Paediatric multisystem inflammatory syndrome

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]

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]
SpecialtyPediatrics

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

Older children tend to be affected.[6] The first symptoms may be acute abdominal pain, diarrhoea or vomiting.[1] Low blood pressure is common.[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]

Myocarditis (inflammation of the heart muscle) is a frequent form of cardiac involvement.[5] Others may include pericarditis, valvulitis, and coronary artery abnormalities,[1][3] such as dilatation.[4] Cytokine storm may occur.[6]

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 has occasionally proved 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 largely regarded children in various parts of Europe and the U.S.[3] It is unclear whether the condition has gone unrecognized elsewhere.[3]

Background

Symptomatic cases of COVID-19 in children have been relatively uncommon,[7] possibly because they generally experience milder disease.[8] While cases with severe symptoms are exceptional, they can occasionally require intensive care.[9][10] A few 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.[11]

Kawasaki disease is a rare syndrome which mainly affects young children.[4][12][13] 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][14] Symptoms of toxic shock occasionally occur – an association sometimes referred to as 'Kawasaki shock syndrome',[15] which is characterized by systolic hypotension or signs of poor perfusion.[4][16] 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.[17][18][19] 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][12][20]

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][11]

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

AND

  • 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)

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.)

PMIS is a systemic inflammation, involving persistent fever, inflammation and organ dysfunction, which is temporally associated with exposure to COVID-19.[1][2] Onset may be delayed or contemporary with ongoing SARS-CoV-2 infection.[5] It may occur several weeks after the initial infection.[15]

The condition may match some or all of the diagnostic criteria for Kawasaki disease (i.e. the 'complete' or 'incomplete'/'atypical' subtypes[20]),[1] or for Kawasaki disease shock syndrome.[15] It tends to affect older children and adolescents, whereas Kawasaki disease most often occurs before the age of five.[6] It can also share clinical features with other paediatric inflammatory conditions, including toxic shock syndrome, septic shock,[21] and macrophage activation syndrome.[1]

Children may present with symptoms not commonly associated with Kawasaki disease,[5] including unusual abdominal symptoms, accompanied by pronounced inflammatory markers.[1] Acute gastrointestinal symptoms can include abdominal pain, and diarrhoea or vomiting.[3] Low blood pressure is common.[1] 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]

Some children display features of a cytokine storm, including high serum interleukin-6 (IL-6) levels, and need inotropic support to maintain cardiac output.[6] Cardiac involvement and features of macrophage activation syndrome appear to be more frequent than in Kawasaki disease.[22] Characteristic laboratory findings that are not usually encountered in Kawasaki disease include leukopaenia and very elevated levels of ventricular natriuretic peptide, a marker of heart failure.[6] Cardiological findings may include clinical features of myocarditis, pericarditis, valvulitis, or coronary artery abnormalities, such as dilatation.[1][3][4] Some children may have coronary artery aneurysms (assuming that Kawasaki disease was not the actual underying cause[6]).[4][11] Shock is often of myocardial origin.[4] Respiratory symptoms are not always present.[4] Breathing difficulties are often linked to shock.[4]

Limited information currently exists regarding clinical course,[2][3] which tends to be more severe than with conventional Kawasaki disease.[5] 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] Myocarditis is frequent.[5] Fatalities (five, as of 11 May 2020[4]) have resulted from complications of extracorporeal membrane oxygenation.[6] Some children exposed to COVID-19 also appear to have a less severe Kawasaki-like disease.[11]

Diagnosis

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 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.[15] In particular:

  • The preliminary WHO case definition is for 'multisystem inflammatory disorder in children and adolescents' (box).[3] 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."[3]
  • 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)."[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] 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).[6] 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.[2]

Differential diagnosis

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]

Differential diagnosis with Kawasaki disease can be challenging, given the lack of a diagnostic test for either condition.[6] It is not currently known whether the newly described condition is superimposable with Kawasaki disease shock syndrome.[15] 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."[24]

Treatment

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 (IVIG) and corticosteroids.[3][25] Cases requiring steroids due to resistance to intravenous immunoglobulin may be more common than in Kawasaki disease.[5] 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. RECOVERY).[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][11] (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).[11]

Causes

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.[26]

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]

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).[6] Genome-wide association studies should provide insights on susceptibility and potential biological mechanisms.[5].

Mechanism

The pathogenesis is unknown.[2][4] SARS-CoV-2 could have one of several roles; it could act as a trigger for the condition either directly or indirectly (by somehow paving the way for a different trigger).[18]

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.[27] 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.[6]

On pathophysiological grounds, the frequent gastrointestinal (rather than respiratory) presentation, along with findings of mesenteric lymph node inflammation, suggests predominant replication in the gastrointestinal tract by a virus with a known predilection for enterocytes.[6] 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.[28]

Key research questions regarding the underlying molecular mechanisms that lead to PMIS 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.[5] 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.[5]

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,[17] and that SARS-CoV-2 is now included in the list of implicated viral triggers.[5]

Epidemiology

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][29][30] 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."[31]

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).[11][32]

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 (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."[4]

Regarding geographical distribution, it is unclear whether the reports of cases in Europe and North America reflect a true pattern, or whether the condition has gone unrecognized elsewhere (diagnosis of Kawasaki disease usually being more frequent in Asian countries[5]).[3] No apparent increase in cases of Kawasaki disease was observed in Asian countries such as Japan and South Korea,[33] where Kawasaki disease is usually much more prevalent than in Europe.[4]

Reports from France and the U.K. raise the possibility that children of Afro-Caribbean descent may be at greater risk, plausibly due to a genetic predisposition.[5] It has been suggested that this condition may affect more children of African American, Caribbean, and Hispanic ancestry, whereas Kawasaki disease affects more of East Asian ancestry, although the role of socioeconomic and other environmental factors in such distinctions is unclear.[18]

This is a newly-proposed clinical entity, and an opinion has also been expressed that cases meeting the criteria for Kawasaki disease or myocarditis should be diagnosed and treated as such.[17] Concerns have also been raised regarding the potential for missed or delayed diagnosis of Kawasaki disease due to heightened diagnostic suspicion for the new entity.[24]

Hopes have been expressed that study of the new condition may help understand the hidden mechanisms behind Kawasaki disease.[11]

History

Cases of Kawasaki disease with concurrent SARS-CoV-2 infection have been recorded among children in Europe and in the United States since 7 April 2020, when a report was published by the American Academy of Pediatrics regarding a case of 'classic' Kawasaki disease in a six-month old girl who tested positive for COVID-19.[4][34] In this case, COVID-19 did not appear to have significant clinical implications.[26][34]

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."[11][35] Details of the eight cases which helped trigger this alert (not all with confirmed exposure to COVID-19) were later reported in The Lancet,[26] where the authors summarized the clinical picture as "a hyperinflammatory syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome."[29]

Accounts of analogous cases – including some that appeared less clinically severe – were also being informally shared among clinicians around Europe.[11] The EU’s Early Warning and Response System flagged supected cases in in Austria, Germany and Portugal that had tested positive for SARS-CoV-2.[4]

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.[26] In France, the government reported on 29 April that around 15 children were in hospital in Paris with symptoms of Kawasaki disease,[26][36] an observation which prompted the organization of national surveillance programme for recent cases of Kawasaki-like disease.[31]

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.[1][11] 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.[37]

By 12 May, some 230 suspected cases had been reported across the EU, EEA and UK[4] (in the following days, sources were reporting up to 100 in the UK,[38] over 135 in France,[39] 20 in the Netherlands,[40] 10 in Switzerland[41] and 10 in Germany[42]). In the United States, more than 200 cases were suspected by mid-May,[43] including some 145 in New York.[44][45] As of 11 May 2020, five fatalities were reported (1 in France, 1 in the UK, 3 in the US).[4]

On 2 June, news emerged of a first case of MIS-C diagnosed in Peru.[46][47]

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.[48]

In peer-reviewed medical journals, case series and related studies of the new condition were rapidly reported from countries including the UK;[29][49] Italy;[32] Spain;[50] France and Switzerland;[25] France;[51][52][53] and the US.[54][55][56]

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