Multisystem inflammatory syndrome in children

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)

Paediatric multisystem inflammatory syndrome (PMIS/PIMS/PIMS-TS)
Other names
  • Multisystem inflammatory syndrome in children (MIS-C)[1]
  • Multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19[2]
  • Paediatric inflammatory multisystem syndrome (PIMS), temporally associated with SARS-CoV-2 infection (PIMS-TS)[3]
  • Kawa-COVID-19[4]
  • Systemic Inflammatory Syndrome in COVID-19 (SISCoV)[5]
supportive care
PrognosisResponse to treatment, generally good; long-term prognosis, unclear[7]
FrequencyRare
Deaths<2% of reported cases

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

intensive care.[7]

All affected children have persistent fever.

Coronary artery abnormalities can develop (ranging from dilatation to aneurysms).[6]

This life-threatening disease has proved fatal in under 2% of reported cases.

Supportive care is key for treating clinical complications.[15] Most children who receive expert hospital care survive.[7]

Knowledge of this newly described

toxic shock and macrophage activation syndromes.[12] Nevertheless, it appears to be a separate syndrome.[19] Older children tend to be affected.[20]

This emerging condition has been

bacterial and other infections, is essential for differential diagnosis.[3] Some general clinical guidance has been provided by the RCPCH,[10] the National Institutes of Health,[20] the American College of Rheumatology,[22] and the American Academy of Pediatrics.[23]

Clusters of new cases have been reported two to six weeks after local peaks in viral transmission.

Afro-Caribbean, and Hispanic descent, whereas Kawasaki disease affects more of East Asian ancestry.[16] 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.[21] Reports have since emerged of cases in various other countries around the world.[24][25] In adults, a similar condition has occasionally been reported, which has been called multisystem inflammatory syndrome in adults (MIS-A).[26]

Name

The disorder has been called by various names, including:

  • Multisystem inflammatory syndrome in children (MIS-C)[1]
  • Multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19[2]
  • Paediatric inflammatory multisystem syndrome (PIMS)[10]
  • Paediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2 infection (PIMS-TS)[3][7]
  • Paediatric multisystem inflammatory syndrome (PMIS)[12]
  • Kawa-COVID-19[4]
  • Systemic inflammatory syndrome in COVID-19 (SISCoV)[5]

Background

Symptomatic cases of COVID-19 in children have been relatively uncommon,[27] possibly because they generally experience milder disease.[28] 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.[29][30] While cases of children with severe symptoms are exceptional, they can occasionally require intensive care.[31][32][33] Fatalities have been rare.[30][34]

In April 2020, a small group of children with evidence of

mucous membranes, and swollen hands and feet).[3][37][44]

Characteristics

MIS-C / PIMS-TS is a

The condition may match some or all of the diagnostic criteria for Kawasaki disease (i.e. the 'complete' or 'incomplete'/'atypical' subtypes[7][44]),[10] or for Kawasaki disease shock syndrome.[40] It tends to affect all paediatric age groups, ranging from infancy to adolescence.[6][17] It can also share clinical features with other paediatric inflammatory conditions, including toxic shock syndrome, and secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome.[10][29] Coinfections with other pathogens have been recorded.[3]

Affected children always present with persistent fever.

paediatric intensive care unit.[12]

Echocardiographic features of myocarditis (inflammation of the heart muscle) have been recorded.[6][7]

Affected children consistently show laboratory evidence of hyperinflammation.

liver enzymes have been reported.[17] 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.[29]

Differences with respect to Kawasaki disease include frequent presentation with gastrointestinal symptoms such as vomiting, diarrhoea, and abdominal pain.

ventricular natriuretic peptide (a marker of heart failure),[13] as well as somewhat lower platelet counts, lower absolute lymphocyte counts, and higher CRP levels.[16] Very high troponin levels (suggestive of myocardial damage) are also common.[17][29][19]

Clinical course

Clinical course tends to be more severe than with Kawasaki disease.

Ventricular function often recovers before discharge from hospital (often after 6–10 days).[7] Coronary artery aneurysms can develop even in the absence of Kawasaki-like features.[6] Their frequency and severity is uncertain.[16] So far, they have been recorded in 7% of reported cases.[7] Long-term prognosis is unclear.[12]

Diagnosis

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
    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.)

Diagnosis is by specialist

abdominal ultrasound.[57] 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.[21]

Case definitions and guidance

A universally accepted

case definition for this newly described syndrome has still not been agreed.[24][58] In the meantime, different names and provisional case definitions are being used around the world.[24][58] 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.[40] 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.[12]

Further case definitions have been formulated by the British Paediatric Surveillance Unit (BPSU) and the Canadian Paediatric Surveillance Program (CPSP).[58] Some provisional diagnostic guidance has been provided by both the American College of Rheumatology[16] and the American Academy of Pediatrics.[11] In the UK, consensus has been reached for diagnostic investigation of children with suspected PIMS-TS.[60] A clinical pathway for diagnostic evaluation of suspected MIS-C has also been proposed by the Children's Hospital of Philadelphia.[56] 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.[18]

Differential diagnosis

It is essential to exclude alternative non-infectious

mesenteric adenitis.[61]

Differential diagnosis with Kawasaki disease can be challenging, given the lack of a diagnostic test for either condition.[13] It is not currently known whether the newly described condition is superimposable with Kawasaki disease shock syndrome.[40] 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."[62]

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.[12] Treatment is tailored for each individual child, with input from the various consulting specialists.[18] Approaches vary.[63] The RCPCH initially outlined a provisional approach to clinical management, including guidance on early medical management, monitoring and some general principles of treatment;[10] for the UK, consensus has since been reached regarding a recommended pathway for clinical management (including access to registered clinical trials).[60] The National Institutes of Health provides some general considerations.[20] The American College of Rheumatology provides guidance for clinical management of MIS-C.[16][6] The American Academy of Pediatrics has also provided some interim guidance.[11] Other proposals have also been made.[12][18][49][63][64] RCPCH guidance recommends that all affected children should be treated as having suspected COVID-19.[10]

Little specific information is available regarding therapeutic effectiveness.

Supportive care is a mainstay of therapy,[20] and for mild or moderate disease it may be sufficient.[10][17] Major complications may respond well to more aggressive supportive care.[15] Cardiac and respiratory support may benefit children who present predominantly with shock.[18]

Strategies for clinical management tend to be broadly based on

vasoactive agents are often used for children with cardiac dysfunction and hypotension.[24] Anticoagulants have been used.[24] Low-dose aspirin has been used as an antiplatelet drug.[12][11][17]

Treatment strategies are being considered to prevent serious long-term complications such as coronary artery aneurysms (the main complication of Kawasaki disease).[35] Close outpatient follow-up by a paediatric cardiology team has been recommended.[12][11]

Causes

While it has been

susceptibility and potential biological mechanisms.[45]

Mechanism

The

environmental trigger for the condition either directly or indirectly (by somehow paving the way for a different trigger).[42]

As with Kawasaki disease,

acquired immune responses to the virus.[24] It has been suggested that the condition may be caused by the cytokine storms induced by COVID-19.[14][69] 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.[13] 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.[47][29]

It is unknown to what extent the pathophysiology resembles that of other paediatric inflammatory syndromes that share similar clinical features.[68] 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.[47][70] In each of these syndromes, a cytokine storm leads to failure of multiple organs.[46] They also share with MIS-C and severe cases of COVID-19 high levels both of ferritin (released by neutrophils) and of haemophagocytosis.[46]

The frequent gastrointestinal presentation and

T-cell responses.[24]

Understanding the pathophysiology is a key research priority.[72] 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.[45] 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.[45]

A potential link with Kawasaki disease is under discussion.[73] 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[44][74]) in some genetically predisposed children, and that SARS-CoV-2 is now "added to the list" of implicated viral triggers.[45] Hopes have been expressed that study of the new condition may help understand the hidden mechanisms behind Kawasaki disease.[35] But current evidence suggest that MIS-C and Kawasaki disease represent two distinct disease entities[47]

Proposed role of the STING pathway

A possible role of the stimulator of interferon genes known as

IRF-3.[5] 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.[5] 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.[5]

Epidemiology

Epidemiological information is limited, and clinical statistics currently derive from review of case series.[6][19][a] This emerging condition is considered rare.[3] Its incidence is not known.[6][53][b] 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).[7] 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."[3]

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.[17][c] 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.[74] 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.[17]

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).

obese (among those who did have some comorbidity, 51% were either overweight or obese).[7]

Regarding

socioeconomic and other environmental factors in such discrepancies is unclear.[42]

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.[3][21] 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.[3][13][74][81][d] Reports of confirmed or suspected cases have since emerged in many different countries around the world.[24][e]

None of the three main provisional case-definitions of the emerging entity is diagnostically

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.[105][55] A suggestion[104] 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.[105]

In adults

There has been uncertainty as to whether the condition is confined to children,

Sporadic reports exist of a similar life-threatening condition, denominated 'multisystem inflammatory syndrome in adults' (MIS-A), which also usually requires intensive care.[26]

History

Cases of Kawasaki disease with concurrent SARS-CoV-2 infection have been recorded among children in Europe and in the United States since 7 April 2020, when a report was published by the American Academy of Pediatrics regarding a case of 'classic' Kawasaki disease in a six-month old girl who tested positive for COVID-19 in California.[3][107] In this case, COVID-19 did not appear to have significant clinical implications.[67][107]

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."[35][108] 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."[67][109] Accounts of analogous cases – including some that appeared less clinically severe – were also being informally shared among clinicians around Europe.[35] The EU's Early Warning and Response System flagged suspected cases in Austria, Germany and Portugal that had tested positive for SARS-CoV-2.[3] 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.[67] In France, the government reported on 29 April that around 15 children were in hospital in Paris with symptoms of Kawasaki disease,[67][110] an observation which prompted the organization of national surveillance programme for recent cases of Kawasaki-like disease.[76]

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.[10][35] Two weeks later, on 15 May, two further preliminary case definitions were published separately by the WHO[21] and by the CDC,[1] while the ECDC released a 'rapid risk assessment' of the condition on behalf of the European Union.[3] In the following weeks, further clinical guidance was released by other medical organizations, including the NIH,[20] the American College of Rheumatology,[22] and the American Academy of Pediatrics.[23] 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,[3] where 15 such cases were already being treated.[111] 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.[112]

By 12 May, some 230 suspected cases had been reported across the

peer-reviewed medical journals, case series and related studies of the new condition were rapidly reported from countries including the UK;[123][124] Italy;[77] Spain;[125][126][127] France and Switzerland;[128] France;[4][129][130] and across the US,[121][131] including New York.[75][132][133] The emerging observations suggested somewhat greater variety in the severity of symptoms than was originally thought.[20] 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.[35][58][67][73][74][81][102][104]

By 15 July 342 confirmed MIS-C cases (including 6 deaths) had been recorded in the US across 36 states plus

Washington DC.[80][134] 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.[80][135] By 29 July, a total of 570 cases and 10 deaths had been reported across 40 states, Washington DC, and New York City.[55]

Until late May, no confirmed case had been documented outside the EU/EEA/UK and USA.[3] No suspicious case had been observed in East Asia or Southeast Asia (or in Australia or New Zealand).[81][136][137] 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.[29] On 2 June, news emerged of a first case of MIS-C diagnosed in Peru.[138][139] In Brazil, cases of MIS-C have been reported in São Paulo,[140] and in the context of a prospective study in Pará;[141] more children with severe late manifestations of COVID-19 were being admitted to paediatric intensive care units in the region.[141] In Chile, 42 confirmed cases of MIS-C had been recorded nationally by 28 June, including 27 in the capital, Santiago.[142] 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.[86] 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,[93] and further cases of the new syndrome have been recorded.[94] 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.[88] 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.[143]

During July, suspected cases were being flagged and reported

Victoria) on 4 September, along with news of other suspected cases under review.[152] In South Korea, news of two confirmed cases broke on 5 October[91] (and the existence of a case dating back to the end of April was reported in November[83]
).

A similar condition began to be recognized in some adults.

Somali origin.[157] 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."[158] Further reports of multisystem inflammatory syndrome linked to COVID-19 exposure emerged in adults.[153][159][160][161][162] In October, the CDC reported on the condition and named it 'multisystem inflammatory syndrome in adults' (MIS-A).[26] Questions have been raised regarding possible relationships between MIS-C and certain severe manifestations of COVID-19 in adults.[106]

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.[163][164]

Explanatory notes

  1. ^ 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.[53]
  2. ^ 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).[6][75]
  3. 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.[79] 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).[79]
  4. ^ No apparent rise in new cases of Kawasaki disease was noted in these countries,[45] including in South Korea[82] (where one diagnosis was subsequently reclassified as MIS-C[83]), and in Singapore.[84] There had been no report of Kawasaki disease or Kawasaki-like symptoms in mainland China.[85]
  5. Latin-American Kawasaki disease surveillance network (REKAM-LATINA) has recorded cases of MIS-C across all its participating countries.[25] Some other countries where cases have been reported include Russia,[86] India,[87][88] Pakistan,[89] Kazakhstan,[90] South Korea,[83][91] Turkey,[92] Iran,[93][94] Saudi Arabia,[95] Israel,[96][97] Algeria,[98] South Africa,[99] and Australia.[100]

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