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Canadian Journal of Cardiology

Emerging Insights into the Pathophysiology of Multi-system Inflammatory Syndrome in Children Associated with COVID-19

Published:January 07, 2023DOI:https://doi.org/10.1016/j.cjca.2023.01.002

      Abstract

      Multisystem inflammatory syndrome in children (MIS-C) has emerged as a rare, delayed hyperinflammatory response to SARS-CoV-2 infection, and causes severe morbidity in the pediatric age group. While MIS-C shares many clinical similarities to Kawasaki disease (KD), important differences in epidemiologic, clinical, immunologic and potentially genetic factors exist and suggest potential differences in pathophysiology and points to be explored and explained. Epidemiologic features include male predominance, peak age of 6-12 years, and specific racial and/or ethnicity predilections. MIS-C is characterized by fever, prominent gastrointestinal symptoms, mucocutaneous manifestations, respiratory symptoms, and neurological complaints, and patients often present with shock. Cardiac complications are frequent and include ventricular dysfunction, valvular regurgitation, pericardial effusion, coronary artery dilation and aneurysms, conduction abnormalities, and arrhythmias. Emerging evidence regarding potential immunologic mechanisms suggest that an exaggerated T-cell response to a superantigen on the SARS-CoV-2 spike glycoprotein, as well as the formation of autoantibodies against cardiovascular, gastrointestinal, and endothelial antigens, are major contributors to the inflammatory milieu of MIS-C. Further studies are needed to determine both shared and distinct immunologic pathway(s) that underlie the pathogenesis of MIS-C versus both acute SARS-CoV-2 infcction and KD. There is evidence to suggest that the rare risk of more benign mRNA vaccine –associated myopericarditis is outweighed by a reduced risk of more severe MIS-C. In the current review, we synthesize the published literature to describe associated factors and potential mechanisms regarding an increased risk of MIS-C and cardiac complications, provide insights into the underlying immunologic pathophysiology, and define similarities and differences with KD.

      Introduction

      Coronavirus Disease 2019 (COVID-19) is the direct clinical manifestation of acute infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Even from the early days of the pandemic, it has been clear that acute COVID-19 in children is often milder and carries a better prognosis compared to adults.

      Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta paediatrica (Oslo, Norway : 1992). 2020;109:1088-1095.

      In mid-2020, a novel syndrome with clinical similarities to Kawasaki disease (KD) was first described in children in the United Kingdom, France, Italy and the United States.
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • Wilkinson N.
      • Theocharis P.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • et al.
      Multisystem Inflammatory Syndrome in U.S. Children and Adolescents.
      • Belhadjer Z.
      • Meot M.
      • Bajolle F.
      • et al.
      Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic.
      This condition, now referred to as multisystem inflammatory syndrome in children (MIS-C), is characterized by acute systemic inflammation and multi-organ dysfunction. Epidemiological data have demonstrated a temporal association between MIS-C and SARS-CoV-2 infection, with MIS-C presenting 3-6 weeks after SARS-CoV-2 infection, often asymptomatic in children.
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      ,
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      The majority of patients also possess neutralizing antibodies specific for SARS-CoV-2, including high titers of IgG.
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      Insights into the pathophysiology underlying this delayed inflammatory process are emerging, and are the focus of this review (Figure 1).
      Figure thumbnail gr1
      Figure 1Pathophysiology and Clinical Manifestations of Multisystem Inflammatory Syndrome in Children Associated with COVID-19. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IFN, interferon; IL, interleukin; MIS-C, multisystem inflammatory syndrome in children; NTproBNP, N-terminal pro-hormone B-type natriuretic peptide; RA, receptor antagonist; TNF, tumor necrosis factor

      MIS-C Case Definition

      Investigations regarding pathophysiology must first begin with accurate and specific case ascertainment to prevent misclassification. The case definition for MIS-C established by the World Health Organization (WHO) early in the pandemic is summarized in Table 1. This definition was adopted by the Public Health Agency of Canada with an expansion to include patients without a COVID-19 diagnosis, as PCR testing may be falsely negative late in the course of infection or, particularly early in the pandemic due to limited access to COVID-19 testing, specifically serology.
      • Laverty M.
      • Salvadori M.
      • Squires S.G.
      • et al.
      Multisystem inflammatory syndrome in children in Canada.
      The definition from the US Centers for Disease Control and Prevention (CDC) differs somewhat from the WHO in extending the age to 20 years, the greater specification of fever and inflammatory markers, and the addition of respiratory, renal, neurologic and dermatologic involvement as additional organ systems involved (https://www.cdc.gov/mis/mis-c/hcp/).
      • Abrams J.Y.
      • Godfred-Cato S.E.
      • Oster M.E.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review.
      Both the WHO and the CDC recognized that patients may also meet diagnostic criteria for complete and incomplete KD.
      • McCrindle B.W.
      • Rowley A.H.
      • Newburger J.W.
      • et al.
      Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
      In contrast, MIS-C has been referred to as Paediatric Multisystem Inflammatory Syndrome temporally associated with COVID-19 (PIMS) in the United Kingdom, and a case definition from the Royal College of Paediatrics and Child Health differs from the WHO and CDC definitions by requiring involvement of only one organ, and stating that “SARS-CoV-2 PCR testing may be positive or negative” and not including a requirement for evidence of a preceding COVID-19 infection (https://www.rcpch.ac.uk/resources/paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims-guidance). Given the clinical overlap with KD, for many MIS-C patients the only differentiating feature may be this evidence of prior infection. However, as the pandemic has progressed and a greater proportion of the population has had prior COVID-19 and/or been vaccinated, this evidence may be less conclusive (particularly for serologic evidence of infection, which may not be temporally related), and there have been calls to exclude this requirement from case definitions.
      • Rhys-Evans S.
      Call for a universal PIMS-TS/MIS-C case definition.
      This will likely impede research into the pathogenesis, given the potential for misclassification. However, there is hope that the development of machine learning algorithms, potentially incorporating multi-omics (concommitant personalized data from analysis of the microbiome, genome, epigenome, transcriptome and proteome), which may allow for more accurate diagnosis without the requirement for evidence of prior COVID-19.
      • Lam J.Y.
      • Shimizu C.
      • Tremoulet A.H.
      • et al.
      A machine-learning algorithm for diagnosis of multisystem inflammatory syndrome in children and Kawasaki disease in the USA: a retrospective model development and validation study.
      Table 1MIS-C case definition from the World Health Organization.*
      MIS-C diagnosis requires all of the following 4 criteria to be met:
      Children and adolescents 0 to 19 years of age with fever for ≥3 days

      1. Clinical signs of multisystem involvement (at least 2 of the following):

      •Rash, bilateral non-purulent conjunctivitis, or mucocutaneous inflammation signs (oral, hands or feet)

      •Hypotension or shock

      •Cardiac dysfunction, pericarditis, valvulitis or coronary artery abnormalities (including echocardiographic findings or elevated troponin/brain natriuretic peptide)

      •Evidence of coagulopathy (prolonged PT or PTT; elevated D-dimer)

      •Acute gastrointestinal symptoms (diarrhea, vomiting or abdominal pain)

      2. Elevated markers of inflammation (e.g., ESR, C-reactive protein or procalcitonin)

      3. No other obvious microbial cause of inflammation, including bacterial sepsis and staphylococcal/streptococcal toxic shock syndromes

      4. Evidence for SARS-CoV-2 infection, any of the following:

      •Positive SARS-CoV-2 RT-PCR

      •Positive serology

      •Positive antigen test

      •Likely contact with an individual with COVID-19
      *World Health Organization. Multisystem inflammatory syndrome in children and adolescents with COVID-19: Scientific Brief. 2020. Available at: https://www.who.int/publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19 (Accessed on May 17, 2020).

      Epidemiologic Features

      Pathophysiologic models should explain the epidemiologic and clinical features of MIS-C, including differences with similar known conditions. These are summarized in Table 2 in comparison to KD. Male sex, peak age from 6-12 years and Black and Hispanic race and/or ethnicity are factors associated with development of MIS-C, with male preponderance also possibly associated with a greater risk of cardiac complications.
      • Abrams J.Y.
      • Oster M.E.
      • Godfred-Cato S.E.
      • et al.
      Factors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study.
      It is incompletely known whether the male preponderance is due to a greater predilection for SARS-CoV-2 infection, or a greater predilection to develop MIS-C given infection. The angiotensin-converting enzyme 2 gene (ACE2), which encodes the receptor used for SARS-CoV-2 entry, is located on the X-chromosome and downregulated by estrogen, predisposing males to infection
      • Scully E.P.
      • Haverfield J.
      • Ursin R.L.
      • Tannenbaum C.
      • Klein S.L.
      Considering how biological sex impacts immune responses and COVID-19 outcomes.
      • Stelzig K.E.
      • Canepa-Escaro F.
      • Schiliro M.
      • Berdnikovs S.
      • Prakash Y.S.
      • Chiarella S.E.
      Estrogen regulates the expression of SARS-CoV-2 receptor ACE2 in differentiated airway epithelial cells.

      Stilhano RS, Costa AJ, Nishino MS, et al. SARS-CoV-2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020;34:14103-14119.

      and impaired viral clearance and prolonged duration of SARS-CoV-2 detection after infection.

      Stilhano RS, Costa AJ, Nishino MS, et al. SARS-CoV-2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020;34:14103-14119.

      ,
      • Shi D.
      • Wu W.
      • Wang Q.
      • et al.
      Clinical Characteristics and Factors Associated With Long-Term Viral Excretion in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection: a Single-Center 28-Day Study.
      Regarding predilection for MIS-C, immune function is influenced by sex-related genetic differences, increasing susceptibility for males towards inflammatory diseases,
      • Maan A.A.
      • Eales J.
      • Akbarov A.
      • et al.
      The Y chromosome: a blueprint for men's health?.
      ,
      • Case L.K.
      • Wall E.H.
      • Dragon J.A.
      • et al.
      The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease.
      and by sex-related differences in levels of testosterone, estrogen and progesterone.
      • Scully E.P.
      • Haverfield J.
      • Ursin R.L.
      • Tannenbaum C.
      • Klein S.L.
      Considering how biological sex impacts immune responses and COVID-19 outcomes.
      ,
      • Furman D.
      • Hejblum B.P.
      • Simon N.
      • et al.
      Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination.
      • Straub R.H.
      The complex role of estrogens in inflammation.
      • Hall O.J.
      • Klein S.L.
      Progesterone-based compounds affect immune responses and susceptibility to infections at diverse mucosal sites.
      Children ages 6 to 12 years are most at risk of MIS-C and more severe outcomes
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • et al.
      Multisystem Inflammatory Syndrome in U.S. Children and Adolescents.
      ,
      • Abrams J.Y.
      • Godfred-Cato S.E.
      • Oster M.E.
      • et al.
      Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review.
      ,
      • Abrams J.Y.
      • Oster M.E.
      • Godfred-Cato S.E.
      • et al.
      Factors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study.
      ,
      • Hoste L.
      • Van Paemel R.
      • Haerynck F.
      Multisystem inflammatory syndrome in children related to COVID-19: a systematic review.
      • Radia T.
      • Williams N.
      • Agrawal P.
      • et al.
      Multi-system inflammatory syndrome in children & adolescents (MIS-C): A systematic review of clinical features and presentation.

      Santos MO, Gonçalves LC, Silva PAN, et al. Multisystem inflammatory syndrome (MIS-C): a systematic review and meta-analysis of clinical characteristics, treatment, and outcomes. Jornal de pediatria. 2021.

      • Yasuhara J.
      • Watanabe K.
      • Takagi H.
      • Sumitomo N.
      • Kuno T.
      COVID-19 and multisystem inflammatory syndrome in children: A systematic review and meta-analysis.
      • Feldstein L.R.
      • Tenforde M.W.
      • Friedman K.G.
      • et al.
      Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • et al.
      Multisystem Inflammatory Syndrome in Children in New York State.
      which, while incompletely understood, may be related to age-related differences in ACE2 expression
      • Bunyavanich S.
      • Do A.
      • Vicencio A.
      Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults.
      or severity of inflammation.
      • Zhao Y.
      • Yin L.
      • Patel J.
      • Tang L.
      • Huang Y.
      The inflammatory markers of multisystem inflammatory syndrome in children (MIS-C) and adolescents associated with COVID-19: A meta-analysis.
      There appears to be an Hispanic and non-Hispanic Black race/ethnicity predominance among MIS-C patients.
      • Hoste L.
      • Van Paemel R.
      • Haerynck F.
      Multisystem inflammatory syndrome in children related to COVID-19: a systematic review.
      ,
      • Yasuhara J.
      • Watanabe K.
      • Takagi H.
      • Sumitomo N.
      • Kuno T.
      COVID-19 and multisystem inflammatory syndrome in children: A systematic review and meta-analysis.
      • Feldstein L.R.
      • Tenforde M.W.
      • Friedman K.G.
      • et al.
      Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • et al.
      Multisystem Inflammatory Syndrome in Children in New York State.
      ,
      • Belay E.D.
      • Abrams J.
      • Oster M.E.
      • et al.
      Trends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic.
      ,
      • Stierman B.
      • Abrams J.Y.
      • Godfred-Cato S.E.
      • et al.
      Racial and Ethnic Disparities in Multisystem Inflammatory Syndrome in Children in the United States, March 2020 to February 2021.
      While race/ethnicity-related differences regarding geographic factors and social determinants of health influencing risk of SARS-CoV-2 exposure may be at play,
      • Rafferty M.S.
      • Burrows H.
      • Joseph J.P.
      • Leveille J.
      • Nihtianova S.
      • Amirian E.S.
      Multisystem inflammatory syndrome in children (MIS-C) and the coronavirus pandemic: Current knowledge and implications for public health.
      ,
      • Javalkar K.
      • Robson V.K.
      • Gaffney L.
      • et al.
      Socioeconomic and Racial and/or Ethnic Disparities in Multisystem Inflammatory Syndrome.
      Black and Hispanic children have a higher incidence of MIS-C per SARS-CoV-2 infection even after adjustments for socioeconomic status.
      • Stierman B.
      • Abrams J.Y.
      • Godfred-Cato S.E.
      • et al.
      Racial and Ethnic Disparities in Multisystem Inflammatory Syndrome in Children in the United States, March 2020 to February 2021.
      ,
      • Payne A.B.
      • Gilani Z.
      • Godfred-Cato S.
      • et al.
      Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2.
      ,
      • Tyris J.
      • Boggs K.
      • Bost J.
      • et al.
      Examining the Association Between MIS-C and the Child Opportunity Index at a Single Center.
      Further epidemiologic and mechanistic studies are needed to elucidate the nature of these associations.
      Table 2Comparison of MIS-C versus Kawasaki Disease.
      MIS-CKawasaki Disease
      Demographics
      SexMales at slightly higher riskMales at greater risk (∼1.5:1)
      AgeMost likely in children ages 6-12 years (median age 8-9)Primarily children <5 years old (median age 3)
      Race/EthnicityHispanic and non-Hispanic Black at highest riskAsian and Pacific Islanders, particularly those with Japanese ancestry, at highest risk
      Etiology
      Causative agentSARS-CoV-2 infection 3-6 weeks priorUnknown; environmental and infectious exposures have been proposed
      Clinical
      SimilaritiesFever, rash, bilateral bulbar conjunctival injection, cervical lymphadenopathy
      DifferencesGastrointestinal symptoms more common

      Neurological symptoms more common

      Admission to intensive care unit more common

      Higher case fatality rate
      Oral mucous membrane changes more common
      Laboratory
      SimilaritiesElevated WBC counts, CRP and ESR
      DifferencesHigher CRP

      Higher procalcitonin

      Higher ferritin

      Lymphopenia

      Thrombocytopenia

      Higher troponin

      Higher BNP, NT-proBNP

      Higher D-dimer
      Thrombocytosis (later sign)

      Monocytosis (?)
      Immunology
      SimilaritiesIncreases in IL-1RA, IL-1β, IL-6, IL-18, TNF-α

      IL-15/IL-15RA-centric cytokine storm

      Autoantibodies directed towards endothelial antigens

      Complement activation
      DifferencesPotential superantigen mechanism with polyclonal expansion of TCR Vβ 21.3+ CD4+ and CD8+ T cells

      Lower levels of naïve CD4+ T cells and follicular helper T cells

      Higher levels of central memory and effector memory CD4+ T cells

      IL-1RA autoantibodies
      T cell activation by conventional antigen

      Marked elevation of IL-17A

      Autoantibodies against EDIL3

      Autoantibodies against DEL-1
      Cardiovascular complications
      SimilaritiesRisk for coronary artery abnormalities (dilatation/aneurysm)

      Risk for myocarditis (usually myocardial edema rather than necrosis)

      Risk for ECG changes (e.g., PR interval prolongation, ST segment changes, T wave changes)

      Risk for valvular regurgitation
      DifferencesHigher likelihood of ventricular dysfunctionCoronary artery sequelae can be serious and long-lasting
      Genetics
      Associated genesSOCS1

      XIAP

      CYBB

      TLR3

      TLR6

      IFNB1

      IFNA6

      IL22RA2

      DOCK8

      HLA-I alleles: HLA-A*02, B*35 and C*04
      CASP3

      BLK

      FCGR2A

      ITPKC

      TGFβ2, TGFβR2, SMAD3 (increased risk of aneurysm formation)

      CD40

      HLA-II

      Genetic Predisposition

      Race/ethnicity predisposition may suggest a contributing role of host genetics in the development of MIS-C.
      • Dennis-Heyward E.A.
      Disparities in Susceptibility to Multisystem Inflammatory Syndrome in Children.
      Early studies exploring genetic associations with MIS-C identified haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1), which functions as a negative regulator of type I and type II interferon (IFN) signaling, as a risk factor.
      • Lee P.Y.
      • Platt C.D.
      • Weeks S.
      • et al.
      Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1.
      A further study linked MIS-C with hemizygous defects in X-linked inhibitor of apoptosis (XIAP) and CYBB, which encodes the beta subunit of cytochrome b-245.
      • Chou J.
      • Platt C.D.
      • Habiballah S.
      • et al.
      Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C).
      Whole exome sequencing of 45 MIS-C patients of primarily Arab and Asian origin revealed the presence of rare heterozygous variants in immune-related genes TLR3, TLR6, IFNB1, IFNA6 and IL22RA2 in 19 patients, which were linked to earlier disease onset and resistance to treatment.
      • Abuhammour W.
      • Yavuz L.
      • Jain R.
      • et al.
      Genetic and Clinical Characteristics of Patients in the Middle East With Multisystem Inflammatory Syndrome in Children.
      Heterozygous missense mutations in primary hemophagocytic lymphohistiocytosis (pHLH) genes and the HLH-associated dedicator of cytokinesis 8 (DOCK8) gene may increase risk of MIS-C.
      • Vagrecha A.
      • Zhang M.
      • Acharya S.
      • et al.
      Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children.
      The combination of three HLA-I alleles, specifically HLA-A*02, B*35 and C*04, may contribute to susceptibility to MIS-C.
      • Porritt R.A.
      • Paschold L.
      • Rivas M.N.
      • et al.
      HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children.
      ,
      • Sacco K.
      • Castagnoli R.
      • Vakkilainen S.
      • et al.
      Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19.
      Genetic influences on immunologic pathways specific to MIS-C require further study.

      Cardiovascular Involvement

      While cardiovascular involvement, specifically ventricular dysfunction and coronary artery dilation/aneurysms, is the predominant morbidity of MIS-C, the underlying mechanism remains incompletely understood. The pathophysiology may be multi-factorial, potentially including direct injury to cardiomyocytes from SARS-CoV-2 viral invasion, and the impact of a dysregulated immune response leading to microvascular dysfunction and endothelial injury.
      • Alsaied T.
      • Tremoulet A.H.
      • Burns J.C.
      • et al.
      Review of Cardiac Involvement in Multisystem Inflammatory Syndrome in Children.
      ,
      • Sharma C.
      • Ganigara M.
      • Galeotti C.
      • et al.
      Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison.
      SARS-CoV-2, like other betacoronaviruses, shows tropism to myocardial and endothelial cells.
      • McMurray J.C.
      • May J.W.
      • Cunningham M.W.
      • Jones O.Y.
      Multisystem Inflammatory Syndrome in Children (MIS-C), a Post-viral Myocarditis and Systemic Vasculitis-A Critical Review of Its Pathogenesis and Treatment.
      Dolhnikoff et al. reported the case of an 11-year old girl with MIS-C who died from cardiac failure.

      Dolhnikoff M, Ferreira Ferranti J, de Almeida Monteiro RA, et al. SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome. The Lancet. Child & adolescent health. 2020;4:790-794.

      An ultrasound-guided minimally invasive autopsy demonstrated myocarditis, endocarditis and pericarditis. SARS-CoV-2 was also detected in cardiac tissue, including cardiomyocytes, endothelial cells, inflammatory cells and mesenchymal cells. A more indepth autopsy study included 5 patients who died with COVID-19, 3 of whom had MIS-C.
      • Duarte-Neto A.N.
      • Caldini E.G.
      • Gomes-Gouvêa M.S.
      • et al.
      An autopsy study of the spectrum of severe COVID-19 in children: From SARS to different phenotypes of MIS-C.
      In all patients, SARS-CoV-2 was detected in the heart, lungs and kidneys. Two of the MIS-C patients had SARS-CoV-2 antigen in endothelial cells of the heart and brain. The third MIS-C patient, who suffered cardiac failure, was found to have SARS-CoV-2 antigen in cardiomyocytes and in the cardiac endothelium, together with diffuse perivascular interstitial inflammatory infiltrate, severe myocarditis and cardiac necrosis. These limited data suggest a role for direct SARS-CoV-2 viral invasion producing cardiac involvement, although given that these few patients had severe and fatal disease, the applicability to the majority of MIS-C patients is unknown. In contrast, case series that have incorporated cardiac magnetic resonance imaging (cMRI) with tissue characterization have noted more myocardial edema with the majority not meeting criteria for myocarditis, and little myocardial fibrosis as indicated by persistence of late gadolinium enhancement in a minority.
      • Aeschlimann F.A.
      • Misra N.
      • Hussein T.
      • et al.
      Myocardial involvement in children with post-COVID multisystem inflammatory syndrome: a cardiovascular magnetic resonance based multicenter international study-the CARDOVID registry.
      ,
      • Dove M.L.
      • Oster M.E.
      • Hashemi S.
      • Slesnick T.C.
      Cardiac Magnetic Resonance Findings after Multisystem Inflammatory Syndrome in Children.
      These data suggest that myocyte necrosis may not be a prominent feature in the majority, despite the clinical finding of elevated cardiac biomarkers and depressed ventricular function during the acute illness.

      Immunology

      Hyperinflammation is a hallmark of MIS-C. Studies have consistently reported an elevation in inflammatory markers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin, procalcitonin and IL-6.
      • Hoste L.
      • Van Paemel R.
      • Haerynck F.
      Multisystem inflammatory syndrome in children related to COVID-19: a systematic review.
      ,
      • Radia T.
      • Williams N.
      • Agrawal P.
      • et al.
      Multi-system inflammatory syndrome in children & adolescents (MIS-C): A systematic review of clinical features and presentation.
      ,

      Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children (Basel, Switzerland). 2020;7.

      Other findings include elevated white blood cell count with neutrophilia and lymphopenia, elevated D-dimer and fibrinogen, and elevated myocardial injury markers such as troponin and brain natriuretic peptide (BNP).
      • Hoste L.
      • Van Paemel R.
      • Haerynck F.
      Multisystem inflammatory syndrome in children related to COVID-19: a systematic review.
      ,
      • Radia T.
      • Williams N.
      • Agrawal P.
      • et al.
      Multi-system inflammatory syndrome in children & adolescents (MIS-C): A systematic review of clinical features and presentation.
      Differences in the laboratory profile of MIS-C compared to acute COVID-19 have been reported. Feldstein et al. reported that MIS-C patients have higher levels of CRP and a greater neutrophil to lymphocyte ratio compared to those with acute COVID-19, as well as a lower platelet count.
      • Feldstein L.R.
      • Tenforde M.W.
      • Friedman K.G.
      • et al.
      Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.
      A systematic review and meta-analysis representing 787 MIS-C patients noted similar findings.
      • Zhao Y.
      • Yin L.
      • Patel J.
      • Tang L.
      • Huang Y.
      The inflammatory markers of multisystem inflammatory syndrome in children (MIS-C) and adolescents associated with COVID-19: A meta-analysis.
      MIS-C patients had a higher CRP, absolute neutrophil count, and D-dimer, as well as a lower absolute lymphocyte count versus non-severe acute COVID-19. When compared with severe COVID-19, those with MIS-C had higher ESR, and lower platelets and LDH. These findings have led to a focus on the immune response and immune dysregulation as the primary drivers of the pathophysiology of MIS-C.

      Cytokines

      A plethora of cytokines have been found to be elevated in the context of MIS-C, including IL-1β, IL-1RA, IL-6, IL-8, IL-10, IL-17, IL-18, IFNγ, and TNFα.
      • Carter M.J.
      • Fish M.
      • Jennings A.
      • et al.
      Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      • Moreews M.
      • Le Gouge K.
      • Khaldi-Plassart S.
      • et al.
      Polyclonal expansion of TCR Vbeta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.
      • Gurlevik S.L.
      • Ozsurekci Y.
      • Sağ E.
      • et al.
      The difference of the inflammatory milieu in MIS-C and severe COVID-19.
      • Gruber C.N.
      • Patel R.S.
      • Trachtman R.
      • et al.
      Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      Some have also identified increases in CCL3, CCL4, CCL20, CCL28, and CDCP1.
      • Gruber C.N.
      • Patel R.S.
      • Trachtman R.
      • et al.
      Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).
      Although the relative contributions of these cytokines is still unclear, it appears that IFNγ, IL-10, and TNFα are particularly elevated and may have important roles in the pathogenesis of MIS-C .
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      A prospective study of 14 MIS-C patients found that the cytokine storm of MIS-C is characterized by IFNγ as a central mediator as opposed to type I IFN, which is enhanced in severe acute COVID-19.
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      This finding is further supported by the observation that CXCL9 and CXCL10, which are signature cytokines of IFNγ, are elevated in MIS-C.
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      ,
      • Caldarale F.
      • Giacomelli M.
      • Garrafa E.
      • et al.
      Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome.
      Diorio et al. also found disproportionately high levels of CXCL9, indicating a dysregulated IFNγ response.
      • Diorio C.
      • Shraim R.
      • Vella L.A.
      • et al.
      Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction.
      A recent longitudinal multicentre study of 110 children with acute COVID-19, 76 with MIS-C and 76 healthy controls with multi-omic profiling (single-cell gene expression, proteomics, soluble biomarkers, immune repertoire analysis) demonstrated strong type I interferon responses in acute COVID-19, whereas MIS-C was characterized by type II IFN- and NF-κB-dependent signatures, elevated levels of circulating spike protein and matrisome activation.
      • Sacco K.
      • Castagnoli R.
      • Vakkilainen S.
      • et al.
      Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19.

      Innate immune system

      MIS-C is associated with a number of features reflective of participation of the innate immune system. MIS-C patients have a decrease in monocyte count, as well as a profound depletion of plasmacytoid dendritic cells.
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      ,
      • Caldarale F.
      • Giacomelli M.
      • Garrafa E.
      • et al.
      Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome.
      The cells that remain exhibit various forms of dysfunction. Carter et al. reported activation of neutrophils and monocytes during the acute phase of MIS-C, as demonstrated by high CD64 expression.
      • Carter M.J.
      • Fish M.
      • Jennings A.
      • et al.
      Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.
      This observation is consistent with another study that found both CD54 and CD64 to be upregulated in neutrophils and monocytes.
      • Gruber C.N.
      • Patel R.S.
      • Trachtman R.
      • et al.
      Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).
      In addition, antigen-presenting cells, including monocytes, dendritic cells and B cells, have been noted to have low expression of CD86 and HLA-DR, which is suggestive of impaired antigen presentation ability.
      • Carter M.J.
      • Fish M.
      • Jennings A.
      • et al.
      Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.
      ,
      • Moreews M.
      • Le Gouge K.
      • Khaldi-Plassart S.
      • et al.
      Polyclonal expansion of TCR Vbeta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.
      Monocyte profiling may be helpful in differentiating MIS-C from acute COVID-19, given that patrolling monocytes dominate in MIS-C, whereas HLA-DRlo classical monocytes are more abundant in severe COVID-19.
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      Complement activation is thought to occur in a subset of MIS-C patients, as evidenced by elevated levels of soluble C5b-9 (the membrane attack complex).
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      ,
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      ,
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.
      McCafferty et al. conducted a study using mass spectrometry proteomics and hypothesized that in MIS-C complement activation is induced via the lectin pathway.
      • McCafferty C.
      • Cai T.
      • Borgel D.
      • et al.
      Pathophysiological pathway differences in children who present with COVID-19 ARDS compared to COVID -19 induced MIS-C.

      T cells (superantigen hypothesis)

      T cell lymphopenia is consistently observed in MIS-C and encompasses CD4+, CD8+ and γδT cells.
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      ,
      • Carter M.J.
      • Fish M.
      • Jennings A.
      • et al.
      Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.
      ,
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      ,
      • Vella L.A.
      • Giles J.R.
      • Baxter A.E.
      • et al.
      Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.
      In MIS-C, there are significantly lower numbers of CD8+ T cells compared to children with only mild acute SARS-CoV-2 infection.
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      Of the remaining cells, a large portion express CD38 and the MHC class II receptor HLA-DR, indicating T cell activation.
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      ,
      • Moreews M.
      • Le Gouge K.
      • Khaldi-Plassart S.
      • et al.
      Polyclonal expansion of TCR Vbeta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.
      ,
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      ,
      • Vella L.A.
      • Giles J.R.
      • Baxter A.E.
      • et al.
      Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.
      There is significant clinical overlap between MIS-C and toxic shock syndrome (TSS), which is most commonly triggered by bacterial superantigens such as staphylococcal enterotoxin B and streptococcal mitogenic exotoxin Z. In TSS, exposure to the superantigen results in widespread T cell activation and massive proinflammatory cytokine release that culminates in multiorgan tissue injury, as seen with MIS-C.
      • Porritt R.A.
      • Paschold L.
      • Rivas M.N.
      • et al.
      HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children.
      ,
      • Cheng M.H.
      • Zhang S.
      • Porritt R.A.
      • et al.
      Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation.
      The similarities between these two conditions has prompted the consideration of a superantigen as a trigger for MIS-C. This hypothesis is supported by two key observations: 1) the discovery of a superantigen-like motif on SARS-CoV-2, and 2) the expansion of T cells expressing T cell receptor (TCR) beta variable gene 11–2 (TRBV11-2), encoding Vbeta(Vβ)21.3 in MIS-C patients. Firstly, using structure-based computational models, Cheng et al. identified a polybasic high-affinity motif for binding TCRs on the SARS-CoV-2 spike glycoprotein. This epitope closely resembles the bacterial superantigen Staphylococcal enterotoxin B with respect to both sequence and structure, and is not found in the spike proteins of betacoronaviruses apart from SARS-CoV-2. A rare mutation found in a European strain of the virus, D839Y, enhanced the interaction between SARS-CoV-2 and human T cells.
      • Cheng M.H.
      • Zhang S.
      • Porritt R.A.
      • et al.
      Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation.
      Secondly, studies have consistently demonstrated an expansion of Vβ21.3+ T cells in MIS-C patients.
      • Porritt R.A.
      • Paschold L.
      • Rivas M.N.
      • et al.
      HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children.
      ,
      • Sacco K.
      • Castagnoli R.
      • Vakkilainen S.
      • et al.
      Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19.
      ,
      • Moreews M.
      • Le Gouge K.
      • Khaldi-Plassart S.
      • et al.
      Polyclonal expansion of TCR Vbeta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.
      ,
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      ,
      • Ramaswamy A.
      • Brodsky N.N.
      • Sumida T.S.
      • et al.
      Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children.
      Vβ21.3, encoded by TRBV11-2, contains polyacidic residues that interact strongly with the superantigen-like motif of the SARS-CoV-2 spike glycoprotein.
      • Porritt R.A.
      • Paschold L.
      • Rivas M.N.
      • et al.
      HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children.
      A study of 4 patients with mild and 16 with severe MIS-C showed that TRBV11-2 T cells comprised up to 24% of the clonal T cell space. This expansion correlated with both serum cytokine levels and MIS-C severity, which is consistent with an immune response triggered by a superantigen.
      • Porritt R.A.
      • Paschold L.
      • Rivas M.N.
      • et al.
      HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children.
      Moreews et al. found that 75% of MIS-C patients displayed an expansion of activated Vβ21.3+ T cells in both CD4 and CD8 subsets, a phenomenon that was not observed in individuals with acute COVID-19, KD or TSS.
      • Moreews M.
      • Le Gouge K.
      • Khaldi-Plassart S.
      • et al.
      Polyclonal expansion of TCR Vbeta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.
      Hoste et al. also observed a skewed TCRβ repertoire enriched for TRBV11-2 in all 14 MIS-C patients in their cohort.
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      The presence of a putative high-affinity binding motif for TCRs on the SARS-CoV-2 spike glycoprotein, in combination with the profound expansion of Vβ21.3+ T cells seen in patients, provides compelling evidence for the role of a superantigen mechanism in the pathogenesis of MIS-C.
      Multiple other abnormalities in T cell biology have been proposed as contributors to the pathogenesis of MIS-C. NK cells and CD8+ T cells are two cytotoxic cells of the immune system that can regulate each other in the context of a viral infection. NK cells play a key role in a process known as CD8+ T cell exhaustion, which can ameliorate inflammatory disease symptoms. However, abnormalities in NK and CD8+ T cell biology identified in MIS-C include a depletion of NK cells as well as dysregulation of the ones that remain. This could disrupt CD8+ T cell exhaustion, leading to the inflammatory milieu seen in MIS-C.
      • Beckmann N.D.
      • Comella P.H.
      • Cheng E.
      • et al.
      Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.
      Moreover, in their analysis of soluble biomarkers in MIS-C patients, Sacco et al. discovered low levels of CCL22, an important mediator of T cell homeostasis.
      • Sacco K.
      • Castagnoli R.
      • Vakkilainen S.
      • et al.
      Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19.
      CCL22 is a chemokine that promotes function and migration of regulatory T cells. Reduced CCL22 may result in a diminished regulatory T cell response, leading to unchecked inflammation. Another feature of the immune response of MIS-C patients that distinguishes it from pediatric COVID-19 is the activation of vascular patrolling CX3CR1+ CD8+ T cells.
      • Vella L.A.
      • Giles J.R.
      • Baxter A.E.
      • et al.
      Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19.
      CX3CR1 is a chemokine receptor that binds the ligand CX3CL1, and this ligand-receptor interaction has been found to have a role in cardiovascular disease. CX3CL1 expression can be increased in the vasculature in cardiovascular conditions, resulting in recruitment of CX3CR1-expressing cytotoxic T cells. This CX3CR1-CX3CL1 axis, therefore, may represent a mechanism for the vascular pathology observed in MIS-C. Overall, these findings suggest that aberrancies in the T cell response may be an important underlying factor in the pathogenesis of MIS-C.

      B cells/antibodies/autoantibodies

      It has been shown that MIS-C patients mount an appropriate antibody response to SARS-CoV-2.
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      ,
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      ,
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      ,
      • Gruber C.N.
      • Patel R.S.
      • Trachtman R.
      • et al.
      Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).
      Despite the presence of neutralizing antibodies specific for SARS-CoV-2, there are numerous anomalies in B cell biology that are thought to contribute to MIS-C pathogenesis. Hoste et al. characterized the B cell populations of MIS-C versus severe acute COVID-19.
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      They found pronounced expression of CD86 in MIS-C patients, particularly in severe cases. There was also downregulation of both HLA-DR and CD25 in MIS-C, whereas only HLA-DR expression was decreased in severe COVID-19. The blood of MIS-C patients has been found to have lower levels of total, effector and memory B cells compared to healthy counterparts,
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      ,
      • Carter M.J.
      • Fish M.
      • Jennings A.
      • et al.
      Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.
      as well as increased levels of circulating plasmablasts.
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      These plasmablasts are short-lived and may secrete antibodies directed against self-antigens.
      • Ramaswamy A.
      • Brodsky N.N.
      • Sumida T.S.
      • et al.
      Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children.
      There is likely a significant autoimmune component underlying the pathogenesis of MIS-C. MIS-C patients have been found to have both IgG and IgA autoantibodies against cardiovascular, gastrointestinal and endothelial antigens.
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      ,
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      ,
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      ,
      • Gruber C.N.
      • Patel R.S.
      • Trachtman R.
      • et al.
      Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).
      Gruber et al. noted the presence of anti-La autoantibodies in MIS-C patients, which also have known associations with autoimmune diseases. These autoantibodies may interact with CD64 (also known as the high-affinity human IgG receptor FcγR1) to trigger inflammation and tissue injury.
      • Gruber C.N.
      • Patel R.S.
      • Trachtman R.
      • et al.
      Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).
      Further evidence for this comes from the observation that CD64 is over-expressed in activated neutrophils and monocytes in MIS-C.
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      ,
      • Carter M.J.
      • Fish M.
      • Jennings A.
      • et al.
      Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.
      ,
      • Wu E.Y.
      • Campbell M.J.
      Cardiac Manifestations of Multisystem Inflammatory Syndrome in Children (MIS-C) Following COVID-19.
      A study including 7 patients with mild and 20 with severe MIS-C demonstrated a strong autoimmune signature.
      • Porritt R.A.
      • Binek A.
      • Paschold L.
      • et al.
      The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children.
      Autoantibodies against a wide variety of targets were detected, including antigens in the gastrointestinal tract (e.g., ATPase H+/K+-transporting α subunit, abbreviated ATP4A), cardiovascular tissue (e.g., PDZ and LIM domain 5, abbreviated PDLIM5), brain tissue (e.g., microtubule-associated protein 9, abbreviated MAP9) and skeletal muscle (e.g., RNA-binding motif protein 38, abbreviated RBM38). Other specific autoantibody targets that have been identified in MIS-C include endoglin, IL-1RA and proteins involved in signal transduction, including MAP2K2, CSNK1A1, CSNK2A1 and CSNK1E1.
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      ,
      • Pfeifer J.
      • Thurner B.
      • Kessel C.
      • et al.
      Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.
      Endoglin is a glycoprotein expressed by endothelial cells, particularly the vascular endothelium, and is essential for the structural integrity of arteries.
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      Finally, in a recent multicentre retrospective cohort study, 13 of 21 (62%) MIS-C patients were found to have autoantibodies against IL-1RA.
      • Pfeifer J.
      • Thurner B.
      • Kessel C.
      • et al.
      Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.
      The authors proposed that the autoantibodies may have been generated due to the presence of a hyperphosphorylated, aberrant isoform of IL-1RA. These anti-IL-1RA antibodies impaired IL-1RA bioactivity, which may contribute to the excessive IL-1β signalling observed in MIS-C. Taken together, these findings are highly suggestive of an autoimmune component to the pathogenesis of MIS-C.

      Associations with prior vaccination and infection

      COVID-19 mRNA-based vaccines may have a significant protective effect against the development of MIS-C. One French study found that compared to unvaccinated adolescents, those who had received one dose of vaccine had a hazard ratio for MIS-C of 0.09.
      • Levy M.
      • Recher M.
      • Hubert H.
      • et al.
      Multisystem Inflammatory Syndrome in Children by COVID-19 Vaccination Status of Adolescents in France.
      These results are consistent with a large-scale U.S. study conducted in hospitalized patients ages 12 to 18 years across 20 states.

      Zambrano LD, Newhams MM, Olson SM, et al. BNT162b2 mRNA Vaccination Against COVID-19 is Associated with Decreased Likelihood of Multisystem Inflammatory Syndrome in U.S. Children Ages 5-18 Years. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2022.

      Using a test-negative case-control design, MIS-C patients had a decreased likelihood of vaccination with an adjusted odds ratio of 0.16, with 92% of vaccine-eligible patients being unvaccinated. A prospective population-base cohort study in Denmark during the period dominated by the Delta variant reported an estimated vaccine effectiveness of 94% against the development of MIS-C.
      • Nygaard U.
      • Holm M.
      • Hartling U.B.
      • et al.
      Incidence and clinical phenotype of multisystem inflammatory syndrome in children after infection with the SARS-CoV-2 delta variant by vaccination status: a Danish nationwide prospective cohort study.
      The incidence of MIS-C was 1 in 3400 among unvaccinated individuals and 1 in 9900 among those vaccinated who had a breakthrough infection, suggesting that the reduction in MIS-C might be due to a combination of reduced infection and a reduced risk of MIS-C in the setting of breakthrough infection.
      Given the known association of mRNA vaccination with rare cases of acute myopericarditis,
      • Truong D.T.
      • Dionne A.
      • Muniz J.C.
      • et al.
      Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.
      concerns have been raised regarding the possibility of MIS-C following vaccination. Ouldali et al. described 12 patients ages 12 to 16 years with a clinical picture consistent with MIS-C (all met WHO criteria) occurring 2 to 42 days after their latest mRNA COVID-19 vaccination.
      • Ouldali N.
      • Bagheri H.
      • Salvo F.
      • et al.
      Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study.
      Using population-based surveillance, this gave an incidence of 2.9 per 1,000,000 vaccinated children ages 12-17 years compared to an incidence of MIS-C of 113 per 1,000,000 children of the same age group who were infected with SARS-CoV-2, favoring vaccination. A similar US-based surveillance study identified 21 cases of MIS-C after vaccination, 15 of whom had evidence of prior infection.
      • Yousaf A.R.
      • Cortese M.M.
      • Taylor A.W.
      • et al.
      Reported cases of multisystem inflammatory syndrome in children aged 12-20 years in the USA who received a COVID-19 vaccine, December, 2020, through August, 2021: a surveillance investigation.
      This gave an incidence of one MIS-C case per 1,000,000 vaccinated adolescents (0.3 cases if restricted to those without prior infection), significantly lower than the incidence of approximately 200 cases of MIS-C per 1,000,000 SARS-CoV-2 infections amongst unvaccinated adolescents.
      • Payne A.B.
      • Gilani Z.
      • Godfred-Cato S.
      • et al.
      Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2.
      While vaccination may be a rare cause of MIS-C, this risk is outweighed by the benefit of vaccination in preventing MIS-C, probably by preventing infection and preventing MIS-C given breakthrough infection.

      MIS-C and Kawasaki Disease

      Kawasaki disease is an acute vasculitis that primarily affects children under 5 years of age, with coronary artery aneurysms being the most important complication occurring in ∼25% of untreated patients.
      • McCrindle B.W.
      • Rowley A.H.
      • Newburger J.W.
      • et al.
      Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
      Similar to MIS-C, the diagnosis of KD rests on the presence of clinical criteria which have changed little since the original description. While the trigger for MIS-C is known, being SARS-CoV-2 infection, the trigger(s) for KD remains elusive, although coronavirus has been possibly implicated in specific outbreaks in the past.
      • Esper F.
      • Shapiro E.D.
      • Weibel C.
      • Ferguson D.
      • Landry M.L.
      • Kahn J.S.
      Association between a novel human coronavirus and Kawasaki disease.
      Similarities and differences regarding epidemiologic and clinical features, and a predilection for cardiovascular involvement, have suggested some shared pathophysiology (Table 2).
      • McCrindle B.W.
      • Manlhiot C.
      SARS-CoV-2-Related Inflammatory Multisystem Syndrome in Children: Different or Shared Etiology and Pathophysiology as Kawasaki Disease?.
      KD has been considered the leading cause of acquired heart disease in children for many years, but it has been overtaken by MIS-C during the current COVID-19 pandemic era.
      • Bukulmez H.
      Current Understanding of Multisystem Inflammatory Syndrome (MIS-C) Following COVID-19 and Its Distinction from Kawasaki Disease.
      Another interesting observation is that during period of pandemic mitigation strategies, such as masking, social distancing and lock-down measures, there has been a decrease in the incidence of KD.
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      ,
      • Kang J.M.
      • Kim Y.E.
      • Huh K.
      • et al.
      Reduction in Kawasaki Disease After Nonpharmaceutical Interventions in the COVID-19 Era: A Nationwide Observational Study in Korea.
      It is possible that some of the decrease in KD may be related to misclassification of KD patients as having MIS-C, although this is more likely related to decrease exposure to possible infectious/environmental triggers.
      • Burney J.A.
      • Roberts S.C.
      • DeHaan L.L.
      • et al.
      Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States.
      ,
      • Kim B.J.
      • Choi A.
      • Kim H.S.
      • et al.
      Changes in the Clinical Characteristics of Kawasaki Disease After Coronavirus Disease (COVID-19) Pandemic: A Database Analysis.
      A case series from Korea, where the incidence of MIS-C during the pandemic has been very low, compared 19 KD patients with a history of prior COVID-19 with 26 KD patients without, and noted few differences, although patients with prior COVID were older with more severe disease, which may suggest some similiarities with MIS-C.
      • Roh D.E.
      • Lim Y.T.
      • Kwon J.E.
      • Kim Y.H.
      Kawasaki disease following SARS-CoV-2 infection: Stronger inflammation with no increase in cardiac complications.
      The association of prior COVID-19 and vaccination with the risk of subsequent KD is largely unknown. In contrast, a report from Seattle noted that patients with a prior history of KD did not have adverse outcomes when either infected with SARS-CoV-2 or vaccinated with mRNA COVID-19 vaccines.
      • Beckley M.
      • Olson A.K.
      • Portman M.A.
      Tolerability of COVID-19 Infection and Messenger RNA Vaccination Among Patients With a History of Kawasaki Disease.
      Given the clinical overlap, the immunological mechanisms proposed underlying the pathophysiology of MIS-C versus KD are of increased interest, with the hope that insights for one condition may shed light on the other. There are conflicting opinions in the literature: some believe that MIS-C and KD are on the same continuum, while others argue that they are distinct entities. There are important similarities in the immunological profiles of the two syndromes. Both KD and MIS-C have comparable pro-inflammatory signatures, including increases in IL-1RA, IL-1β, IL-6, IL-18 and TNF-α.
      • Sharma C.
      • Ganigara M.
      • Galeotti C.
      • et al.
      Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison.
      ,
      • Moreews M.
      • Le Gouge K.
      • Khaldi-Plassart S.
      • et al.
      Polyclonal expansion of TCR Vbeta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.
      ,
      • Gruber C.N.
      • Patel R.S.
      • Trachtman R.
      • et al.
      Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).
      ,
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      ,
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.
      ,
      • Sancho-Shimizu V.
      • Brodin P.
      • Cobat A.
      • et al.
      SARS-CoV-2-related MIS-C: A key to the viral and genetic causes of Kawasaki disease?.
      ,
      • Rodriguez-Smith J.J.
      • Verweyen E.L.
      • Clay G.M.
      • et al.
      Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study.
      Other shared features include the presence of autoantibodies against endothelial cell antigens
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      ,
      • Sharma C.
      • Ganigara M.
      • Galeotti C.
      • et al.
      Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison.
      ,
      • Gruber C.N.
      • Patel R.S.
      • Trachtman R.
      • et al.
      Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).
      and activation of the complement system.
      • Henderson L.A.
      • Yeung R.S.M.
      MIS-C: early lessons from immune profiling.
      ,
      • Sharma C.
      • Ganigara M.
      • Galeotti C.
      • et al.
      Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison.
      ,
      • Hoste L.
      • Roels L.
      • Naesens L.
      • et al.
      TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.
      ,
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.
      One recent study has provided convincing evidence suggesting that MIS-C and KD share proximal pathways of immunopathogenesis.
      • Ghosh P.
      • Katkar G.D.
      • Shimizu C.
      • et al.
      An Artificial Intelligence-guided signature reveals the shared host immune response in MIS-C and Kawasaki disease.
      Using an artificial intelligence-based approach, Ghosh et al. found that both syndromes are characterized by a cytokine storm centering on IL-15/IL-15RA. They posit that MIS-C and KD exist on the same continuum of the host immune response, with MIS-C positioned further on the spectrum of severity.
      There are many differences in the immune responses of the two conditions. MIS-C appears to be associated with markedly elevated IL-10
      • Diorio C.
      • Henrickson S.E.
      • Vella L.A.
      • et al.
      Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.
      and some patients have higher concentrations of IFNγ-induced CXCL9
      • Rodriguez-Smith J.J.
      • Verweyen E.L.
      • Clay G.M.
      • et al.
      Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study.
      compared to KD. In contrast, a distinct feature of KD is a strong type 17 T helper cell response that drives IL-17A-mediated hyperinflammation.
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      ,
      • Sharma C.
      • Ganigara M.
      • Galeotti C.
      • et al.
      Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison.
      ,
      • Sancho-Shimizu V.
      • Brodin P.
      • Cobat A.
      • et al.
      SARS-CoV-2-related MIS-C: A key to the viral and genetic causes of Kawasaki disease?.
      Whereas a superantigen mechanism is thought to play an important role in the pathogenesis of MIS-C (as described in-depth earlier), the current evidence favours an immune response to a conventional antigen in KD.
      • McCrindle B.W.
      • Rowley A.H.
      • Newburger J.W.
      • et al.
      Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.
      ,
      • Sharma C.
      • Ganigara M.
      • Galeotti C.
      • et al.
      Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison.
      MIS-C is also characterized by an expansion of Vβ21.3+ T cells, which distinguishes it from KD.
      • Vella L.A.
      • Rowley A.H.
      Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.
      ,
      • Moreews M.
      • Le Gouge K.
      • Khaldi-Plassart S.
      • et al.
      Polyclonal expansion of TCR Vbeta 21.3(+) CD4(+) and CD8(+) T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.
      Consiglio et al. described a number of differences in T cell subsets between the two conditions: MIS-C patients were found to have lower levels of naïve CD4+ T cells and follicular helper T cells, but higher levels of central memory and effector memory CD4+ T cells compared to individuals with KD.
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      Another study demonstrated that MIS-C patients had a higher proportion of HLA-DR+ CD4+ T cells compared to KD.
      • Carter M.J.
      • Fish M.
      • Jennings A.
      • et al.
      Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.
      Finally, while both syndromes have autoimmune components, the specific autoantibodies differ. KD has been associated with autoantibodies against DEL-1
      • Sancho-Shimizu V.
      • Brodin P.
      • Cobat A.
      • et al.
      SARS-CoV-2-related MIS-C: A key to the viral and genetic causes of Kawasaki disease?.
      and EDIL3,
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      which are proteins that normally function to limit vascular inflammation. Autoantibodies against proteins of the casein kinase family
      • Consiglio C.R.
      • Cotugno N.
      • Sardh F.
      • et al.
      The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
      ,
      • Sancho-Shimizu V.
      • Brodin P.
      • Cobat A.
      • et al.
      SARS-CoV-2-related MIS-C: A key to the viral and genetic causes of Kawasaki disease?.
      and IL-1RA
      • Pfeifer J.
      • Thurner B.
      • Kessel C.
      • et al.
      Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.
      are unique to MIS-C. In summary, there is currently no consensus as to whether or not MIS-C and KD represent distinct immunopathogenic illnesses, or if they are two syndromes on the same continuum of the host immune response. Further investigations are likely ongoing.

      Conclusions

      The emergence of the novel and clinically important condition MIS-C associated with prior COVID-19 in children together with the pivot during the pandemic to prioritize research and publication associated with COVID-19 has created a rapid and unprecedented understanding of the underlying pathophysiology. While the hope is that the relevance of this pandemic will die out, the detailed understandings achieved will likely find some applicability to other immune conditions, most notably Kawasaki disease, a condition that has remained largely an enigma and for which therapy has been largely empiric. Any comprehensive understanding must explain epidemiologic, clinical, genetic, pathologic and immunologic features, and additionally incorporate mediating factors such as the microbiome, environment and social determinants of health. Likewise, understanding disease mechanisms might lead to more specific and targeted diagnostic tests and treatments, and perhaps the prospect of prevention. Advances in research methods, including artificial intelligence and machine learning, will likely bring new insights into the complex interplay of factors underlying the pathophysiology of MIS-C.

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