Paediatric multisystem inflammatory syndrome

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Pediatric multi-system inflammatory syndrome (PMIS)[1]
Other namesMultisystem inflammatory syndrome in children (MIS-C);[2]
multisystem inflammatory disorder in children and adolescents;[3]
pediatric inflammatory multisystem syndrome (PIMS), temporally associated with SARS-CoV-2 infection (PIMS-TS)[4]

Paediatric multisystem inflammatory syndrome (PMIS), or multisystem inflammatory syndrome in children (MIS-C), is a systemic disease involving persistent fever, inflammation and organ dysfunction following exposure to SARS-CoV-2, the virus responsible for COVID-19.[1][2][3]

This syndrome resembles Kawasaki disease (a rare disease of unknown origin that affects young children, in which blood vessels become inflamed throughout the body).[4][5] It can also appear similar to other serious paediatric inflammatory conditions, including toxic shock and macrophage activation syndromes.[1] Failure of one or more organs can occur.[1] Early recognition of this disease is essential, followed by prompt admission to hospital for specialist attention.[1][4]

Low blood pressure is common.[1] The first symptoms are sometimes acute abdominal pain, diarrhoea or vomiting.[1] Other symptoms can include conjunctivitis, rashes, mucous membrane changes, enlarged lymph nodes, swollen hands and feet, sore throat, cough, fainting, irritability and confusion.[1][3][4] Respiratory symptoms are not always present.[4] Cardiological findings may include clinical features of myocarditis, pericarditis, valvulitis, or coronary artery abnormalities,[1][3] including dilatation and aneurysms.[4]

Oxygen therapy may be needed, and some children require paediatric intensive care.[1] Limited information exists regarding clinical course of this life-threatening disease,[2][3] which may occasionally be fatal.[4]

Several major health organizations have issued statements on this emerging condition (using various names).[1][2][3][4] In particular:

Although the condition is thought to follow SARS-CoV-2 viral infection, antigen or antibody tests are not always positive.[4] Exclusion of other possible microbial (including bacterial) causes is always essential for differential diagnosis.[4]

The biological mechanism of the disease is not known, and no risk factors are known either.[4] The condition is considered rare.[4] 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.[4] So far, reports have regarded children in various parts of Europe and the U.S.[3] It is unclear whether the condition has gone unrecognized elsewhere.[3]

This is a newly-proposed clinical entity, and it has also been argued that cases meeting the criteria for Kawasaki disease or myocarditis should be diagnosed and treated as such.[6]


Paediatric cases of COVID-19 have been relatively uncommon, possibly because children generally appear to display milder symptoms.[1][3][4] While cases with severe symptoms are much rarer, they can occasionally require intensive care.[4] Some children with evidence of SARS-CoV-2 infection or exposure to COVID-19 display clinical features corresponding to the diagnostic criteria of Kawasaki disease, sometimes accompanied by shock.[4][7]

Kawasaki disease is a rare syndrome which mainly affects young children.[4][8][5] It is a form of vasculitis, where blood vessels become inflamed throughout the body, and it results in a persistent fever.[4] Recovery typically occurs spontaneously, though some children go on to develop mid-sized or giant coronary artery aneurysms in the heart – a potentially fatal complication.[4][9] Symptoms of toxic shock occasionally occur – an association sometimes referred to as 'Kawasaki shock syndrome', which is characterized by systolic hypotension or signs of poor perfusion.[4][10] While the cause of Kawasaki disease is unknown, one possible explanation is that it may stem from an infection triggering an autoimmune (or autoinflammatory[6][11]) response in children who are genetically predisposed.[4][8] 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, lymphadenopathy, conjunctivitis, and changes to the mucous membranes and extremities).[4][8][12]

Review of the characteristics of cases of Kawasaki-like disease with links to COVID-19 prompted a preliminary case definition of PMIS (as formulated by the RCPCH).[1][7]


Preliminary WHO case definition[3]
Children and adolescents
  • 0–19 years of age with fever >3 days


  • Two of the following:
  1. Rash or bilateral non-purulent conjunctivitis
    or muco-cutaneous inflammation signs
    (oral, hands or feet)
  2. Hypotension or shock
  3. Features of myocardial dysfunction, pericarditis,
    valvulitis, or coronary abnormalities
    (including ECHO findings or elevated Troponin/NT-proBNP)
  4. Evidence of coagulopathy
    (by PT, PTT, elevated d-Dimers)
  5. Acute gastrointestinal problems
    (diarrhoea, vomiting, or abdominal pain)


  • Elevated markers of inflammation
    such as ESR, C-reactive protein, or procalcitonin


  • No other obvious microbial cause of inflammation,
    including bacterial sepsis,
    staphylococcal or streptococcal shock syndromes


  • 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.)

PMIS is a systemic inflammation, involving persistent fever, inflammation and organ dysfunction, which is suspected to be associated with COVID-19.[1][2] The condition may match some or all of the diagnostic criteria for Kawasaki disease (i.e. the 'complete' or 'incomplete'/'atypical' subtypes[12]).[1] It can also share clinical features with other paediatric inflammatory conditions, including toxic shock syndrome, septic shock,[13] and macrophage activation syndrome.[1] Some children have a less severe Kawasaki-like disease.[7]

Low blood pressure is common.[1] The condition can present with unusual abdominal symptoms, accompanied by pronounced inflammatory markers.[1] Acute gastrointestinal symptoms can include abdominal pain, and diarrhoea or vomiting.[3] Other symptoms may include conjunctivitis, rashes, mucous membrane changes, enlarged lymph nodes, swollen hands and feet, sore throat, cough and respiratory symptoms, fainting, irritability and confusion.[1][3][4] Cardiological findings may include clinical features of myocarditis, pericarditis, valvulitis, or coronary artery abnormalities, such as dilatation.[1][3][4] Some patients have coronary artery aneurysms.[4][7] Shock is often of myocardial origin.[4] Respiratory symptoms are not always present.[4] Breathing difficulties are often linked to shock.[4]

Early recognition of the disease is essential, followed by prompt admission to hospital, with referral to specialists (in paediatric infectious diseases, cardiology, rheumatology, etc).[1][4] Supplemental oxygen may be required, and paediatric intensive care may also be needed.[1] Limited information currently exists regarding clinical course.[2][3] Fatalities have been recorded (five, as of 11 May 2020).[4]


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.[3] Early recognition and specialist referral, including to critical care, is considered essential.[1]

  • The World Health Organization (WHO) has released a scientific brief on links between multisystem inflammatory syndrome and COVID-19.[3] The brief, released on 15 May, 2020, includes a preliminary WHO case definition (for 'multisystem inflammatory disorder in children and adolescents'), based on currently available knowledge.[3] The WHO has established a platform for standardized, anonymized clinical data, along with a dedicated case report form.[3] The WHO underlines the "urgent need for collection of standardized data describing clinical presentations, severity, outcomes, and epidemiology."[3]
  • The Centers for Disease Control and Prevention (CDC) has also published a case definition.[2] The CDC 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)."[2]

    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.[2] The CDC advises U.S. health providers to inform public health authorities of suspected cases.[2]

Differential diagnosis[edit]

It is essential to exclude other alternative microbial causes, including bacterial sepsis, staphylococcal and streptococcal shock, and infections associated with myocarditis, such as enterovirus.[1][4] (Of note, coinfection with additional pathogens, such as human metapneumovirus, may sometimes occur.)[4]


The RCPHC has provided guidance on clinical management and treatment.[1]

Little specific information is available regarding therapeutic effectiveness.[2][3] Anti-inflammatory treatments have been used, including intravenous immunoglobulin and corticosteroids.[3][15] RCPCH guidance recommends that all affected children should be treated as having suspected COVID-19, and that for mild or moderate disease supportive care alone may be sufficient.[1]

The RCPHC recommends that any administration of a candidate antiviral therapy should − whenever possible − be performed in the context of a registered clinical trial (e.g. the RECOVERY study).[1] In the U.K., ongoing collaborations are aiming to ensure that all infected children are able to take part in a mechanistic study such as DIAMONDS or ISARIC-CCP.[1][7] (In the European Union, children do not usually participate in clinical trials of new antiviral and monoclonal antibody treatments for severe COVID-19.)[4]

Treatment strategies are being considered to prevent serious long-term complications such as coronary artery aneurysms (the main complication of Kawasaki disease).[7]


Based on laboratory findings, it has been hypothesized that the condition may be related to COVID-19.[3][4] Further characterization of the syndrome is essential to identify risk factors and help understand causality.[3] Improved understanding will have potential implications for clinical management.[16]

It has been emphasized that the potential link of this rare condition with COVID-19 "is neither established nor well understood."[4] A temporal association between SARS-CoV-2 infection and clinical presentation of the syndrome is plausible.[4] 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.[4]


The pathogenesis is unknown.[2][4] It has been suggested that, as with Kawasaki disease, one possible mechanism is antibody-dependent enhancement, whereby development of antibodies facilitates viral entry into host cells.[4] It has also been suggested that the condition may be caused by the cytokine storms induced by COVID-19.[17] It has been noted that a leading hypothesis for the pathogenesis of Kawasaki disease also involves a hyperinflammatory response to viral infection in some genetically predisposed children.[6]

On pathophysiological grounds, it has been argued that association of Kawasaki disease with COVID-19 may support the view that SARS-CoV-2 can cause a systemic vasculitis by targeting endothelial tissue via angiotensin-converting enzyme 2 (ACE2), the protein which the virus uses to gain access to cells.[18]


Epidemiological information is scarce.[3] Suspected cases began to be recorded in Europe and the U.S. around April 2020, and several hundred possible cases were recorded by mid-May, along with at least five fatalities.[4][19][20]

Clinicians in Bergamo (Italy) reported an apparent 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 the country).[7][21]

This emerging diagnosis is considered rare.[4] 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, European Economic Area and the U.K. "is considered 'low', based on a 'very low' probability of [the disease] in children and a 'high' impact of such disease."[4]

Regarding geographical distribution, it is unclear whether currently available reports of cases in Europe and North America reflect a true pattern, or whether the condition has gone unrecognized elsewhere.[3]

This is a newly-proposed clinical entity, and it has also been argued that cases meeting the criteria for Kawasaki disease or myocarditis should be diagnosed and treated as such.[6]


Cases of Kawasaki disease with concurrent SARS-CoV-2 infection have been recorded among children in Europe and the U.S.A. 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.[4][22] In this case, COVID-19 did not appear to have significant clinical implications.[16][22]

On 25 April, concerns were initially raised in the U.K. 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."[7][23] Details of the eight cases which helped trigger this alert (not all with confirmed exposure to COVID-19) were later reported in The Lancet,[16] where the authors summarized the clinical picture as "a hyperinflammatory syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome."[19]

Accounts of analogous cases – including some that appeared less clinically severe – were also being informally shared among clinicians around Europe.[7] 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.[16] In France, the government reported on 29 April that around 15 children were in hospital in Paris with symptoms of Kawasaki disease.[16][24]

On 1 May, the RCPCH published a preliminary case definition based on review of the characteristics of the cases identified in the U.K., accompanied by some clinical guidance.[1][7] Two weeks later, on 15 May, two further preliminary case definitions were published separately by the WHO[3] and by the CDC,[2] while the ECDC released a 'rapid risk assessment' of the condition on behalf of the European Union.[4]

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,[4] where 15 such cases were already being treated.[25]

By mid-May, several hundred potential cases were being investigated in areas affected by COVID-19 across Europe and the U.S.A.[4] (including 200 or more across the United States,[26] with some 145 in New York,[27][28] as well as up to 100 in UK,[29] over 135 in France,[30] 20 in the Netherlands, [31] 10 in Switzerland,[32] and 10 in Germany[33]). As of 11 May 2020, five fatalities were reported (1 in France, 1 in the UK, 3 in the US).[4]


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