Kawasaki Disease Versus Multisystem Inflammatory Syndrome in Children: Exploring the Complexities of Pediatric Cardiac Inflammatory Disorders

Authors: Dalia Safi, Christophe El Rassi, Maria Abou Mansour, Bshara Sleem, Issam El Rassi, Mariam Arabi

Abstract

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are both pediatric inflammatory conditions that pose significant challenges in diagnosis and management due to their overlapping clinical features and distinct pathophysiological profiles. KD is a well-established acute vasculitis that primarily affects children under 5. In contrast, MIS-C is a recently identified condition associated with SARS-CoV-2 infection, typically affecting older children and adolescents. Reported mortality for MIS-C remains below 2%, compared with less than 0.1% for KD, although both can result in significant cardiac morbidity if untreated. This review highlights the critical differences between KD and MIS-C, including their genetic underpinnings, clinical manifestations, and responses to treatment. While KD has a well-established treatment protocol involving intravenous immunoglobulin and aspirin, MIS-C treatment is still evolving. The manuscript underscores the importance of distinguishing between these conditions for accurate diagnosis and tailored treatment, which is crucial for improving patient outcomes.

Introduction

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are pediatric inflammatory conditions that share a multitude of clinical similarities but present distinct challenges in diagnosis, management, and pathophysiology.^1,2^

KD is an acute, self-limited vasculitis that predominantly affects children under the age of 5.^ 3 ^ It was first described by Tomisaku Kawasaki in 1967 in Japan and published under the title ‘Infantile acute febrile mucocutaneous lymph node syndrome with specific desquamation of the fingers and toes’.^ 4 ^ KD is characterized by high fever, mucocutaneous inflammation, and cervical lymphadenopathy.^3,4^ Over the years, a multitude of studies regarding treatment, epidemiology, and pathophysiology have been published. Without treatment using intravenous immunoglobulin (IVIG) during the acute phase, about 20% of children develop coronary artery aneurysms (CAAs).^ 3 ^ KD has now surpassed rheumatic fever as the leading cause of acquired heart disease in children in developed nations.^ 3 ^

MIS-C is a pediatric condition associated with SARS-CoV-2, characterized by KD-like and toxic shock syndrome-like symptoms including prolonged fever, abdominal pain, mucositis, conjunctivitis, lymphadenopathy, cardiac involvement including CAAs, and multi-organ failure.^1,2^ It first emerged in the spring of 2020 as a suspected post-infectious complication of SARS-CoV-2, warranting the use of immunomodulatory therapy like IVIG despite the lack of evidence or understanding of the condition’s pathophysiology simply based on its similarity to KD.^ 5 ^ Since then, efforts have been made to understand MIS-C’s etiology and triggers in order to determine the optimal treatment regimen.^ 1 ^

Both KD and MIS-C present in children with hyperinflammation and multi-organ involvement with an unclear etiology.^ 6 ^ While there is a significant overlap of clinical presentation, laboratory features, and symptoms between KD and MIS-C, differences in supplementary treatment, prognosis, long-term monitoring, and public health implications necessitate differentiating between the 2 entities.^1,7,8^ Recent studies published through 2024 have emphasized the continued evolution of diagnostic and therapeutic criteria for both KD and MIS-C, prompting the need for updated comparative analyses that integrate findings from the post-pandemic era.^9 -11^

Methods

This literature review was conducted in July 2024, focusing on the pediatric inflammatory conditions Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C). The databases PubMed, Scopus, and Google Scholar were utilized for the search, employing the following “Kawasaki Disease,” “Multisystem Inflammatory Syndrome in Children,” “MIS-C,” “COVID-19,” “SARS-CoV-2,” “pediatric vasculitis,” “coronary artery aneurysm,” “hyperinflammation,” “genetic predisposition,” and “immunomodulatory therapy” as Medical Subject Headings (MeSH) terms.

The search strategy aimed to identify articles exploring the epidemiology, pathophysiology, clinical manifestations, and treatment approaches of KD and MIS-C. Articles were selected based on their relevance, accuracy, and contribution to understanding the similarities and differences between the 2 conditions. The inclusion criteria encompassed studies without restrictions on study type or country of origin, provided they were written in or translated into English. The review focused primarily on studies published between 2020 and 2024 to capture recent advancements and findings.

A comprehensive literature search was performed in PubMed, Scopus, and Google Scholar for articles published between January 2020 and July 2025 using combinations of the terms “Kawasaki Disease,” “Multisystem Inflammatory Syndrome in Children,” “MIS-C,” and “COVID-19.” Approximately 230 records were screened, and 97 were included after removing duplicates, preprints, and case reports with incomplete data. Articles were selected based on relevance to epidemiology, pathophysiology, clinical features, and management of KD and MIS-C.

In addition to primary research articles, relevant reviews and meta-analyses were included to provide comprehensive coverage of the topic. References from selected articles were also examined to identify additional pertinent studies. The literature review process involved a thorough evaluation of each article’s validity and relevance to ensure a robust and comprehensive synthesis of current knowledge regarding KD and MIS-C.

Ethical approval and informed consent were not required for this study, as it is a review based solely on previously published literature and does not involve any human participants, personal data, or animal subjects.

Epidemiology

Kawasaki Disease

As a disease predominantly of childhood, 80% of cases occur in children under 5, with the male female ratio approximately being 1.3 to 1.4:1.^ 12 ^ Incidence varies according to season, albeit the peak season differs from country to country.^12,13^ For instance, the trends in the Northern hemisphere exhibit higher numbers in late winter and early spring while lower numbers in late summer and autumn whilst nations in the Southern hemisphere or tropics did not feature a statistically significant seasonal variation.^14,15^ Similarly, epidemiological studies in Japan have also shown a seasonal variation of CAAs, with the occurrence being significantly lower in summer compared to other seasons.^ 16 ^

The incidence of KD is 10-30 times higher in Northeast Asia, particularly Japan, South Korea, China, and Taiwan, compared to Europe and USA.^17,18^ While the general trend is of increasing incidence in Northeast Asia, the incidence of KD did not significantly change over several decades in the US and Canada.^ 18 ^ Of note, epidemiological studies in Hawaii found a higher incidence than the US overall, with an incidence of 32 per 100 000 children under 5 years of age compared to 25 per 100 000, the majority of which being Asian children and the remainder encompassing Native Hawaiians and Pacific Islanders.^ 19 ^ With an incidence rate of 210.5 per 100 000 Japanese children, comparable to the incidence in Japan, this points toward a genetic susceptibility to KD.^ 19 ^ Furthermore, based on data gathered between 1995 and 2017, the incidence in Canada is similar to that in the US, with approximately 25.0 cases per 100 000 children under 5.^ 20 ^

The most recent epidemiological survey in South Korea reported an incidence of 196.9 per 100 000 children under 5 over the 3-year period of 2015 to 2017.^ 21 ^ A 2013 to 2017 survey based in Shanghai reported an incidence of 68.8 to 107.3 per 100 000 children.^ 22 ^ Demographic data from Taiwan in 2010 found an incidence ranging 68.46 to 82.77 per 100 000 children under 5 years of age.^ 23 ^ In Japan, data prior to the COVID-19 pandemic found an incidence of 359 per 100 000 children aged 0 to 4 years old in 2018, following the trend of increasing incidence since 1970.^ 24 ^ Similarly, in 2019, the rate increased to 371 cases per 100 000 children.^ 25 ^ However, in 2020, the incidence decreased by approximately one-third compared to 2019, with a variation in reduction between those under 12 months old and those 12 months or older.^ 25 ^ Considering the hypothesis that KD pathogenesis might be due to an infectious agent transmitted asymptomatically among children through human-to-human contact, implementing strict infection control measures as had been done during the pandemic could help prevent the development of KD in older children.^ 25 ^ Data from the 2017 to 2018 survey found that within 30 days of KD onset, 9.0% developed cardiac complications, and following acute illness, 2.6% developed cardiac sequelae.^ 24 ^ Such trends similarly follow the pattern of a decreasing percentage of cardiac complications since 1999, which may potentially be attributed to improvements in KD treatment.^ 24 ^ A 2024 review of KD epidemiology reported that while the incidence remains highest in East Asia, emerging national registries have identified a mild post-pandemic rebound in Europe and North America, suggesting renewed viral or environmental triggers.^ 10 ^

Given the lack of a gold standard for the diagnosis of KD as well as the methodology to identify KD cases, it is important to note the limitations in interpreting epidemiologic data.^ 17 ^ Figure 1 highlights the countries with a predominance of KD and MIS-C.^17,26 -37^

Multisystem Inflammatory Syndrome in Children

The mean age of presentation of MIS-C is 8.1 years with a male-female ratio of 1.2:1.^32,38^ MIS-C typically presents around 27 days after a SARS-CoV-2 infection, and the incidence tends to rise approximately 1 month after a preceding peak of COVID-19 in specific geographic regions.^ 39 ^ Incidence varies from country to country; however, comprehensive global incidence data is limited. Cases have been reported in the UK, Italy, France, Spain, and United States.^ 1 ^ The United States CDC reports an incidence of 6.79 per 1 000 000 person-months in the months October 2020 to April 2021 early in the pandemic prior to the emergence of the Delta variant but decreased to 0.11 per 1 000 000 person-months in 2023 as Omicron subvariants circulated.^ 40 ^ A 2025 Italian cohort found that although MIS-C incidence declined with later SARS-CoV-2 variants, the severity of cases remained essentially unchanged, suggesting persistent risk of serious cardiac or systemic involvement despite lower incidence.^ 41 ^ Of particular note, countries that report the highest incidence of KD such as Japan and China have little to no reported cases of MIS-C.^1,42,43^ Some hypothesize that it may be due to the higher infection and fatality rate of COVID-19 in European cities compared to Asian countries.^44,45^ Furthermore, based on a systematic review published in 2022, the most affected races are African black (24.89%) and Hispanic white (25.18%), then Asians (23.51%) and non-Hispanic whites (19.01%).^ 38 ^ While the racial distribution may correlate to COVID-19 related health inequities, such as deficiency in nutrients, overcrowding, or poorer access to healthcare, the possibility of a genetic predisposition to MIS-C has not been ruled out.^38,39,46^ Moreover, with obesity being the most common comorbidity in children with MIS-C, the interrelation between obesity and age, race, being Hispanic, and education of the head of the household (particularly in the US) emphasizes the importance of ethnicity and socioeconomic status in the context of MIS-C.^ 47 ^ To further highlight the potential role of socioeconomic determinants, MIS-C cases in developing countries including Pakistan, India, and Iran exhibited higher mortality rates than those in high-income countries.^ 47 ^ Finally, there is an increased risk of shock in older patients and an overall increased risk of mortality relative to KD.^ 8 ^ A multicenter registry published in 2024 comparing MIS-C and KD across Asian and Western cohorts further confirmed that MIS-C tends to present with greater myocardial dysfunction and shock, but less coronary aneurysm formation than classic KD.^ 48 ^

Pathophysiology

Kawasaki Disease

The etiology of KD remains unknown. Furthermore, the triggering factor has yet to be identified, albeit research points toward a conventional antigen.^ 49 ^ Research has suggested that KD occurs due to an infectious agent, whether known or novel, including viruses like adenovirus, Epstein Barr virus, and herpesvirus as well as bacterial species like streptococci, staphylococci, Rickettsia, Neisseria, and Chlamydia.^13,50,51^ For instance, a subset of patients from Europe, Australia, the United States, and Japan, infected with Yersinia entercolitica developed symptoms matching KD’s diagnostic criteria.^ 52 ^ Proponents in favor of this theory also consider the familial and community clustering of KD as well as its seasonality, peaking in late winter to spring just as respiratory viral infections do within the same age group.^ 51 ^ However, any link to an infectious agent has yet to be consistently repeated in cohorts comprising those of multiple ethnicities.^ 51 ^

In addition, the higher prevalence of KD among children of East Asian and Pacific Islander descent indicates a genetic component of its pathogenesis.^ 1 ^ Furthermore, siblings of children diagnosed with KD have a higher likelihood of developing the disease itself.^ 50 ^ While KD does not appear to be inherited according to Mendelian genetics, many single-nucleotide polymorphisms (SNPs) have been identified in genes such as CASP3, ITPKC, CD40, FCGR2a, and BLK.^1,53^ However, the role these SNPs play in the progression of KD is not yet fully understood.^ 49 ^ For instance, a SNP in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC), an integral part of various signaling pathways by preventing IP3 from interacting with its receptor, increased the risk of developing lesions in the coronary arteries in patients of Taiwanese, Japanese, or American ethnicities, perhaps due to promoting the activation of the NLRP3 inflammasome, increasing T-cell activity, and heightening the production of IL-1β and IL-18.^ 49 ^

Many researchers theorize that the development of KD starts when an antigen-presenting cell recognizes a pathogen through pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), leading to the release of cytokines like TNF-α, IL-6, and VEGF from macrophages, T cells, and other immune cells of both the innate and adaptive immune system.^50,54^ This eventually leads to an inflammatory response to an autoantigen in the vessel walls that has yet to be ascertained, resulting in the infiltration of immune cells into the vessel walls during the first 2 weeks by neutrophils.^49,50^ This results in a necrotizing arteritis that destroys part of the vessel wall and is followed by a subacute chronic arteritis characterized by a macrophage, eosinophil, CD8+ T cell, monocyte, and IgA+ plasma cell inflammatory infiltrate.^ 49 ^ Upon the secretion of pro-inflammatory cytokines, luminal myofibroblasts proliferate and produce matrix contents, gradually obstructing the coronary lumen, potentially culminating in stenosis and thrombosis.^ 49 ^ Overall, KD is characterized by activated CD8^+^ T cells, IgA^+^ plasma cells, and a Th17 response, with higher levels of IL-17, IL-22, and Il-23, particularly in patients who have developed lesions in the coronary arteries.^54,55^

Other theories have considered the role of a superantigen, RNA virus, or the gastrointestinal tract microbiota, but there is yet to be any conclusive evidence supporting any of these theories.^13,50,56^ A few studies have indicated that patients with KD exhibit an altered Vβ T cell repertoire and higher frequencies of circulating Vβ2+ and Vβ8.1+ T cells compared to healthy individuals, suggesting the presence of a superantigen trigger, but these results were not reproducible in following studies.^ 49 ^ With the presence of CD8^+^ T cells, oligoclonal IgA, and cytoplasmic inclusion bodies within the bronchial epithelium combined with upregulation of cytotoxic T cells and genes of the interferon pathway, some researchers support a viral etiology—whether an identified or a yet-to-be identified novel virus.^56,57^ In addition, as recurrence of KD is rare, occurring in less than 1% of all KD patients, proponents propose the development of immunity to the agent in 97% to 99% of patients.^ 56 ^ Metagenomic data has shown that KD patients feature an altered gut microbiota.^ 58 ^ Furthermore, recent evidence found that KD features an imbalance between regulatory T cells and Th17 helper cells and that the differentiation of these cells depends in part on the production of short chain fatty acids by gut microbiota.^ 58 ^ As such, the theory that a dysbiosis altering the production of these signaling factors and therefore producing this imbalance in cells and contributing to the aberrant immune response found in KD has emerged.^59,60^ This stems from a similar line of reasoning explaining the pathogenesis of other immune-mediated inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease.^ 60 ^

Multisystem Inflammatory Syndrome in Children

The pathophysiology of MIS-C is not fully understood. As MIS-C features hyperinflammation and responds to anti-inflammatory treatments, it is thought to be due to immune dysregulation.^ 39 ^ Patients with MIS-C experience a cytokine storm consisting of an increased release of IFN-γ, IL-10, TNF-α, and derangements of innate immune cells, such as a decrease in HLA-DR expression on monocytes—a well-characterized finding in critical illness corresponding to dysfunctional monocytes and worse prognosis.^39,61^ MIS-C is characterized by a polyclonal expansion of T-cell receptor (TCR) Vβ 21.3+ CD4+ and CD8+ T cells.^ 61 ^ Some studies have pointed to the production of autoantibodies to endothelial, cardiovascular, and gastrointestinal antigens in response to SARS-CoV-2 superantigen, with the auto-antibodies in turn mediating the clinical picture of MIS-C.^61 -63^ Examples include anti-cardiolipin, anti-neutrophilic cytoplasmic antibodies, and anti-rheumatoid factor, among others.^ 64 ^ Advancing this, a 2025 proteomic analysis identified distinct plasma protein signatures in MIS-C patients—particularly elevated complement- and coagulation-related proteins—providing molecular support for immune-coagulation cross-talk in MIS-C pathogenesis.^ 65 ^ MIS-C is exclusively characterized by autoantibodies against the casein kinase family of proteins (CSNK1A, CSNK2A1, and CSNK1E), MAP2K2, and IL-1RA.^61,66,67^ Still, others have explored the role of host genetics, with studies identifying mutations in genes such as SOCS1, XIAP, CYBB, TLR3, TLR6, IFNB1, IFNA6, IL22RA2, pHLH, DOCK8, and HLA alleles HLA-A02, B35, and C04.^61,68,69^

Discussion

KD and MIS-C are pediatric inflammatory conditions that exhibit significant differences and overlaps in terms of etiology, pathophysiology, clinical presentation, and treatment. Both conditions have garnered significant attention due to their potentially severe outcomes, with KD being recognized for decades but MIS-C emerging more recently with the advent of the COVID-19 pandemic. MIS-C cases were initially simply considered KD with an accompanying SARS-CoV-2 infection,^ 70 ^ but clinicians then gradually realized that despite the overlap between the 2 conditions, they appeared to be distinct clinical entities. This distinction, however, is increasingly viewed as fluid rather than absolute; recent molecular studies suggest that KD and MIS-C may represent points along a shared inflammatory continuum, differing more in immunologic trigger and host susceptibility than in overall pathogenic logic. Many retrospective studies were aimed at distinguishing between KD and MIS-C, and a summary of the study characteristics can be found in Table 1. Moreover, a 2025 Romanian prospective 12-month follow-up study demonstrated that while most children recovered in terms of cardiovascular outcomes, a subset continued to exhibit subtle impairments in exercise tolerance and autonomic regulation, underscoring the importance of long-term monitoring in MIS-C.^ 71 ^ These findings reinforce the notion that MIS-C may not simply resolve with clinical recovery but could carry subtle cardiovascular and autonomic sequelae, an area that future longitudinal studies should further elucidate.

Epidemiology

When it comes to epidemiology, KD shows a predilection toward those of Asian ancestry, even with transmigration.^1,92^ A study by Holman et al^ 93 ^ on children in the US demonstrated that the annual incidence rate of KD was highest among Asians and Pacific Islanders and lowest among Caucasians. This is not the case in MIS-C, where children of African or Hispanic descent are affected more when compared to those of Asian descent.^94,95^ Sex-wise, there is a significantly higher incidence of KD in males than in females.^96,97^ Specifically, KD is known to primarily affect infants and young children, where almost 76% of affected children are younger than 5 years of age.^92,98^ The sex ratio in the case of MIS-C shows a mild dominance of males, where a systematic review that compiled a total of 655 MIS-C patients from 16 studies reported the male-to-female ratio to be 1.2:1.^ 32 ^ Such subtle sex-based differences in disease burden likely reflect hormonal or chromosomal modulation of cytokine responses, which is an underexplored but potentially crucial determinant of disease severity. The severity in disease phenotype also shows gender variability, where male children tend to exhibit a higher expression of pro-inflammatory cytokines like IL-1,^99,100^ which can explain the higher impact of both KD and MIS-C on the male pediatric population. In contrast to KD, the pediatric population significantly affected in MIS-C includes older children and adolescents, with a median age of 8 to 11 years and an average age of 8 years.^7,98,101^

Etiology

The etiology of KD remains unknown, but the current consensus converges on the fact that KD is an immune-mediated disease triggered by one or more infections in susceptible patients who have a genetic predisposition.^102 -104^ A potential pathogenic mechanism involves immune complex formation in KD, which triggers reactive thrombocytosis and a severe inflammation that renders subsequent organ injury.^7,105^ Another interrelated mechanism involves the presence of anti-endothelial cell antibodies (AECAs) and their binding to the vasa vasorum can trigger panvasculitis, which, alongside the platelet- and coagulation factor-driven thrombosis, triggers immunothrombosis.^106,107^ The AECAs can also be produced at mucosal surfaces and centered around IgA-producing plasma cells.^70,108^ As for the exact cause of MIS-C, it is not fully understood, but it is thought to be related to an abnormal immune response following COVID-19, with the prodrome typically developing 3 to 6 weeks post-SARS-CoV-2 infection. This latency period likely reflects an aberrant adaptive immune response rather than direct viral cytotoxicity, emphasizing the post-infectious nature of MIS-C in contrast to the more immediate immune activation seen in KD. Like KD, MIS-C’s pathogenesis is thought to be mediated by autoantibodies, with virus-induced cytopathic effects and widespread inflammation in multiple organ systems. Thus, autoantibodies engaging with Fcγ receptors on monocytes and neutrophils and resulting in the formation of immune complexes probably contribute to disease pathogenesis in both MIS-C and KD.^6,62^ However, IL-1 has direct pro-inflammatory effects on coronary endothelial cells in KD; in MIS-C, IL-6, and IL-10 predominantly exacerbate the myocardial dysfunction.^92,109,110^

Genetic susceptibility is especially pertinent to KD. Kumrah et al^ 111 ^ reported that the 4 major groups of genes that are studied in KD can be classified under 4 major those associated with T-cell activation (ORAI1 and STIM1), B cell signaling (CD40, BLK and FCGR2A), apoptosis (CASP3), and transforming growth factor-β (TGFβ) signaling (TGFB2, TGFBR2, MMP, and SMAD).^ 102 ^ Of additional value is ITPKC, a gene involved in the negative regulation of T lymphocyte responses, which was the first gene to be associated with the development of KD and with CAAs.^ 112 ^ In MIS-C, a clear genetic basis outlining the development of MIS-C after SARS-CoV-2 infection in children is yet to be determined, but ongoing studies attribute genetic susceptibility to mutations and polymorphisms in genes encoding pattern recognition molecules.^ 102 ^ In addition, an in-silico analysis by Nguyen et al^ 113 ^ demonstrated that the HLA-B46:01 allele was associated with the fewest SARS-CoV-2-binding peptides, hinting at a particular vulnerability to COVID-19, whereas the HLA-B15:03 allele was predicted to have the greatest capacity for highly conserved SARS-CoV-2 peptide presentation (among common human coronaviruses), suggesting a protective T cell-based immunity. A study by Ghosh et al^ 85 ^ that implemented Artificial Intelligence-guided gene signatures revealed that KD and MIS-C may not be entirely separate entities and in fact could represent 2 ends of the same spectrum of host immune responses to infectious triggers. Specifically, the authors used a previously identified 166-gene signature they termed a viral pandemic (ViP) gene expression signature which captures an invariant spectrum of the host response that is universally conserved across 3 respiratory viral pandemics (influenza, avian flu and now SARS-CoV-2), and they also used a 20-gene subset of the ViP signature, termed severe ViP (sViP) signature. The persistence of these overlapping gene expression profiles highlights how host immune programming, rather than the inciting pathogen itself, may drive the shared inflammatory phenotype observed in both entities. The ViP and sViP signatures were upregulated in acute KD compared to healthy controls. The researchers also used the ViP and sViP gene expression signatures to compare KD and MIS-C patients and reported that they could not differentiate between those with 1 entity or the other.^85,114^

Clinical Profile

The most notable common characteristic between KD and MIS-C is febrile illness involving inflammation of the blood vessels, with possible CAA sequelae.^ 92 ^ Notwithstanding the other similarities in symptoms, physical findings, and lab results, KD and MIS-C have different diagnostic criteria that are outlined in Table 2.^115,116^

Cardiovascular Manifestations

The cardiac hallmark of KD is coronary artery abnormalities, with dilation and aneurysm being well-known cardiac complications pursuant to classic KD.^104,117 -119^ In contrast, coronary artery involvement is much less common in MIS-C.^ 92 ^ A study by Feldstein et al^ 120 ^ that included a population of 424 children with MIS-C in whom coronary arteries were evaluated reported that only 13.4% of them had CAAs and 93% of the CAAs were mild, with none being giant or large. In a multicenter cohort study by Kostik et al,^ 79 ^ there were no significant differences in coronary artery lesions between MIS-C and KD patients, but in MIS-C, the lesions were presented with mild-to-moderate coronary artery dilatation and were reversible; however, in the KD cohort, aneurysms, including giant ones, were predominantly present. Untreated CAAs in KD are associated with subsequent coronary remodeling with luminal myofibroblast proliferation that may predispose to coronary stenosis, ischemia, and myocardial fibrosis as long-term sequelae. Thus, Rivas and Arditi^ 121 ^ have suggested that children with MIS-C should also be followed longitudinally to determine if any long-term complications may emerge. Figure 2 highlights coronary artery anomalies seen in KD and MIS-C.

Intracardiac inflammation can lead to severe tachycardia and hypotension, heightening the risk of cardiovascular collapse. This constellation of events is best termed KD shock syndrome (KDSS), an uncommon presentation of KD.^117,122^ In a retrospective study by Lee et al^ 123 ^ comparing MIS-C to KDSS, 61.3% of the total number of patients suffered from cardiac dysfunction, as represented by an ejection fraction (EF) <55%, the presence of CAAs, or an elevated troponin level. Moreover, this percentage can be broken down to 77.8% of KDSS patients and 54.5% of MIS-C suffering from cardiac dysfunction.^ 123 ^ Although shock is rare in KD, most patients with MIS-C develop hypotension that necessitates intensive care unit admission.^ 95 ^ In a study based on data from the Pediatric Health Information System administrative database, it was reported that during the COVID-19 period, 38.7% of patients with a diagnosis of MIS-C met the authors’ definition of shock (the use of vasoactive/inotropic cardiac support) compared with 5.1% of patients with a diagnosis of KD.^ 8 ^

Ventricular dysfunction is the most common cardiovascular complication in MIS-C.^7,124^ In the study by Feldstein et al,^ 120 ^ 34.2% of patients had decreased left ventricular function with decreased left ventricular ejection fraction. A systematic review and meta-analysis by Tong et al^ 125 ^ revealed that left ventricular dysfunction was more common in MIS-C patients than in KD patients. Also, the pooled outcome from 5 out of the 14 studies included showed that MIS-C patients had a higher incidence of pericardial effusion and valvular regurgitation, and the pooled outcome from another set of 4 studies showed a higher incidence of myocarditis in MIS-C patients.^ 125 ^ Myocarditis in MIS-C can be characterized by a fast progression that may be associated with arterial hypotension, requiring inotropic support with cardiotonic.^79,126^

Gastrointestinal Manifestations

In the first case report of MIS-C in Korea, an 11-year-old male patient presented with abdominal pain, shock, and heart failure with an absence of KD characteristics, so he was initially considered a patient with septic shock of gastrointestinal origin.^123,127^ The lack of a history of COVID-19 infection as well as uncertainty in the positive antibody test for SARS-CoV-2 rendered the lack of an adequate diagnosis of MIS-C, which was determined 2 months post-discharge based on positive IgG serology, confirming that this patient was indeed infected by the SARS-CoV-2 virus.^ 127 ^ This highlights the importance of abdominal pain as a presenting symptom of MIS-C. In fact, gastrointestinal symptoms including abdominal pain, vomiting, and diarrhea are the second most common set of symptoms (with fever being the most common symptom) in MIS-C patients, where they are reportedly present in almost 80% of patients.^32,117^ When compared to KD, gastrointestinal symptoms are far more common in MIS-C.^128 -130^ Rare MIS-C presentations that resemble appendicitis have also been reported in the literature.^79,131,132^ It should be additionally noted that in a pre-COVID-19 study by Fabi et al,^ 133 ^ gastrointestinal symptoms in KD patients helped in identifying those with a higher risk of developing CAAs in a predominantly Caucasian population.

Neurologic Manifestations

In a study by LaRovere et al^ 134 ^ on 616 patients with MIS-C, neurologic involvement was found in 20% of the patients, with life-threatening severe complications like stroke, Guillain-Barré syndrome, severe encephalopathy, and acute fulminant cerebral edema observed in 20 patients. Like gastrointestinal symptoms, neurologic symptoms are more commonly encountered in MIS-C when compared to KD.^102,135^ Some neurological manifestations serve as an area of significant overlap between KD and MIS-C, and they include stroke, encephalopathy, aseptic meningoencephalitis, cerebral vasculitis, seizures, and cranial nerve palsy.^ 135 ^ However, cerebellitis, delirium, and pseudotumor cerebri are rare entities that have been described exclusively in MIS-C patients.^ 136 ^ In a retrospective study by Liu et al^ 137 ^ on KD patients, it was shown that patients with neurological involvement were more likely to develop IVIG resistance and showcase an inflammatory burden of higher severity than patients without neurological involvement. In addition, there was no association between neurological involvement and the development of coronary artery lesions.

Pulmonary Manifestations

In KD, pulmonary symptoms are usually absent, with post-viral cough and congestion sometimes occurring.^ 7 ^ In a pilot study by Sengler et al^ 138 ^ on the respiratory manifestations of KD, infants younger than 6 months of age and children with atypical KD were reported to have a higher prevalence of respiratory symptoms such as tachypnea, dyspnea, cough, or coryza in the setting of KD. As for MIS-C, respiratory symptoms are considered fairly common, with studies showing that they could affect one-third to one-half of patients.^120,139,140^ In MIS-C, respiratory involvement usually consists of hypoxemia, respiratory insufficiency, pleural effusions, and pulmonary infiltrates that are usually responsive to supplemental oxygen.^7,139^

Mucocutaneous and Dermatologic Manifestations

A maculopapular rash, mucocutaneous ulcerations, and a strawberry red tongue are some of the most well-established manifestations of KD.^104,141,142^ In addition, erythema of the palms and soles are common.^7,141^ However, a maculopapular rash and mucocutaneous symptoms have also been reported in MIS-C.^143,144^ This complicates the differentiation between KD and MIS-C, making mucocutaneous and dermatologic manifestations very non-specific.

Other Manifestations

Additional manifestations that can help distinguish between KD and MIS-C and may sometimes complicate this distinction include hematologic (mainly deep vein thrombosis and pulmonary embolism), renal (mainly AKIs), and musculoskeletal (mainly arthritis) manifestations. A summary of the common and distinguishing manifestations of KD and MIS-C can be found in Figure 3.^7,102,117,125,145^

Laboratory Profile

In KD, inflammatory biomarkers including ESR, lactate dehydrogenase, D-dimer, ferritin, and CRP tend to most often be mildly to moderately elevated.^79,117^ This is not the case for MIS-C, where these markers, especially CRP, tend to reach values as high as 22 mg/d L.^ 117 ^ As for white blood cell count, it can be considered a distinguishing factor when considering the acute phases of KD and MIS-C, whereby leukocytosis is often seen in the former, whereas leukopenia is expected in the latter.^ 7 ^ Lymphopenia has also been considered an independent predictor of MIS-C.^ 146 ^ In addition, platelets are activated in both KD and MIS-C, but interestingly, a reactive thrombocytosis is seen in KD, whereas thrombocytopenia is noted in MIS-C due to bone marrow suppression.^147,148^ Common features also include increased transaminase levels and hypoalbuminemia, which can be seen in both illnesses.^ 83 ^ As for cardiac biomarkers, the elevation of troponin and B-type natriuretic peptide is a noteworthy similarity between patients with MIS-C and those with KD.^ 83 ^

Of note is a Kawasaki/MIS-C differentiation score (KMDscore) developed by Kostik et al^ 79 ^ and based on multivariate analysis that ultimately yielded 5 criteria of CRP>11 mg/dl, D-dimer > 607ng/ml, age >5 years, thrombocytopenia, and GI involvement. Each criterion has a characteristic range of points, and a score of 55 points or more yielded a diagnosis of MIS-C, with a sensitivity of 87.5% and a specificity of 89.1% based on the data from this study.^ 79 ^ However, given the retrospective nature of the population study that led to the development of the score, especially the historic nature of the KD cohort, this score requires further validation by other studies to perhaps become a useful tool in distinguishing between KD and MIS-C.

Treatment and Long-Term Outcomes

To comprehensively address the treatment strategies for KD and MIS-C, it is essential to compare and contrast the approaches used for each condition. Both KD and MIS-C involve significant inflammatory responses and can lead to severe cardiovascular complications if not managed appropriately. However, the therapeutic protocols for each condition have distinct characteristics due to their differing etiologies and clinical presentations. Table 3 outlines the comparison between treatment approaches between KD and MIS-C while Table 4 summarizes the most recent guidelines developed or updated after 2021. Supplementary Table 1 addresses older guidelines.

Given the clinical relevance and relative novelty of MIS-C, it is important to further expand on its rapidly evolving management strategies. As summarized in Table 4, current international guidelines generally recommend early and first-line administration of IVIG at diagnosis, combined with glucocorticoids. Some societies, however, reserve steroids for patients with severe or high-risk presentations,^151,154^ or add them only when there is inadequate clinical response to IVIG alone.^ 149 ^ There remains no universally accepted “gold standard” therapeutic protocol, largely owing to insufficient comparative evidence. In refractory cases, second-line management of MIS-C relies on biologic response-modifying agents such as the IL-6 inhibitor Tocilizumab, the TNF-α inhibitor Infliximab, and IL-1 receptor antagonist Anakinra, though data favoring one over another is lacking.^156,157^ In an observational study by Celikel et al,^ 158 ^ it was found that the administration of Tocilizumab alongside corticosteroids and IVIG was associated with rapid improvement of LVEF and normalization of BNP, troponin, and CRP. Anti-coagulation represents another cornerstone of MIS-C management, reflecting the hypercoagulable state of this condition. A recent systematic review by Castillo et al^ 159 ^ demonstrated that thromboprophylaxis reduces thromboembolic events in patients with MIS-C, particularly in patients with additional risk factors are present. Current international guidelines (Table 4) suggest the administration of low-dose aspirin for all MIS-C patients unless contra-indicated, and regardless of the presence of risk factors.^ 160 ^ However, escalation in anticoagulation is advised in the presence of risk factors or more severe presentations of MIS-C such as CAAs, ICU admission, myocarditis, LVEF <35%, documented thrombosis. Notably, the complement inhibitor eculizumab, traditionally used for paroxysmal nocturnal hemoglobinuria, has shown success in treating thrombotic microangiopathy secondary to MIS-C.^ 160 ^

Long-Term Follow-Up of MIS-C

Long-term outcomes of MIS-C are heterogeneous in the literature, with studies reporting almost complete resolution of symptoms 6 months post-disease,^ 161 ^ and others indicating that nearly 1 in 3 patients have persistent symptoms or activity impairment within the 4 months following the disease.^ 162 ^ In a large multicenter NHLBI Study on Long-terM OUtcomes after the Multisystem Inflammatory Syndrome in Children (MUSIC) cohort that included 1204 patients from 32 North American hospitals, 99% of patients with MIS-C went back to normal LVEF, while 92.3% had normalization of coronary dimensions, both by 6 months.^ 163 ^ In addition, by 6 months, more than 95% reported feeling mostly back to pre-disease health in a patient-reported outcome survey about energy, appetite, cognition, and mood.^ 163 ^ In particular, fatigue and low energy were the most common sequelae reported by patients, whose prevalence largely dropped between 2 weeks and 6 months post-MIS-C.^ 163 ^ An advanced imaging study using cardiac MRI (magnetic resonance imaging) in the MUSIC cohort indicated that only a small number of patients had residual ventricular or tissue abnormalities at 3 and 6 months. Another relatively smaller single-center study in Italy reported resolution of most non-specific symptoms (such as headache, pain, palpitations, and dizziness) at a rate of 76% by a month, 94% by 2 months, and almost complete resolution by 6 months.^ 161 ^ Cognitive improvements were also noted on follow-up in a prospective observational cohort study by Üstündağ et al^ 164 ^ Greater scores were attained in a selective attention and mental concentration assessment (D2 test) at 6 months post-MIS-C compared to baseline levels. Interestingly, they found that high levels of WBC, procalcitonin, and ferritin were associated with lower scores on cognitive tests, suggesting that the inflammatory processes of MIS-C temporary affect cognition in patients.^ 164 ^ Moreover, a study by Rollins et al^ 165 ^ evaluated children 6 to 12 months after MIS-C diagnosis and hospitalization in comparison to control children. They report lower parent reports of psychosocial scores in MIS-C participants, who also performed worse on working-memory testing, and had more depression and somatization at follow-up.^ 165 ^ Although most studies, including the MUSIC cohort indicate reassuring outcomes post-MIS-C, definitive conclusions about the long-term effects of MIS-C will require larger, multicenter studies with objectively measured outcomes spanning all organ systems affected in the acute phase of the disease.

Limitations

Although this review summarizes the main clinical and therapeutic contrasts between KD and MIS-C, most of the available evidence remains retrospective, hospital-based, and limited by small sample sizes. Differences in case definitions, diagnostic thresholds, and timing of follow-up may have influenced reported incidence and outcome variability across studies. Selection bias toward severe cases and regional disparities in testing and management protocols further constrain the generalizability of current findings. Few randomized or prospective studies directly compare treatment responses, leaving uncertainty about the optimal immunomodulatory strategy, particularly in MIS-C. Recognizing these limitations is essential for interpreting existing data and for guiding future multicenter, longitudinal research that can clarify long-term cardiovascular and immunologic outcomes.

Conclusion

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are distinct yet overlapping pediatric inflammatory conditions with significant implications for child health. KD, long recognized as a leading cause of acquired heart disease in children, primarily affects young children of Asian descent and is characterized by vasculitis and potential coronary artery complications. Its etiology remains unknown, although genetic predispositions and environmental triggers are considered critical factors. Treatment with IVIG and aspirin has proven effective in reducing CAAs. In contrast, MIS-C emerged as a novel condition during the COVID-19 pandemic, associated with SARS-CoV-2 infection. It affects older children and is characterized by hyperinflammation, multisystem involvement, and significant cardiovascular manifestations, including shock and myocardial dysfunction. Unlike KD, MIS-C shows a broader racial distribution, affecting children of African, Hispanic, and Caucasian descent more frequently than those of Asian descent. Treatment strategies for MIS-C are still evolving, often involving a combination of IVIG, steroids, and, in some cases, biologic agents. Despite their similarities, KD and MIS-C require distinct clinical approaches. Understanding their epidemiological, pathophysiological, and clinical differences is essential for accurate diagnosis and effective management. Future research should focus on elucidating the precise mechanisms underlying these conditions and developing tailored treatment strategies to improve outcomes for affected children. Due to most studies being observational, standardized multicenter randomized controlled trials are needed to fill this critical gap. Additionally, due to recent emergence of MIS-C as a clinical entity, further longitudinal studies evaluating the long-term cardiac outcomes are necessary to clarify similarities and distinctions between it and KD as well as evaluate whether long-term treatment may have a role in mitigating any complications. This may be addressed through the establishment of prospective registries for MIS-C, through which data on its clinical spectrum and potential sequelae may be recorded in a more accurate, complete, and relevant manner. As our knowledge expands, healthcare providers must remain vigilant and adaptable in their approaches to managing these complex pediatric inflammatory conditions.

Supplemental Material