Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a delayed postinflammatory disorder associated with the previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially, MIS-C was described as highly similar to Kawasaki disease (KD), a pediatric febrile systemic vasculitis that can lead to the development of coronary artery aneurysms (CAAs). While KD and MIS-C are both inflammatory disorders, the 2 entities differ in their epidemiological, clinical, immunological, and pathological features. MIS-C clinical and laboratory characteristics are more closely related to toxic shock syndrome (TSS) than KD, which informs the understanding of pathogenesis and potential therapeutic approaches.

Key points

• •While multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) are considered 2 distinctive diseases triggered by different infectious agents, these 2 entities share inflammatory characteristics. They may belong to the same umbrella of inflammatory disorders but differ in many aspects of etiology, demography, epidemiology, clinical and laboratory findings, and pathology.
• •The intensity of the inflammatory response and long-term cardiovascular sequelae diverge between KD and MIS-C. Whereas MIS-C presents as a more intense inflammatory syndrome, myocardial dysfunction, and cardiogenic shock, KD vasculitis is associated with pathologic changes in the coronary arteries and long-term cardiovascular sequelae.
• •Intravenous immunoglobulin (IVIG) is efficient in treating both MIS-C and patients with KD; however, affected patients need to be followed over time to monitor the emergence or persistence of cardiovascular sequelae.

Introduction

Kawasaki disease (KD) is a febrile pediatric systemic vasculitis of unknown origin, usually affecting children younger than five years.¹ KD can result in coronary artery aneurysms (CAAs) in ≈ 25% of untreated children, and it is the leading cause of acquired heart disease in children in developed countries.¹ Multiple aspects of this pediatric illness are not completely understood, including the causative agent(s), the immune mechanisms underlying KD pathogenesis, and the potential long-term cardiovascular sequelae. Multisystem hyperinflammatory syndrome in children (MIS-C) is a novel pediatric illness that emerged during the COVID-19 pandemic.2, 3, 4, 5, 6, 7, 8 While in most children SARS-CoV-2 infection is asymptomatic or results in mild symptoms, a subset of infected children develops MIS-C, which presents as fever, hypotension, gastrointestinal (GI) symptoms, and myocardial dysfunction.2, 3, 4, 5, 6, 7, 8 Initially, MIS-C was called a “Kawasaki-like” disease due to mucocutaneous symptoms and the overlap of some clinical features.^{3 , 5} Indeed, overlapping clinical features, including conjunctional injection, mucositis, and swelling of the hands and feet, hint that MIS-C and KD may belong to the same spectrum of inflammatory disorders. However, the observed epidemiological, pathological, inflammatory, and immunological differences between MIS-C and KD indicate that these 2 diseases are different entities^{2 ,} 8, 9, 10 (Fig. 1 ). Here, we review the recent advances in KD and MIS-C research.

Fig. 1.

Divergent and overlapping features of KD and MIS-C. (A) Clinical, pathological, and immunological features specific to KD. (B) Clinical, pathological, and immunological features that overlap between KD and MIS-C. (C) Clinical, pathological, and immunological features specific to MIS-C.

(Created with BioRender.com.)

Viral Triggers as a Shared Etiology Between Multisystem Inflammatory Syndrome in Children and Kawasaki Disease

MIS-C is a postacute hyperinflammatory syndrome that develops after either SARS-CoV-2 infection or exposure. Most patients with MIS-C have serologic evidence of previous SARS-CoV-2 infection or exposure 2 to 6 weeks before disease onset.2, 3, 4, 5, 6, 7, 8 ^{, 10} In contrast, although KD's clinical presentation and epidemiology hint toward an infectious origin, the causative agent(s) remain unidentified today.^{11 , 12} Patients with KD do not respond to antibiotic treatment, often given pre-KD diagnosis during the acute phase, indicating that KD triggering agent(s) might be of viral origin rather than bacterial.¹²

Multisystem clinical findings common to MIS-C and KD, such as rash, fever, GI tract abnormalities, swollen lymph nodes, headaches, and fatigue, also overlap with clinical manifestations triggered by other pediatric viral illnesses.^{1 , 12} Associations between common respiratory viruses, including coronaviruses, and KD development have been previously reported.^{13 , 14} However, they were not confirmed in follow-up studies.15, 16, 17 For example, intracytoplasmic inclusion bodies detected in ciliated bronchial epithelium tissues from patients with KD, months to years after acute KD, support the hypothesis of a viral causative agent.^{12 , 18} Serological profiling did not detect differences in antiviral antibody profiles between acute KD and control patients.¹⁹ However, another study identified a protein epitope targeted by antibodies produced in patients with KD during the acute phase of the disease.¹⁸ Although the source of this protein epitope remains unidentified, the authors hypothesized the possibility of a novel, uncharacterized virus.¹⁸ The infectious agent hypothesis is further supported by the observation that KD incidence decreased in multiple areas when mitigation measures were implemented to control the spread of COVID-19.^{20 , 21}

Epidemiological Differences Between Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Key epidemiological differences differentiate KD and MIS-C. First, KD incidence is approximately 25 per 100,000 children under five years in the US,¹ whereas a cross-sectional study of a large US cohort of patients with MIS-C estimated MIS-C incidence to be ≈ 2 per 100,000 in individuals younger than 21 years.²² Most KD cases occur in patients younger than five years,¹ while the median age of MIS-C is 9 years.²² Although rare, KD can also occur in adults and usually presents with fewer electrocardiographic abnormalities and CAAs than pediatric KD.²³ A rare multisystem inflammatory syndrome, called MIS-A, is also reported in adults and is highly similar to MIS-C.²⁴ KD prevalence is consistently greater in males (1.5 male-to-female ratio in the US).¹ In MIS-C, while the proportion of males and females is 1:1 between the ages of 0 to 4 years, it increases and reaches 2:1 for patients between 18 and 20 years.²²

KD incidence is higher in Asian countries such as Japan, South Korea, China, and Taiwan than in the USA and Europe.¹ In contrast, reports of MIS-C in East Asia are limited,^{25 , 26} and in the US, the incidence of MIS-C is higher in children from Hispanic or Black ethnicities and the lowest in Asian children.^{22 , 27} The variation in the incidence of both KD and MIS-C among ethnic groups may be at least in part related to genetic predisposition. Indeed, single-nucleotide polymorphisms (SNPs) in various genes, such as ITPKC, CASP3, FCGR2A, ORAI1, BLK, and CD40 are associated with increased susceptibility to KD.^{11 , 28} Genetic analysis from a limited number of patients with MIS-C identified rare variants in genes associated with autoimmunity pathways and regulation of inflammatory responses, which may potentially predispose to MIS-C.29, 30, 31

Several studies indicate that HLA class I alleles are associated with MIS-C.32, 33, 34 The expansion of Vβ11-2⁺ T cells in patients with MIS-C correlates with inflammatory markers and MIS-C severity.33, 34, 35, 36 Severe patients with MIS-C with Vβ11-2⁺ T cell expansion share a combination of 3 HLA class I alleles (A02, B35, and C04).³³ The same combination was detected in patients with MIS-C from an Italian and an American cohort, however, they were not associated with disease severity.^{32 , 34} While these observations were not reproduced in another cohort,³⁶ the combination of these 3 HLA classes I alleles might confer increased susceptibility to MIS-C, which may explain the rarity of MIS-C and why the disease disproportionately affects specific ethnicities.

Clinical, Biological, and Pathological Findings of Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Using data collected from retrospective cohorts of patients with KD, several studies have compared the clinical, biological, and pathological characteristics of patients with MIS-C and KD.^{2 ,} 37, 38, 39, 40 In the absence of a specific test to identify KD, the diagnosis is based on the presence of persistent fever lasting more than five days and 4 of 5 primary clinical criteria: changes in the extremities, erythematous rash, conjunctivitis, cracked lips and strawberry tongue, and cervical lymphadenopathy.¹ Only ≈30% of patients with MIS-C meet these criteria for complete KD.³⁹ Patients with MIS-C have higher levels of C-reactive protein (CRP), ferritin, D-dimer, troponin, and N-terminal probrain natriuretic peptide (NT-proBNP) than patients with KD, indicating hyperinflammation and potential cardiovascular involvement.^{2 , 37 , 38} However, compared with patients with KD, children with MIS-C have lower lymphocyte and platelet counts.^{2 ,} 37, 38, 39, 40

Patients with MIS-C commonly present with prominent cardiac involvement manifested by left ventricular (LV) systolic and diastolic dysfunction, myocardial inflammation, and coronary artery dilations.^{41 , 42} LV dysfunction is more severe in patients with MIS-C than in patients with KD.⁴¹ However, KD can also lead to myocarditis, which is associated with arrhythmias and may result in long-term fibrosis.^{1 , 11 , 43} Coronary arteries are predominantly affected during KD and may result in dilation and aneurysms.^{1 , 11} Children with MIS-C have fewer coronary artery abnormalities than patients with KD and they are almost always transient and resolve rapidly over time.^{38 , 39 , 41 , 44} In patients with KD, the small and moderate CAAs can take 2 years to regress to standard lumen size.⁴⁵ The prompter resolution of cardiovascular complications after the MIS-C acute phase suggests they may result from hyperinflammation associated with capillary leakage and vasodilation rather than immune infiltrations damaging the myocardium.⁴⁶

Immune Responses During Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Immunophenotyping studies have revealed that immune dysregulation, cytokine storm, and increased the activation of immune cells are hallmarks of MIS-C, and these correlate with disease severity.^{34 , 36 ,} 47, 48, 49 Notably, elevated cytokines include IL-6, IL-10, TNF-α, IFN-γ, IL-1β, IL-1RA, and soluble CD25.34, 35, 36 ^{, 40 , 50 , 51} While acute KD is also associated with high levels of IL-1β, TNF-α, IFN- γ, IL-10, and IL-8,^{36 ,} 52, 53, 54 concentrations of these cytokines appear higher during MIS-C.⁵⁵ IL-1β plays a crucial role in KD development. Clinical trials are currently ongoing to test the efficacy of Anakinra, an IL-1 receptor antagonist (IL-1Ra), for patients with KD refractory to IVIG treatment.^{56 , 57} IL-17A plasma levels and the proportions of circulating Th17 T cells are increased during acute KD and may be involved in KD pathogenesis.⁵⁸ IL-17A is also elevated in MIS-C, however, to a lesser degree than in KD.³⁷

Dysregulated cellular and humoral immune responses occur in MIS-C, including reductions in the proportions of plasmacytoid dendritic cells (pDCs),^{49 , 59} monocytes,⁴⁷ and natural killer (NK) cells.^{47 , 59} NK cells from patients with MIS-C upregulate the expression of several cytotoxic genes,⁵⁹ and monocytes from children with MIS-C upregulate alarmin-related S100A genes, indicative of an activated phenotype.⁵⁹ Similarly, monocytes from patients with KD also upregulate the S100A proteins, IL1B, and TNF transcripts.⁶⁰ The frequency of neutrophils and monocytes expressing the activation marker CD64 increases during the acute phase of the MIS-C.^{47 , 48} Neutrophils from patients with MIS-C exhibit higher rates of spontaneous release of neutrophil extracellular traps (NETs), which may be a driver of MIS-C vascular inflammation and endothelial damage.⁶¹ Neutrophils are similarly implicated in the early phase of CAAs formation in KD⁶² and the spontaneous release of NETs by neutrophils is also enhanced in patients with KD.⁶³

A hallmark of patients with MIS-C is lymphopenia, which affects both CD4⁺ and CD8⁺ T cells,^{37 , 48 , 49 , 59} which is not usually observed in KD.⁹ Patients with MIS-C show increased frequencies of activated and proliferating T cells^{37 ,} 47, 48, 49 ^{, 59}; activated CD8⁺ T cells express the fractalkine receptor CX3CR1, which can interact with fractalkine-expressing vascular endothelium and may potentiate vascular endothelial damage.⁴⁹ Patients with MIS-C also exhibit elevated frequencies of plasmablast cells.^{34 , 35 , 49 , 59} The frequency of circulating activated B cells and plasmablasts is also increased during KD.⁶⁴

The presence of autoantibodies targeting ubiquitously expressed antigens and self-antigens has been reported in multiple cohorts of patients with MIS-C.^{34 , 37 , 47 , 50 , 59} A high proportion of patients with MIS-C also express autoantibodies targeting the endogenous IL-1 receptor antagonist (IL-1Ra).⁶⁵ The expansion of B cells during KD acute may similarly lead to autoimmune responses and the production of autoantibodies.⁶⁴ Indeed, the presence of antibodies targeting type III collagen, myosin, alpha-enolase, and anti-endothelial antibodies is also observed in KD.⁶⁴ Nevertheless, further studies are still required to determine the specific role of autoantibodies in both MIS-C and KD.

The Superantigen Hypothesis and Expansion of TRBV11-2 T Cell Clonotypes in Multisystem Inflammatory Syndrome in Children

Superantigens (SAgs) are microbial proteins able to activate large fractions of T cells non-specifically by cross-linking major histocompatibility complex (MHC) class II molecules at the surface of antigen-presenting cells (APCs) with T cell Receptor (TCR) β-chains (Vβ) at their variable domain.⁶⁶ Vβ skewing with junctional diversity indicates SAg involvement.⁶⁶ Over-activation of T cells by SAg results in an uncontrolled release of chemokines and proinflammatory cytokines and underlies toxic shock syndrome (TSS). KD shares some clinical features with SAg-mediated diseases, including fever, desquamating rash, and SAgs have been considered as potential KD triggers. While a few studies reported the expansion of different Vβ T cell populations during acute KD,this has not been confirmed by follow-up studies on independent cohorts of patients with KD.67, 68, 69 Additionally, the development of coronary artery abnormalities, a hallmark of KD, is rarely associated with SAg-mediated disease.⁷⁰ In contrast, patients with TSS present with severe GI symptoms, myocardial cardiogenic shock, and neurological manifestations.⁷⁰ These symptoms are infrequent in KD and more commonly reported during MIS-C.2, 3, 4, 5, 6, 7, 8, 9 ^{, 71 , 72}

Computational studies comparing SARS-CoV-2 with bacterial toxins revealed the presence of a motif in SARS-CoV-2 Spike protein subunit S1 that harbors high sequence and structural similarities with a segment of staphylococcal enterotoxin B (SEB), a bacterial SAg.⁷³ This SAg-like motif is an insertion, P₆₈₁RRA₆₈₄ (PRRA), unique to SARS-CoV-2 and adjacent to the furin cleavage site between the S1 and S2 subunits.71, 72, 73 In silico modeling indicates this insert has a propensity to bind to TCRs and MHC Class II.^{33 , 50 ,} 71, 72, 73, 74 Studies in mice and hamsters show that SARS-CoV-2 mutations resulting in the deletion of the S1-S2 furin cleavage site result in attenuated disease.^{75 , 76} Furthermore, supporting the potential involvement of the SAg-like motif in SARS-CoV-2 pathogenesis, incubation of SARS-CoV-2 with the 6D3 anti-SEB mAb inhibited cellular viral infection in vitro.⁷⁴

TCR repertoire sequencing performed on independent cohorts of patients with MIS-C indicate TCRVβ skewing and expansion of TRBV11-2 (Vβ21.3⁺) T cell clonotypes, suggestive of superantigenic stimulation.33, 34, 35, 36 ^{, 59} This TRBV11-2 enrichment affects both CD4⁺ and CD8⁺ T cells, is transient, and returns to baseline after MIS-C resolution.34, 35, 36 ^{, 59} Expansion of TRBV11-2 clonotypes correlates with disease severity and cytokine storm.33, 34, 35, 36 Severe patients with MIS-C with TRBV11-2 T cell expansion also exhibit more robust autoantibodies responses, a solid imprint of antigenic selection in their BCR repertoires, and increased usage of autoantibody-associated IGHV genes.⁵⁰ In silico modeling indicates that TRBV11-2 engages in a CDR3-independent interaction with the polybasic insert “PRRA” in the SARS-CoV-2 SAg-like motif.^{33 , 73}

Autopsy studies of fatal MIS-C cases indicate the sustained presence of SARS-CoV-2 in multiple tissues, including lung, heart, brain, and intestinal tissues.77, 78, 79, 80 Yonker and colleagues⁸¹ observed the prolonged presence of SARS-CoV-2 RNA in the GI tract of patients with MIS-C weeks after initial exposure and elevated levels of Zonulin and other markers indicative of increased intestinal permeability. This suggests that the GI tract may act as a viral reservoir for SARS-CoV-2. Increased intestinal permeability might be permissive for SARS-CoV-2 antigens to breach the intestinal barrier and enter the systemic circulation.⁸¹ Indeed, patients with MIS-C with a severe clinical phenotype and TBRV11-2 expansion have higher levels of circulating S1, which contains the SARS-CoV-2 SAg-like motif.⁸¹ These data support the hypothesis that MIS-C is a unique disease entity driven by the SAg-like motif in SARS-CoV-2 Spike.

Long-Term Sequelae of Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Vascular inflammation stemming from acute KD can result in long-term cardiovascular sequelae and ischemic heart diseases.^{11 , 43 , 82} Up to ≈7% of IVIG-treated children with KD will develop coronary artery abnormalities, which may progress to stenosis, occlusion, and/or thrombosis over time.⁸³ A history of KD during childhood is associated with an increased prevalence of abnormal electrocardiogram (ECG).⁸⁴ Long-term KD complications include coronary artery stenosis and calcification, myocardial infarction, fibrosis, and long-term systolic or diastolic dysfunction, and may predispose to premature atherosclerosis.^{11 , 43 , 82 , 83 , 85}

While the cardiovascular manifestations of acute MIS-C improve rapidly, little is known regarding the long-term outcomes, and myocardial inflammation could lead to long-term sequelae such as fibrosis and scaring.⁴² Potential long-term outcomes in patients with MIS-C are documented in a few studies.^{44 , 46 ,} 86, 87, 88, 89 A multicenter follow-up study of US children that developed MIS-C indicates that some symptoms, such as fatigue, weakness, activity impairment, and headache may persist beyond 2 months after hospitalization.⁸⁷ In another cohort of patients with MIS-C, six months after acute disease, markers of systemic inflammation returned to baseline, electrocardiograms were normal, GI symptoms were absent, and minimal functional neurological impairment was observed.⁸⁹ However, in this study, 18 of the 40 patients exhibited a reduced functional exercise capacity six months post-MIS-C. Whether this resulted from MIS-C or involved other factors, such as a sedentary lifestyle, remains unclear.⁸⁹ Additional and extended studies are still required to determine the long-term impacts of MIS-C on cardiovascular function, and a multicenter observational cohort study (COVID MUSIC study) is currently ongoing.⁸⁶

Decreased Incidence of Multisystem Inflammatory Syndrome in Children with SARS-CoV-2 Variants of Concern and Vaccination

Since the beginning of the COVID-19 pandemic, several SARS-CoV-2 variants of concern (VOCs) have been characterized as the virus evolves.⁹⁰ Omicron, which exhibits more than 30 amino acid substitutions, quickly became the dominant circulating variant in 2022, raising potential concerns about increased MIS-C incidence. However, MIS-C severity and incidence dramatically decreased during the Omicron wave compared with Alpha and Delta waves.^{91 , 92} Indeed, since June 2022, the number of MIS-C cases reported to the CDC has been dramatically reduced.²⁷ Multiple parameters may account for such a decrease in MIS-C frequency, including the strong association between children's vaccination (Pfizer-BioNTech) and prevention of MIS-C,⁹³ prior SARS-CoV-2 infections and induction of immune memory, better management, and, potentially, mutations in the Omicron variant itself.^{91 , 92} Indeed, mutations in SARS-CoV-2 Spike may explain disease severity differences between variants. The highly pathogenic Delta harbors a Spike mutation, P681R, which becomes more polybasic in nature and is further cleaved by the acidic motif furin, releasing higher amounts of the shed S1 subunit.⁹⁴ On the other hand, the relatively less pathogenic Omicron harbors several mutations in Spike that result in inefficient use of TMPRSS2, suboptimal S1/S2 cleavage, and reduced levels of shed S1.⁹⁵ Since the SAg-like motif is in the S1 SARS-CoV-2 subunit, these findings may potentially support the SAg hypothesis of MIS-C and may explain the significant reduction of MIS-C incidence during the Omicron wave, in addition to vaccines-induced protection.

Summary

Several clinical features overlap between MIS-C and KD. These 2 entities share inflammatory characteristics, indicating that MIS-C and KD may belong to the same broad umbrella of inflammatory disorders involving the master cytokine IL-1β,⁹⁶ but differ in many aspects of etiology, demography, epidemiology, clinical and laboratory findings, as well as pathology. The intensity of the inflammatory response and long-term cardiovascular sequelae diverge between KD and MIS-C. Whereas MIS-C presents with a more intense inflammatory syndrome, KD vasculitis is associated with pathologic changes in the coronary arteries and associated with long-term cardiovascular sequelae. The 2 to 6 weeks delay between SARS-CoV-2 exposure and MIS-C development may account for the development of the autoinflammatory response involving dysregulated B and T cell responses, plasmablast differentiation, and autoantibody production.^{50 , 72} While the general hypothesis is that KD is triggered by a viral infectious agent(s), the causative agents remain unidentified, and whether KD can be considered a postinfectious syndrome, like MIS-C, remains unclear. In conclusion, the data available so far support the hypothesis that MIS-C and KD belong to the same broad spectrum of inflammatory disorders but with clearly distinct etiopathology, presentation, and long-term consequences.

Clinics care points

• •MIS-C and KD are considered 2 distinctive diseases triggered by different infectious agents. However, these 2 entities share inflammatory characteristics. It is, therefore, not surprising that both diseases respond well to IVIG ± steroids. Furthermore, anti-IL-1 receptor therapies, such as Anakinra, are expected to treat these 2 conditions efficiently.
• •KD is associated with the development of coronary artery aneurysms and later coronary remodeling with luminal myofibroblast proliferation that leads to coronary stenosis, ischemia, and myocardial fibrosis as long-term sequelae. Children with MIS-C should also be followed longitudinally to determine if any long-term complications will emerge.
• •COVID-19 vaccinations is associated with decreased MIS-C incidence and should be encouraged among all eligible age groups.

Disclosure

The authors have nothing to disclose.

Funding

We gratefully acknowledge support from NIH awards R01AI072726 to M. Arditi, R01HL139766 and R01HL159297 to MNR, R01AI157274 to M. Arditi and MNR.