last1=Pond |first1=E |title=ACR guidelines for the management of pediatric multisystem inflammatory syndrome associated with SARS-CoV-2 |url=https://www.rheumatologyadvisor.com/home/topics/pediatric-rheumatology/acr-guidelines-management-of-pediatric-multisystem-inflammatory-syndrome-sarscov2/ |website=Rheumatology Advisor |archive-url=https://web.archive.org/web/20200721092942/https://www.rheumatologyadvisor.com/home/topics/pediatric-rheumatology/acr-guidelines-management-of-pediatric-multisystem-inflammatory-syndrome-sarscov2/ |archive-date=21 July 2020 |date=20 July 2020 |url-status=live}}</ref> and the American Academy of Pediatrics.<ref name="Hester2020"/> 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,<ref name="ECDC-2020"/> where 15 such cases were already being treated.<ref name="NYC-Alert13">{{cite web |last=Daskalakis |first=DC |title=2020 Health alert #13: pediatric multi-system inflammatory syndrome potentially associated with COVID-19 |url=https://www1.nyc.gov/assets/doh/downloads/pdf/han/alert/2020/covid-19-pediatric-multi-system-inflammatory-syndrome.pdf |publisher=NYC Health |archive-url=https://web.archive.org/web/20200506033213/https://www1.nyc.gov/assets/doh/downloads/pdf/han/alert/2020/covid-19-pediatric-multi-system-inflammatory-syndrome.pdf |archive-date=6 May 2020 |url-status=live |date=4 May 2020}}</ref> 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.<ref>{{cite web |title=Governor Cuomo announces State is helping to develop the national criteria for identifying and responding to COVID-related illness in children |url=https://www.governor.ny.gov/news/governor-cuomo-announces-state-helping-develop-national-criteria-identifying-and-responding |website=Governor Andrew M. Cuomo |archive-url=https://web.archive.org/web/20200510235722/https://www.governor.ny.gov/news/governor-cuomo-announces-state-helping-develop-national-criteria-identifying-and-responding |archive-date=10 May 2020 |url-status=live |language=en |date=9 May 2020}}</ref>

By 12 May, some 230 suspected cases had been reported across the EU and EEA, and in the UK<ref name="ECDC-2020"/> (in the following days, sources were reporting up to 100 in the UK,<ref>{{cite web |title=Coronavirus: Children affected by rare Kawasaki-like disease |url=https://www.bbc.com/news/health-52648557 |website=BBC News |access-date=24 May 2020 |date=14 May 2020}}</ref> over 135 in France,<ref>{{cite web |last1=d'Adhémar |first1=Margaux |title=Coronavirus: 135 enfants français atteints d'une forme proche de la maladie de Kawasaki, un mort |url=https://www.lefigaro.fr/sciences/coronavirus-135-enfants-francais-atteints-d-une-forme-proche-de-la-maladie-de-kawasaki-un-mort-20200515 |website=Le Figaro.fr |access-date=16 May 2020 |language=fr |date=15 May 2020}}</ref> 20 in the Netherlands,<ref>{{cite news |last1=Deloughry |first1=Rachel |title=20 children in the Netherlands contract illness thought to be linked to COVID-19 |url=https://www.iamexpat.nl/expat-info/dutch-expat-news/20-children-netherlands-contract-illness-thought-be-linked-covid-19 |access-date=27 May 2020 |work=www.iamexpat.nl |date=26 May 2020}}</ref> 10 in Switzerland<ref>{{cite web |title=COVID-19 Fragen und Antworten Teil 11 |url=https://paediatrica.swiss-paediatrics.org/covid-19-fragen-und-antworten-teil-11/ |website=Paediatrica |access-date=16 May 2020 |language=de |date=12 May 2020}}</ref> and 10 in Germany<ref>{{cite news |last1=Irmer |first1=Juliette |title="Kawasaki" durch Covid-19?: Auch deutsche Kinder mit schweren Entzündungsreaktionen |url=https://www.faz.net/aktuell/wissen/corona-auch-deutsche-kinder-mit-schweren-entzuendungsreaktionen-16770951.html |website=Faz.net |access-date=16 May 2020 |language=de |date=15 May 2020}}</ref>). In the United States, more than 200 cases were suspected by mid-May,<ref>{{cite web |title=With over 200 possible cases, doctors warn reports of rare, coronavirus-linked child inflammatory illness likely to rise |url=https://abcnews.go.com/Health/200-cases-doctors-warn-reports-rare-coronavirus-linked/story?id=70703314 |website=ABC News |access-date=16 May 2020 |date=15 May 2020}}</ref> including some 145 in New York;<ref>{{cite news |last1=McNamara |first1=Audrey |title=15 states now investigating child illness possibly linked to coronavirus, Cuomo says |url=https://www.cbsnews.com/news/kawasaki-disease-15-states-child-illness-coronavirus-cuomo/ |access-date=14 May 2020 |work=www.cbsnews.com |date=13 May 2020}}</ref><ref>{{cite news |last1=Marsh |first1=Julia |last2=Musumeci |first2=Natalie |title=145 NYC kids have rare Kawasaki-like disease linked to coronavirus |url=https://nypost.com/2020/05/18/145-nyc-kids-have-rare-kawasaki-like-disease-linked-to-coronavirus/ |access-date=19 May 2020 |work=New York Post |date=18 May 2020}}</ref> 186 confirmed cases were eventually diagnosed between 15 March and 20 May in 26 US states.<ref name=Feldstein2020/><ref name="CDC-earlyinfo">{{cite web |title=Infographic: Early Cases of MIS-C: Multi-System Inflammatory Syndrome in U.S. Children |url=https://www.cdc.gov/coronavirus/2019-ncov/covid-data/infographic-mis-c.html |website=cdc.gov |publisher=Centers for Disease Control and Prevention |archive-url=https://web.archive.org/web/20200710025733/https://www.cdc.gov/coronavirus/2019-ncov/covid-data/infographic-mis-c.html |url-status=live |archive-date=10 July 2020 |language=en-us |date=9 July 2020}}</ref> As of 11 May 2020, five fatalities were reported (1 in France, 1 in the UK, 3 in the US).<ref name="ECDC-2020"/> In peer-reviewed medical journals, case series and related studies of the new condition were rapidly reported from countries including the UK;<ref name=Whittaker2020>{{cite journal |vauthors=Whittaker E, Bamford A, Kenny J, et al. |title=Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 |journal=JAMA |volume= 324|issue= 3|date=June 2020 |pages=259–269 |pmid=32511692 |doi=10.1001/jama.2020.10369 |pmc=7281356 |doi-access=free }}</ref><ref name=Ramcharan2020>{{cite journal |vauthors=Ramcharan T, Nolan O, Lai CY, et al. |title=Paediatric inflammatory multisystem syndrome: temporally associated with SARS-CoV-2 (PIMS-TS): cardiac features, management and short-term outcomes at a UK tertiary paediatric hospital |journal=Pediatric Cardiology |volume= 41|issue= 7|pages= 1391–1401|date=June 2020 |pmid=32529358 |pmc=7289638 |doi=10.1007/s00246-020-02391-2 }}</ref> Italy;<ref name=Verdoni2020/> Spain;<ref name=Cabrero2020>{{cite journal |vauthors=Cabrero-Hernández M, García-Salido A, Leoz-Gordillo I, et al. |s2cid=218984945 |title=Severe SARS-CoV-2 infection in children with suspected acute abdomen: a case series from a tertiary hospital in Spain |journal=The Pediatric Infectious Disease Journal |volume= 39|issue= 8|pages= e195–e198|date=May 2020 |pmid=32467457 |doi=10.1097/INF.0000000000002777 |doi-access=free }}</ref><ref name=Moraleda2020>{{cite journal |vauthors=Moraleda C, Serna-Pascual M, et al. |title=Multi-inflammatory syndrome in children related to SARS-CoV-2 in Spain |journal=Clinical Infectious Diseases |date=July 2020 |volume=72 |issue=9 |pages=e397–e401 |pmid=32710613 |doi=10.1093/cid/ciaa1042 |pmc=7454331 |doi-access=free }}</ref><ref name=Pino2020>{{cite journal |vauthors=Pino R, Izurieta AC, Ríos-Barnés M, et al. |title=Correspondence on: 'Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort' by Pouletty et al |journal=Annals of the Rheumatic Diseases |pages= annrheumdis-2020-218538|date=August 2020 |volume=81 |issue=9 |pmid=32759264 |doi=10.1136/annrheumdis-2020-218538 |s2cid=220974885 |doi-access= }}</ref> France and Switzerland;<ref name=Belhadjer2020>{{cite journal |vauthors=Belhadjer Z, Méot M, Bajolle F, et al. |title=Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic |journal=Circulation |date=2020 |volume=142 |issue=5 |pages=429–436 |pmid=32418446 |doi=10.1161/CIRCULATIONAHA.120.048360 |s2cid=218679879 |doi-access=free}}</ref> France;<ref name=Pouletty2020>{{cite journal |vauthors=Pouletty M, Borocco C, Ouldali N, et al. |s2cid=219607184 |title=Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort |journal=Annals of the Rheumatic Diseases |volume= 79|issue= 8|pages= 999–1006|date=June 2020 |pmid=32527868 |doi=10.1136/annrheumdis-2020-217960 |pmc=7299653 }}</ref><ref name=Grimaud2020>{{cite journal |vauthors=Grimaud M, Starck J, Levy M, et al. |title=Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children |journal=Annals of Intensive Care |volume=10 |issue=1 |page=69 |date=June 2020 |pmid=32488505 |pmc=7266128 |doi=10.1186/s13613-020-00690-8 |doi-access=free }}</ref><ref name=Toubiana2020>{{cite journal |vauthors=Toubiana J, Poirault C, Corsia A, et al. |title=Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study |journal=BMJ |volume=369 |article-number=m2094 |date=June 2020 |pmid=32493739 |doi=10.1136/bmj.m2094 |pmc=7500538 |doi-access=free }}</ref> and across the US,<ref name=Feldstein2020>{{cite journal |vauthors=Feldstein LR, Rose EB, Horwitz SM, et al. |title=Multisystem inflammatory syndrome in U.S. children and adolescents |journal=The New England Journal of Medicine |volume= 383|issue= 4|pages= 334–346|date=June 2020 |pmid=32598831 |doi=10.1056/NEJMoa2021680 |pmc=7346765 |doi-access=free }}</ref><ref name=Chiotos2020>{{cite journal |vauthors=Chiotos K, Bassiri H, Behrens EM, et al. |title=Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series |journal=Journal of the Pediatric Infectious Diseases Society |volume= 9|issue= 3|pages= 393–398|date=May 2020 |pmid=32463092 |doi=10.1093/jpids/piaa069 |pmc=7313950 |doi-access=free }}</ref> including New York.<ref name=Dufort2020>{{cite journal |vauthors=Dufort EM, Koumans EH, Chow EJ, et al. |title=Multisystem inflammatory syndrome in children in New York State |journal=The New England Journal of Medicine |volume= 383|issue= 4|pages= 347–358|date=June 2020 |pmid=32598830 |doi=10.1056/NEJMoa2021756 |pmc=7346766 |doi-access=free }}</ref><ref name=Kaushik2020>{{cite journal |vauthors=Kaushik S, Aydin SI, Derespina KR, et al. |title=Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 infection: a multi-institutional study from New York City |journal=The Journal of Pediatrics |volume= 224|pages= 24–29|date=June 2020 |pmid=32553861 |doi=10.1016/j.jpeds.2020.06.045 |pmc=7293760 |doi-access=free }}</ref><ref name=Cheung2020>{{cite journal |vauthors=Cheung EW, Zachariah P, Gorelik M, et al. |title=Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City |journal=JAMA |volume= 324|issue= 3|date=June 2020 |pages=294–296 |pmid=32511676 |doi=10.1001/jama.2020.10374 |pmc=7281352 |doi-access=free }}</ref> The emerging observations suggested somewhat greater variety in the severity of symptoms than was originally thought.<ref name=NIHchildren/> 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.<ref name=Viner2020/><ref name=Kanthimathinathan2020/><ref name=Schroeder2020/><ref name=Loke2020/><ref name=Kam2020/><ref name=Wiwanitkit2020/><ref name=Rowley2020b/><ref name=Yeung2020/>

By 15 July 342 confirmed MIS-C cases (including 6 deaths) had been recorded in the US across 36 states plus Washington DC.<ref name=CDC-15July>{{cite web |title=Multisystem Inflammatory Syndrome in Children (MIS-C) |url=https://www.cdc.gov/mis-c/cases/index.html |website=cdc.com |publisher=Centers for Disease Control and Prevention |date=15 July 2020 |archive-url=https://web.archive.org/web/20200717095454/https://www.cdc.gov/mis-c/cases/ |archive-date=17 July 2020 |language=en-us |quote=As of 7/15/2020, CDC has received reports of 342 cases and 6 deaths in 37 jurisdictions... the majority of MIS-C patients have been Hispanic/Latino or Non-Hispanic Black....Additional studies into MIS-C are needed to learn why certain racial or ethnic groups may be affected in greater numbers... }}</ref><ref>{{cite news |title=U.S. counts 342 child inflammatory syndrome cases |url=https://triblive.com/news/health-now/u-s-counts-342-child-inflammatory-syndrome-cases/ |work=TribLIVE.com |agency=Associated Press |date=16 July 2020 |archive-url=https://web.archive.org/web/20200717101538/https://triblive.com/news/health-now/u-s-counts-342-child-inflammatory-syndrome-cases/ |archive-date=17 July 2020}}</ref> 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.<ref name=CDC-15July/><ref>{{cite journal |vauthors=Jenco M |title=CDC: 71% of MIS-C patients Hispanic or Black |url=https://www.aappublications.org/news/2020/07/16/miscdata071620 |website=AAP News |publisher=American Academy of Pediatrics |archive-url=https://web.archive.org/web/20200717124958/https://www.aappublications.org/news/2020/07/16/miscdata071620 |archive-date=17 July 2020 |language=en |date=16 July 2020 |url-status=live}}</ref> By 29 July, a total of 570 cases and 10 deaths had been reported across 40 states, Washington DC, and New York City.<ref name=Cato2020/>

Until late May, no confirmed case had been documented outside the EU/EEA/UK and USA.<ref name="ECDC-2020"/> No suspicious case had been observed in East Asia or Southeast Asia (or in Australia or New Zealand).<ref name=Wiwanitkit2020/><ref name=AHPPC2020>{{cite web |title=Australian Health Protection Principal Committee (AHPPC) coronavirus (COVID-19) statements on 14 May 2020 |url=https://www.health.gov.au/news/australian-health-protection-principal-committee-ahppc-coronavirus-covid-19-statements-on-14-may-2020#statement-on-paediatric-inflammatory-multisystem-syndrome |website=Australian Government Department of Health |archive-url=https://web.archive.org/web/20200524143623/https://www.health.gov.au/news/australian-health-protection-principal-committee-ahppc-coronavirus-covid-19-statements-on-14-may-2020 |archive-date=24 May 2020 |url-status=live |language=en |date=15 May 2020}}</ref><ref>{{cite news |vauthors=Barraclough B |title=Chances of Kiwi kids contracting mysterious syndrome linked to Covid-19 'very low', but authorities on the lookout |url=https://www.tvnz.co.nz/one-news/new-zealand/chances-kiwi-kids-contracting-mysterious-syndrome-linked-covid-19-very-low-but-authorities-lookout |work=TVNZ |date=18 May 2020 |archive-url=https://web.archive.org/web/20200602075823/https://www.tvnz.co.nz/one-news/new-zealand/chances-kiwi-kids-contracting-mysterious-syndrome-linked-covid-19-very-low-but-authorities-lookout |url-status=live |archive-date=2 June 2020 |language=en}}</ref> 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.<ref name=Nakra2020/> On 2 June, news emerged of a first case of MIS-C diagnosed in Peru.<ref name=Yanez2020>{{cite journal |vauthors=Yáñez JA, Alvarez-Risco A, Delgado-Zegarra J |s2cid=219970740 |title=COVID-19 in Peru: from supervised walks for children to the first case of Kawasaki-like syndrome |journal=BMJ |volume=369 |article-number=m2418 |date=June 2020 |pmid=32571770 |doi=10.1136/bmj.m2418 |doi-access=free |hdl=20.500.12724/11105 |hdl-access=free }}</ref><ref>{{cite news |title=COVID-19: aparece primer caso de Kawasaki en Perú |url=https://panamericana.pe/buenosdiasperu/salud/294991-covid-19-aparece-primer-caso-kawasaki-peru |work=Panamericana Televisión |date=2 June 2020 |archive-url=https://web.archive.org/web/20200610225535/https://panamericana.pe/buenosdiasperu/salud/294991-covid-19-aparece-primer-caso-kawasaki-peru |archive-date=10 June 2020 |url-status=live |language=es}}</ref> In Brazil, cases of MIS-C have been reported in São Paulo,<ref name=Pereira2020>{{cite journal |vauthors=Pereira MF, Litvinov N, Farhat SC, et al. |title=Severe clinical spectrum with high mortality in pediatric patients with COVID-19 and multisystem inflammatory syndrome |journal=Clinics (Sao Paulo) |volume=75 |article-number=e2209 |date=2020 |pmid=32844958 |doi=10.6061/clinics/2020/e2209 |pmc=7426591 }}</ref> and in the context of a prospective study in Pará;<ref name=Farias2020/> more children with severe late manifestations of COVID-19 were being admitted to paediatric intensive care units in the region.<ref name=Farias2020>{{cite journal |vauthors=de Farias EC, Pedro Piva J, de Mello ML, et al. |title=Multisystem inflammatory syndrome associated with coronavirus disease in children: a multi-centered study in Belém, Pará, Brazil |journal=The Pediatric Infectious Disease Journal |volume= 39|issue= 11|pages= e374–e376|date=August 2020 |pmid=32826724 |doi=10.1097/INF.0000000000002865 |doi-access=free }}</ref> In Chile, 42 confirmed cases of MIS-C had been recorded nationally by 28 June, including 27 in the capital, Santiago.<ref name=Torres2020>{{cite journal |vauthors=Torres JP, Izquierdo G, Acuña M, et al. |title=Multisystem inflammatory syndrome in children (MIS-C): report of the clinical and epidemiological characteristics of cases in Santiago de Chile during the SARS-CoV-2 pandemic |journal=International Journal of Infectious Diseases |date=August 2020 |volume=100 |pages=75–81 |doi=10.1016/j.ijid.2020.08.062 |pmid=32861823 |pmc=7452906 |doi-access=free }}</ref> 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.<ref name=Семенова2020>{{cite news |last1=Семенова |first1=Мария |title=В Москве умер первый ребенок из-за новой болезни, вызванной COVID-19 |url=https://ria.ru/20200617/1573020546.html |access-date=18 June 2020 |agency=RIA Novosti |date=17 June 2020 |language=ru}}</ref> 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,<ref name=Bahrami2020>{{cite journal |vauthors=Bahrami A, Vafapour M, Moazzami B, Rezaei N |title=Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: first case from Iran |journal=Journal of Paediatrics and Child Health |date=July 2020 |volume=57 |issue=6 |pages=922–925 |pmid=32640066 |doi=10.1111/jpc.15048 |pmc=7361532 |doi-access=free }}</ref> and further cases of the new syndrome have been recorded.<ref name=Mamishi2020>{{cite journal |vauthors=Mamishi S, Heydari H, Aziz-Ahari A, et al. |title=Novel coronavirus disease 2019 (COVID-19) outbreak in children in Iran: atypical CT manifestations and mortality risk of severe COVID-19 infection |journal=Journal of Microbiology, Immunology, and Infection |date=August 2020 |volume=54 |issue=5 |pages=839–844 |pmid=32814650 |doi=10.1016/j.jmii.2020.07.019 |pmc=7406416 |doi-access=free }}</ref> 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.<ref name=Rauf2020>{{cite journal |vauthors=Rauf A, Vijayan A, John ST, Krishnan R, Latheef A |title=Multisystem inflammatory syndrome with features of atypical Kawasaki disease during COVID-19 pandemic |journal=Indian Journal of Pediatrics |volume= 87|issue= 9|pages= 745–747|date=May 2020 |pmid=32462354 |doi=10.1007/s12098-020-03357-1 |pmc=8823324 |doi-access=free }}</ref> 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.<ref name=Shah2020>{{cite journal |vauthors=Shah SK, Munoz AC |title=Multisystem inflammatory syndrome in children in COVID-19 pandemic |journal=Indian Journal of Pediatrics |volume= 87|issue= 9|pages= 671–673|date=July 2020 |pmid=32621172 |doi=10.1007/s12098-020-03440-7 |pmc=7332842 |doi-access=free }}</ref>

During July, suspected cases were being flagged and reported in Mumbai,<ref name=Jain2020>{{cite journal |vauthors=Jain S, Sen S, Lakshmivenkateshiah S, et al. |title=Multisystem inflammatory syndrome in children with COVID-19 in Mumbai, India |journal=Indian Pediatrics |date=August 2020 |volume=57 |issue=11 |pages=1015–1019 |pmid=32788432 |doi= 10.1007/s12098-020-03497-4|issn=0019-5456 |pmc=7678602 |s2cid=221674522 }}</ref> in Delhi,<ref name=Saxena2020>{{cite news |vauthors=Saxena A |title=Delhi hospitals see Kawasaki-like symptoms in children with Covid |url=https://indianexpress.com/article/cities/delhi/delhi-hospitals-see-kawasaki-like-symptoms-in-children-with-covid-6511309/ |work=The Indian Express |date=18 July 2020 |archive-url=https://web.archive.org/web/20200718074915/https://indianexpress.com/article/cities/delhi/delhi-hospitals-see-kawasaki-like-symptoms-in-children-with-covid-6511309/ |archive-date=18 July 2020 |language=en |url-status=live}}</ref> Chennai,<ref name=Dhanalakshmi2020>{{cite journal |vauthors=Dhanalakshmi K, Venkataraman A, Balasubramanian S, et al. |title=Epidemiological and clinical profile of pediatric inflammatory multisystem syndrome - temporally associated with SARS-CoV-2 (PIMS-TS) in Indian children |journal=Indian Pediatrics |date=August 2020 |volume=57 |issue=11 |pages=1010–1014 |doi=10.1007/s13312-020-2025-1 |pmid=32769230 |pmc=7678572 }}</ref> and elsewhere.<ref>{{cite news |title=Kawasaki syndrome or MIS-C: Children recovering from COVID-19 also face the brunt of the disease |url=https://www.firstpost.com/health/kawasaki-syndrome-or-mis-c-children-recovering-from-covid-19-also-face-the-brunt-of-the-disease-8538361.html |work=Firstpost |date=20 July 2020 |archive-url=https://web.archive.org/web/20200720085344/https://www.firstpost.com/health/kawasaki-syndrome-or-mis-c-children-recovering-from-covid-19-also-face-the-brunt-of-the-disease-8538361.html |archive-date=20 July 2020 |access-date=20 July 2020 }}</ref> In Pakistan,<ref name=Khan2020>{{cite journal |vauthors=Khan KS, Ullah I |title=SARS-CoV-2 causes Kawasaki like disease in children; cases reported in Pakistan |journal=Journal of Medical Virology |date=July 2020 |volume=93 |issue=1 |pages=20–21 |pmid=32706410 |doi=10.1002/jmv.26340 |pmc=7405107 |doi-access=free }}</ref> at least 24 children were said to have Kawasaki-like symptoms in Lahore,<ref name=Umer2020>{{cite news |vauthors=Umer D, Ahmed T |title=Post-coronavirus Kawasaki-like inflammatory syndrome reported in eight children in Lahore |url=https://www.samaa.tv/news/2020/07/post-coronavirus-kawasaki-like-inflammatory-syndrome-reported-in-eight-children-in-lahore/ |work=Samaa TV |date=8 July 2020 |archive-url=https://web.archive.org/web/20200709010643/https://www.samaa.tv/news/2020/07/post-coronavirus-kawasaki-like-inflammatory-syndrome-reported-in-eight-children-in-lahore/ |archive-date=9 July 2020 |url-status=live}}</ref> where 8 cases fulfilling WHO criteria were prospectively identified by 30 June.<ref name=Sadiq2020>{{cite journal |vauthors=Sadiq M, Aziz OA, Kazmi U |title=Multisystem inflammatory syndrome associated with COVID-19 in children in Pakistan |journal=The Lancet Child & Adolescent Health |date=August 2020 |volume=4 |issue=10 |pages=e36–e37 |pmid=32791052 |doi=10.1016/S2352-4642(20)30256-X |pmc=7417160 |doi-access=free}}</ref> In Kazakhstan, 14 cases were confirmed by 20 August (among 2,357 children known to have been infected).<ref name=Ali2020>{{cite news |vauthors=Ali M |title=Kazakh ministry refutes claims about Kawasaki syndrome outbreak in children amid COVID-19 |url=https://www.urdupoint.com/en/world/kazakh-ministry-refutes-claims-about-kawasaki-1007293.html |work=www.urdupoint.com |publisher=UrduPoint |date=20 August 2020 |archive-url=https://web.archive.org/web/20200821162114/https://www.urdupoint.com/en/world/kazakh-ministry-refutes-claims-about-kawasaki-1007293.html |archive-date=21 August 2020 |url-status=live |language=en}}</ref> Cases have been recorded in Israel,<ref name=Sheba2020>{{cite web |title=New inflammatory syndrome |url=https://www.shebaonline.org/new-inflammatory-syndrome/ |website=Sheba Medical Center |archive-url=https://web.archive.org/web/20200711091231/https://www.shebaonline.org/new-inflammatory-syndrome/ |archive-date=11 July 2020 |url-status=live |date=25 May 2020}}</ref> including one of a child who presented with severe central nervous system involvement and complement deficiency.<ref name=Regev2020>{{cite journal |vauthors=Regev T, Antebi M, Eytan D, et al. |title=Pediatric inflammatory multisystem syndrome with central nervous system involvement and hypocomplementemia following SARS-CoV-2 infection |journal=The Pediatric Infectious Disease Journal |volume= 39|issue= 8|pages= e206–e207|date=June 2020 |pmid=32639461 |doi=10.1097/INF.0000000000002804 |doi-access=free }}</ref> 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.<ref name=Akca2020>{{cite journal |vauthors=Akca UK, Kesici S, Ozsurekci Y, et al. |title=Kawasaki-like disease in children with COVID-19 |journal=Rheumatology International |volume= 40|issue= 12|pages= 2105–2115|date=September 2020 |pmid=32936318 |doi=10.1007/s00296-020-04701-6 |pmc=7492688 |doi-access=free }}</ref> In Algeria, a first case was recorded in June.<ref name=Saada2020>{{cite news |vauthors=Saada H |title=Algeria registers first case of Kawasaki disease |url=https://www.dzbreaking.com/2020/06/16/algeria-registers-first-case-of-kawasaki-disease/ |work=DZ Breaking |archive-url=https://web.archive.org/web/20200711092523/https://www.dzbreaking.com/2020/06/16/algeria-registers-first-case-of-kawasaki-disease/ |archive-date=11 July 2020 |url-status=live}}</ref> In Egypt, on 10 July the authorities denied rumours of the existence of cases of Kawasaki-like disease in the country.<ref>{{cite news |title=Egypt free from Kawasaki disease: Cabinet |url=https://www.egypttoday.com/Article/1/89509/Egypt-free-from-Kawasaki-disease-Cabinet |work=EgyptToday |date=10 July 2020 |archive-url=https://web.archive.org/web/20200711093936/https://www.egypttoday.com/Article/1/89509/Egypt-free-from-Kawasaki-disease-Cabinet |archive-date=11 July 2020 |url-status=live}}</ref> 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.<ref name=Webb2020>{{cite journal |vauthors=Webb K, Abraham DR, Faleye A, et al. |title=Multisystem inflammatory syndrome in children in South Africa |journal=The Lancet Child & Adolescent Health |date=August 2020 |volume=4 |issue=10 |pages=S2352464220302728 |doi=10.1016/S2352-4642(20)30272-8|pmid=32835654 |pmc=7442431 |s2cid=221217603 }}</ref> In Ecuador, the Ministry of Health announced on 19 July the presence of 46 probable cases.<ref name="Teleamazonas">{{cite news |title=45 casos probables de menores con síndrome inflamatorio multisistémico |url=http://www.teleamazonas.com/etiqueta/sindrome-relacionado-al-covid/ |work=Teleamazonas |date=19 July 2020 |archive-url=https://web.archive.org/web/20200720082615/http://www.teleamazonas.com/etiqueta/sindrome-relacionado-al-covid/ |archive-date=20 July 2020 |language=es}}</ref> In Costa Rica, a national public health organization announced towards the end of August that three children had been diagnosed with MIS-C.<ref name=Diario2020>{{cite news |title=Costa Rica registra récord de casos diarios y niños con peligroso síndrome |url=https://www.diariolibre.com/actualidad/internacional/costa-rica-registra-record-de-casos-diarios-y-ninos-con-peligroso-sindrome-OC21102862 |work=www.diariolibre.com |publisher=Diario Libre |date=29 August 2020 |archive-url=https://web.archive.org/web/20200831120910/https://www.diariolibre.com/actualidad/internacional/costa-rica-registra-record-de-casos-diarios-y-ninos-con-peligroso-sindrome-OC21102862 |archive-date=31 August 2020 |language=es-ES}}</ref> 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.<ref name=Ulloa2020/> News of a first confirmed case of PIMS-TS in Australia emerged (from Victoria) on 4 September, along with news of other suspected cases under review.<ref name=Scott2020>{{cite news |vauthors=Scott S, McElroy N|title=A children's inflammatory illness associated with COVID-19 has emerged in Australia. Here's what we know |url=https://www.abc.net.au/news/2020-09-04/pims-ts-kawasaki-covid-19-children-disease-australia-explained/12627610 |access-date=4 September 2020 |work=ABC news |date=4 September 2020 |language=en-AU}}</ref> In South Korea, news of two confirmed cases broke on 5 October<ref name=Yonhap2020>{{cite news |title=S. Korea confirms 2 MIS-C cases |url=https://en.yna.co.kr/view/AEN20201005006800320 |work=Yonhap News Agency |date=5 October 2020 |archive-url=https://web.archive.org/web/20201031145944/https://en.yna.co.kr/view/AEN20201005006800320 |archive-date=31 October 2020 |language=en}}</ref> (and the existence of a case dating back to the end of April was reported in November<ref name=Kim2020a/>).

A similar condition began to be recognized in some adults.<ref name=Most2020/><ref name=Morris2020/><ref name=Wood2020/> In June, an adult case of a Kawasaki-like multisystem inflammatory syndrome following SARS-CoV-2 infection was described in a 54-year-old woman from Israel with no history of autoimmune disease, who experienced uveitis in both eyes.<ref name=Bettach2020>{{cite journal |vauthors=Bettach E, Zadok D, Weill Y, Brosh K, Hanhart J |title=Bilateral anterior uveitis as a part of a multisystem inflammatory syndrome secondary to COVID-19 infection |journal=Journal of Medical Virology |date=June 2020 |volume=93 |issue=1 |pages=139–140 |pmid=32592496 |doi=10.1002/jmv.26229 |pmc=7361787 |doi-access=free }}</ref> (A further suspected adult case was covered in the Israeli national press.)<ref>{{cite news |title=Youngest Israeli victim: 26-year-old man dies from rare complication of COVID-19 |url=https://www.timesofisrael.com/26-year-old-man-dies-from-rare-complication-of-covid-19/ |work=Times of Israel |date=14 June 2020 |archive-url=https://web.archive.org/web/20200706070759/https://www.timesofisrael.com/26-year-old-man-dies-from-rare-complication-of-covid-19/ |archive-date=6 July 2020 |url-status=live}}</ref> A case involving a 36-year-old Hispanic American woman with clinical features otherwise consistent with MIS-C was reported from New York.<ref name=Sokolovsky2020>{{cite journal |vauthors=Sokolovsky S, Soni P, Hoffman T, Kahn P, Scheers-Masters J |title=COVID-19 associated Kawasaki-like multisystem inflammatory disease in an adult |journal=The American Journal of Emergency Medicine |date=June 2020 |volume=39 |pages=253.e1–253.e2 |pmid=32631771 |doi=10.1016/j.ajem.2020.06.053 |pmc=7315983 }}</ref> A diagnosis consistent with PMIS was also reported in a UK-born, 21-year-old man of Somali origin.<ref name=Jones2020a>{{cite journal |vauthors=Jones I, Bell L, Manson J, Last A |s2cid=220460929 |title=An adult presentation consistent with PIMS-TS |journal=The Lancet Rheumatology |date=July 2020 |volume=2 |issue=9 |pages=e520–e521 |doi=10.1016/S2665-9913(20)30234-4 |pmid=32838310 |pmc=7351404 |url=}}</ref> A case report published in ''The Lancet'' regarding a 45-year-old Hispanic man who presented in New York with features strongly resembling MIS-C called for awareness of "a potential MIS-C-like condition in adults."<ref name=Shaigany2000>{{cite journal |vauthors=Shaigany S, Gnirke M, Guttmann A, et al. |title=An adult with Kawasaki-like multisystem inflammatory syndrome associated with COVID-19 |journal=The Lancet |volume= 396|issue= 10246|pages= e8–e10|date=July 2020 |pmid=32659211 |doi=10.1016/S0140-6736(20)31526-9 |pmc=7351414 |doi-access=free }}</ref> Further reports of multisystem inflammatory syndrome linked to COVID-19 exposure emerged in adults.<ref name=Wood2020>{{cite news |last1=Wood |first1=S |title=COVID-19's Kawasaki-like MIS-C diagnosis is cropping up in adults |url=https://www.tctmd.com/news/covid-19s-kawasaki-mis-c-diagnosis-cropping-adults |work=TCTMD.com |date=22 July 2020 |archive-url=https://web.archive.org/web/20200723091901/https://www.tctmd.com/news/covid-19s-kawasaki-mis-c-diagnosis-cropping-adults |archive-date=23 July 2020 |url-status=live |language=en}}</ref><ref name=Fox2020>{{cite journal |vauthors=Fox SE, Lameira FS, Rinker EB, Vander Heide RS |title=Cardiac endotheliitis and multisystem inflammatory syndrome after COVID-19 |journal=Annals of Internal Medicine |date=July 2020 |volume=173 |issue=12 |pages=1025–1027 |pmid=32726150 |doi=10.7326/L20-0882 |pmc=7506743 |doi-access=free }}</ref><ref name=Cherif2020>{{cite journal |vauthors=Chérif MY, de Filette JM, André S, et al. |title=Coronavirus disease 2019-related Kawasaki-like disease in an adult: a case report |journal=JAAD Case Reports |volume=6 |issue=8 |pages=780–782 |date=August 2020 |pmid=32754629 |doi=10.1016/j.jdcr.2020.06.023 |pmc=7311326 |doi-access=free }}</ref><ref name=Lidder2020>{{cite journal |vauthors=Lidder AK, Pandit SA, Lazzaro DR |title=An adult with COVID-19 kawasaki-like syndrome and ocular manifestations |journal=American Journal of Ophthalmology Case Reports |volume=20 |article-number=100875 |date=December 2020 |pmid=32839740 |doi=10.1016/j.ajoc.2020.100875 |pmc=7437437 }}</ref><ref name=Chowdhary2020>{{cite journal |vauthors=Chowdhary A, Joy E, Plein S, Abdel-Rahman SE |title=Multisystem inflammatory syndrome in an adult with SARS-CoV-2 infection |journal=European Heart Journal: Cardiovascular Imaging |date=September 2020 |volume=22 |issue=5 |pages=e17 |pmid=32887992 |doi=10.1093/ehjci/jeaa232 |pmc=7499519 |doi-access=free }}</ref> In October, the CDC reported on the condition and named it 'multisystem inflammatory syndrome in adults' (MIS-A).<ref name=Morris2020/> Questions have been raised regarding possible relationships between MIS-C and certain severe manifestations of COVID-19 in adults.<ref name=Most2020/>

Children's neurological symptoms, as studied in London in mid-2020, often involved "both the central and peripheral nervous systems," according to a report by the American Academy of Neurology released on 13 April 2021.<ref>{{Cite web|last=American Academy of Neurology|date=13 April 2021 |title=73rd AAN ANNUAL MEETING ABSTRACT (PDF) |url=https://aanfiles.blob.core.windows.net/aanfiles/6776ad04-51b5-4048-a329-4dfd91eaddb1/EMBARGOED%20AAN%20Abstract%20-%20Neurologic%20and%20radiographic%20findings%20associated%20with%20Pediatric%20Inflammatory%20Multisystem%20Syndrome...%20-%20Abdel-Mannan%20titled.pdf |access-date=20 April 2021}}</ref><ref>{{Cite news |last=Belluck |first=Pam |date=2021-04-13 |title=Some Children With Covid-Related Syndrome Develop Neurological Symptoms|language=en-US|work=The New York Times|url=https://www.nytimes.com/2021/04/13/health/covid-children-inflammatory-syndrome.html |access-date=2021-04-20|issn=0362-4331}}</ref>

== Explanatory notes == {{Notelist|2|group=n}}

==References== {{Reflist}}

== External links == * [https://www1.nyc.gov/assets/doh/downloads/pdf/imm/covid-19-school-children-faq.pdf Fact sheet for parents and Caregivers of Pre-School and School-Age Children] {{Webarchive|url=https://web.archive.org/web/20201017040643/https://www1.nyc.gov/assets/doh/downloads/pdf/imm/covid-19-school-children-faq.pdf |date=17 October 2020 }} released by New York City's Health Department * [https://www.chla.org/blog/health-and-safety-tips/pediatric-inflammatory-multisystem-syndrome-pims-what-parents-should Information for parents] provided by the Children's Hospital Los Angeles * [https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.html#anchor_1589580133375 Information for paediatric health care providers] in the U.S.A. (from the CDC)

{{medical resources | ICD11 = {{ICD11|RA03}} | ICD10 = {{ICD10|U10.9}} | SNOMED CT = 895448002 }} {{COVID-19 pandemic}} {{Portal bar|Medicine|COVID-19}}

Category:Ailments of unknown cause Category:Impact of the COVID-19 pandemic on other health issues Category:Inflammations Category:Pediatrics Category:Syndromes