Is COVID-19 multisystem inflammatory syndrome a new variant of Kawasaki Disease?

Abstract

Objectives: In this systematic review, we aimed to evaluate the clinical features, therapeutic options, and outcomes of children with multisystem inflammatory syndrome in children (MIS-C) and to investigate whether MIS-C is a new variant of Kawasaki disease.

Materials and methods: Adhering to PRISMA principles, we searched for eligible studies between December 2019 and June 2020 through the following databases: PubMed, ISI Web of Science, SCOPUS, and Science Direct. Studies including original data of patients aged <21 years with MIS-C and descriptions of clinical signs, laboratory or radiological investigations were selected.

Results: A total of 84 studies were identified, for which 48 were eligible for full screening and only 13 studies (n=657) met our inclusion criteria. More than 70% of patients with MIS-C tested positive for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The most common symptoms were gastrointestinal (80 to 100%) and most patients presented with fever for >4 days. Mucocutaneous manifestations are similar to Kawasaki disease presented in up to 64% in some studies. Almost all patients had significant elevations in inflammatory markers, and up to 50 to 100% had elevated troponin suggesting myocardial damage. Intravenous immunoglobulin (IVIG) was administered to 60% of patients in 12 studies and 80 to 100% in five studies. Steroids were administered to 10 to 95% of patients. The overall mortality rate was 0.9%.

Conclusion: The temporal association between novel coronavirus disease 2019 (COVID-19) onset and Kawasaki-like disease and MIS-C suggests a causal link. Both syndromes have similar cascades of symptoms and hyperinflammation, which likely explain their response to the same immunomodulatory agents. However, it is unclear yet why some children appear more susceptible to develop MIS-C.

Introduction

In early January 2020, a new type of coronavirus was isolated (i.e., severe acute respiratory syndrome-coronavirus 2 [SARS-CoV-2]) responsible for the disease known later as novel coronavirus disease 2019 (COVID-19). It was recorded that the first death caused by COVID-19 was on January 9^th, 2020 in Wuhan and, since then, nearly one million deaths have occurred worldwide.[1] Compared to adults, children with COVID-19 infection appear to have a milder clinical presentation and, additionally, there is scarcity in death reports among children.[2,3] However, the clinical course and patterns of COVID-19 presentations remain unclear among this population.

Kawasaki disease (KD) was first described in 1967. This disease describes a series of Japanese children suffering from acute febrile mucocutaneous syndrome associated with specific desquamation of the toes and fingers.[4] This syndrome is more common in boys than girls.[5] Nonetheless, the etiology is still unknown.[4] The current concept is that it is systemic inflammation in multiple organs resulting from an immune cascade of reactions enhanced as a response to exposure in the respiratory or gastrointestinal (GI) systems. It has been highlighted that infectious agents could be the primary triggering causes, as the peak of the incidence of this syndrome occurs mainly during winter and spring.[4]

In late April 2020, a description of a new novel syndrome in children and adolescents, namely multisystem inflammatory syndrome in children (MIS-C), with relation to SARS-CoV-2 infection took place worldwide.[6] This syndrome was first identified in Europe, and it was known initially as a pediatric inflammatory multisystem syndrome associated with SARS-CoV-2 and, then, the Centers for Disease Control and Prevention (CDC) issued the case definition of MIS-C.[7] These are the same or overlapping syndromes. The CDC case definition included a minimum of 24-h history of subjective or objective fever, clinically severe illness necessitating hospitalization, along with two or more organ system affected and laboratory evidence of inflammation, with no alternative diagnosis. Recently, the researchers have highlighted the relationship of KD which affects children, with the emerging coronavirus.[8] Also, Abuhammour and Dawoud[9] indicated that the laboratory results of the virus in COVID-19 patients with symptoms of cytokine storms, are very similar to KD syndrome that also leads to cytokine storm, and the direct cause is alerting the virus to the patient’s immune system, while the other reason, which is susceptibility in patients, is often linked to the genetic inheritance factor.

In this systematic review, we aimed to evaluate clinical features, diagnostic tests, current therapeutic management, and outcomes of MIS-C cases in children and adolescents reported in the literature and to evaluate the common points between the MIS-C and KD.

Patients and Methods

Compliance with the PRISMA principles

In the current analysis, we utilized the PRISMA principles to optimize the review process. The PRISMA statement involves a flow diagram and a checklist encompassing 27 items and these items are considered necessary for transparent reporting of systematic reviews.[10]

Search strategy

The following search term was utilized (((((COVID-19) OR coronavirus) OR SARS-CoV-2)) AND (((((((pediatrics) OR children) OR neonates) OR child) OR neonate) OR infant) OR infants) AND (MIS-C) or multi-system inflammatory syndrome) to retrieve all articles published between December 1^st, 2019 and June 6^th, 2020 through the following databases: PubMed, ISI Web of Science, SCOPUS, Science Direct, all resources excluding (book chapters, encyclopedias, conference abstracts, conference information, discussions, editorials, short communications, case report, case series) from inception, until the day the search was finalized (June 2020).

No language restrictions were applied. No attempts were made to contact the study authors for identifying missing and confusing data. A manual search of the references found in the selected articles and reviews was also performed.

Study selection and risk of bias

In keeping with the quality standards for reporting systematic reviews and meta-analysis of observational studies, two authors screened the titles and abstracts independently and in duplicate for potential eligibility. They subsequently read the full texts to determine final eligibility. An appraisal of the risk of bias for observational studies was conducted through the quality assessment tool published by the National Institutes of Health (NIH).[11] Independent risk of bias was assessed by at least two investigators. Discrepancies were resolved through discussion and consensus, and if necessary, the assistance of a third author was sought. Eligible studies fulfilled the following criteria: (i) studied patients younger than 21 years old; (ii) presented original data from cases of COVID-19 with a clinical MIS-C; and (iii) contained descriptions of clinical manifestations, laboratory tests, radiological examinations, or description of the therapeutic option (Figure 1).

Figure 1. PRISMA flow diagram.

Data extraction

A structured data extraction form was piloted and, then, used to extract data from the reports of all included studies in duplicate and independently by two authors. Discrepancies in extracted data were resolved through discussion. The following data were extracted, when available, from each selected article: site, publication date, and study design, number of cases, sex, age, clinical manifestations, laboratory tests, radiological examinations, therapeutic management, and outcomes (hospitalization, intensive care unit [ICU] admission, or death).

Results

Study identification

A total of 84 potentially relevant articles were identified by the search strategy. Following duplicate removal, title and/or abstract screening ensued, 48 studies were eligible for full-text screening. Of these, 35 studies were excluded, as they did not match the inclusion criteria. We identified 13 studies[12-24] for our systematic review from five countries across six continents (Table 1).

Table 1. Description of the study and demographic data

Characteristics of included studies

Thirteen studies investigated in this review were all observational and no randomized trials were identified of any interventions that directly addressed the included study populations. The included studies were published between December 2019 and June 2020 and encompassed the children (<21 years). A total of 657 descriptions of pediatric were obtained, including 359 males (54.6%). Of these 13 studies, seven studies took a form of retrospective analysis of the included cases,[12,13,16,18,20-22] whereas other included studies were prospective in nature[14,15,17,19,23] and one single study took a form of surveillance methodology.[24] Except for six multi-center studies,[13-16,19,24] all others were unicentric studies. Almost half of the included studies (n=6) were conducted in the United State of America,[12,14,19,21-23] three in France,[15,17,24] two in the United Kingdom,[13,20] one in France and Switzerland,[16] and one in Italy.[18]

Clinical manifestations

Patients with evidence of COVID-19 infection or recent exposure to COVID-19 infection in the absence of testing were included. Of these, 12 studies revealed that more than 70% of the included patients tested positive for SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction (RT-PCR), antibody testing, or both.[12-17,19-24] Across nine studies, most of the patients had fever present for more than four days,[12-16,20-23] and the most common presenting symptoms included GI symptoms which presented by 80 to 100% of the cases presented in eight studies,[12-15,20-23] these symptoms include vomiting, abdominal pain, and/or diarrhea. In addition, KD symptoms including mucocutaneous manifestations such as conjunctivitis and rash with neurological findings were common in these children who were diagnosed to have MIS-C. Neurological findings in nine of the included studies were common in these children who were diagnosed with MIS-C. The most common neurological findings were headache followed by aseptic meningitis, meningeal irritation, stiff neck, and cranial nerve palsy.[12-15,17,21-24] It was reported in the present review that 22 to 64% of the included cases presented with signs and symptoms similar to complete KD,[12,13,15,17,22,23] whereas 29.4 to 70% of the included cases admitted with some of KD features (incomplete KD).[16-20,22] One single study indicated that 36% of the patients present with signs and symptoms of KD or atypical KD.[14] Of note, four studies revealed that 50 to 76% of the included cases were diagnosed with KDSS (Table 2).[12,15,17,18] Universally, results of the laboratory testing revealed the significant elevation in the inflammatory markers including but not limited to C-reactive protein and ferritin. Another major finding was that troponin levels were elevated in many patients (50 to 100% of the patients in the included studies), suggesting myocardial damage as presented in Table 3. The majority of the included cases in the present review were previously healthy children. Nonetheless, it was noted that overweight (6 to 39%), obesity (8 to 39%), and asthma (5.2 to 26.7%) were the most common comorbidities among these included cases (Table 2).

Table 2. Clinical presentation of the included cases

Table 3. Inflammation markers and prognosis of the included cases

There are overlapping features between MIS-C and KD symptoms suggesting that this new condition may be a new variant of KD, triggered by SARS-CoV-2 infection (Table 5). However, the striking and significant elevation in the inflammatory markers is higher in the MIS-C in comparison to KD.

Table 5. Differences in clinical features of typical KD and included cases in the present review

Therapeutic management and outcomes

Several children in the majority of the included studies developed severe hypotension requiring admission to the ICUs. Of note, more than 79% of the included patients in eight studies were admitted to the ICU,[12,14,16-19,22,23] whereas 38 to 67% of other patients in four studies needed ICU admission.[13,15,20,24] Mechanical ventilation was required for the included patients in 12 studies (10 to 66%).[12-22,24] Most of the patients who were admitted to ICU required inotropes and vasopressors (Table 3).

Across 12 studies, the majority of affected children (more than 60%) were managed therapeutically with intravenous immunoglobulin (IVIG).[12-23] In five studies, 80 to 100% of the included cases received IVIG.[12,16,17,21,22] Steroids were used in all studies ranging from 10 to 95% of the included patients. In 12 studies, 66 to 100% of the included cases were treated with IVIG as first-line therapy as a single dose[12-23] of whom four studies indicated that 1 to 62% required a second dose of IVIG doses.[15,16,17,20] Steroids were used for the included cases in 12 studies as first-line therapy or adjunctive therapy ranging from 20 to 100%.[12-23] It is worth noting that death occurred in two of the included cases in one study[14] and neither of them received IVIG, systemic glucocorticosteroids, or immunomodulators. On the other hand, acetylsalicylic acid was used in a few studies,[12,22,23] whereas anticoagulant was used in a single study.[23] Remdesivir was used in one single study in 13% of the included children.[22] In two studies, the broad-spectrum antibiotics were used in all included patients.[20,22] Most patients responded favorably to therapeutic management with an improvement in the vital signs and cardiac dysfunction, few cases in six studies[12,13,14,19,21,22] required additional therapies such as biological modulating drugs. Clinical outcomes of death, discharged, or still hospitalized were described for all cases in the included studies (Table 4). Of these, the majority of cases were discharged when studies were submitted. Overall mortality rates have been low with six deaths (0.9% among included cases) occurred among the included studies. It was reported that 13 patients from the included cases in the present review died representing a range of 1 to 66%.[13,14,18,19,22,24]

Table 4. Therapeutic management

Discussion

In this review article, we described the main clinical manifestations for patients younger than 21 years who presented with MIS-C, and were infected with or had a recent exposure to COVID-19 patients reported in 13 observational studies published in the literature during between December 2019 and June 2020. Among the included patients, more than 70% tested positive for SARS-CoV-2 infection, and it was observed that the severity of the COVID-19 infection among the positive cases in the included studies was mild to moderate, with the majority of patients responded favorably to therapeutic management and with only six reported deaths. In general, COVID-19 has a favorable clinical course in children and usually progresses with a mild course.[2,3] Nonetheless, in April 2020, a new life-threatening condition in children named MIS-C emerged.[8,25] In most of the included studies, the temporal association between the onset of the SARS-CoV-2 pandemic worldwide with Kawasaki-like disease and MIS-C suggests a causal link.

As presented by Riphagen et al.,[26] hyperinflammatory shock is a common component in MIS-C. From the clinical manifestations presented in the recruited studies, it was evident that MIS-C has a cascade of symptoms which include fever, abdominal pain, diarrhea, vomiting, mucocutaneous manifestations, and elevation of inflammatory biomarkers. However, KD affects predominantly young children <5 years of age, whereas the median age in our review is (7 to 12) years.[27] Until now, there is no available test used to diagnose KD in children, with the diagnosis based solely on the clinical manifestations according to the American Heart Association (AHA) criteria.[28] This disease is considered among the most common causes of heart disease in children, including coronary heart disease, which can lead to sudden death in some children.[28] Physicians have noted some clinical similarities between MIS-C and KD; however, these clinical signs can be noticed in many infectious diseases in children and are not specific for any one diagnosis. The main question raised in this review is whether MIS-C is a new spectrum of KD, suggesting that it is a KD with SARS-CoV-2 as the main triggering factor leading to a new spectrum of KD.

While children with COVID-19 present with upper respiratory tract symptoms, MIS-C is distinguished by fever, GI symptoms such as vomiting, significant elevation in the inflammatory markers, and mucocutaneous manifestations such as rash. In this review, it was evident that all of the included patients showed a confirmed elevation of the inflammatory markers in addition to some other features related to KD such as fever, GI symptoms, and mucocutaneous manifestation. Among the included studies, six studies reported that around 29 to 64% of the patients presented with features consistent with KD,[1,4,6,10,12,13] while around 40 to 61% of patients in other studies were diagnosed with incomplete KD.[7,9,13,14] In addition, three studies reported that 48%, 44%, and 50% of the included patients met the criteria for KD shock syndrome (KDSS). This may support the claim that MIS-C is a new variant of KD with a striking elevation of inflammatory markers in comparison to KD. The triggering factor in both is the SARS-CoV-2 virus. The present reports indicate that MIS-C typically manifests three to four weeks after SARS-CoV-2 infection.[19,29] This may justify why some children in the present review had positive antibodies to SARS-CoV-2, but negative RT-PCR at the time of MIS-C assessment.[12,13,17]

The prevalence of cardiac manifestations in children with MIS-C was dominant (48 to 100%). Many of the included cases in the present review had an initial echocardiogram that was normal and showed depressed ejection fraction or dilation/aneurysm of the coronary arteries after few days. The results revealed that the most common cardiac abnormality, on echocardiogram, was a depressed ejection fraction. In line with these outcomes, a recent research has shown that adult cases who recently recovered from COVID-19 had myocardial inflammation in addition to ongoing cardiac involvement.[30] Thus, pediatric patients undergoing evaluation for MIS-C must have a baseline assessment echocardiogram, electrocardiogram, and their cardiac function and artery changes should be followed through repeating imaging. Additionally, close follow-up is important, since the long-term implications of MIS-C cardiac involvement are still unknown.

Kawasaki disease typically presents with high fever and peeling skin with inflammation.[31] The overlapping features between MIS-C and KD suggest that they may share a similar pathophysiology and likely explains why these patients respond to similar therapies. As described in this review, most children respond to similar therapies.[32] It was observed in the recruited studies that more than 60% of the affected children received IVIG.[12-23] Acetylsalicylic acid was used in a few studies.[12,15,17,20,23] Corticosteroids, on the other hand, were used in almost all studies ranging from 10 to 95% of the included patients.[12-23] This indicates that some patients with severe COVID-19 may need to start the treatment protocol for KD, as they show a favorable response to IVIG. Initiating such treatment protocol may prevent the occurrence of the cytokine storm and subsequent multi-organ failure. Although the mortality rate in the present reviews is low (0.9%), it is much higher than the reported mortality rate (0.09%) observed in pediatric patients with COVID-19.[33]

More research is needed to understand why some children may be more susceptible to develop MIS-C. This disease is rare, in a single published report, the estimated incidence of laboratory-confirmed SARS-CoV-2 infection in individuals aged <21 years was 322/100,000 and the incidence of MIS-C was 2/100,00014. However, the long-term sequelae from this condition are currently not clear. The results of the present review are consistent with the previous report.[8] In a recent study, the two most common systemic involvements in their study were cardiac and GI. Additionally, older age was found to be an independent predictor for pediatric ICU admission. Moreover, respiratory, renal, and neurological involvement rates were significantly higher in patients admitted to ICUs.[8]

This review summarizes the clinical presentation of a new childhood disease that is most likely linked to SARS-CoV-2 infection. Multisystem inflammatory syndrome in children is a severe systemic infection characterized by inflammation, fever, abdominal symptoms, conjunctivitis, and rash. Children would present with signs and symptoms of MIS-C in most of the cases three to four weeks after COVID-19 infection and many would progress rapidly into shock and cardiorespiratory failure. The results of the present review are consistent with the previous report.[8] The majority of include cases of the present review had higher inflammatory markers with higher cardiac involvement. Moreover, most of them suffering from cytokine storm that is reflected clinically by heart failure, GI, neurological, and renal features associated with a high level of inflammatory markers, such as C-reactive protein, ferritin, interleukin 1 (IL1), IL6 at the time of admission or shortly after the admission. It is worth noting that patients who were admitted to the ICU units had a higher level of systemic inflammatory markers and had a more severe disease course. Interestingly, most of these patients had a good recovery by the time of discharge. Nonetheless, long-term follow-up is required to assess the impact of such a condition on organ functions.

The overlapping features between MIS-C and KD symptoms suggest that this new condition may be a new variant of KD triggered by SARS-CoV-2 infection. The clinical features and laboratory findings and pathogenesis, which involves mainly cytokine storm, of MIS-C in the present review appear to be similar to KD; however, we found that GI and cardiac involvement and the risk of developing shock state were more common and severe in MIS-C than KD. Moreover, while 80% of KD are encountered in children younger than five years; MIS-C extends to older children with a median age of seven to 12 years old. Additionally, both KD and MIS-C respond to the same management which includes high-dose IVIG.

This review has several limitations. First, we were rigorous in our search, but there is a possibility we may have missed studies. Second, our review is mainly descriptive, and international statistical conclusions cannot be drawn from it. However, we believe that this report is clinically important and may affect the patient care in the clinical setting.

In conclusion, this review discusses the clinical presentation of a new childhood disease that is most likely linked to SARS-CoV-2 infection. Multisystem inflammatory syndrome in children is a rare and dangerous systemic infection characterized by hyperinflammation, fever, and abdominal symptoms, and the potential long-term sequelae are currently unknown. The similarities between MIS-C and KD suggest that MIS-C may be a new variant of KD triggered by the SARS-CoV-2 virus. However, MIS-C is more severe than KD and this may be due to significantly higher inflammatory markers than KD. Parents should seek medical advice and physicians should be vigilant not to miss MIS-C in any child presenting with fever or history of fever along with confirmed COVID-19 infection or history of exposure to individuals with COVID-19 infection. We strongly believe, despite the presence of few differences between MIS-C and KD, MISC is a spectrum of KD, but to a more severe extent.

Citation: Hammour KA, Farha RA, Manaseer Q, Dawoud T, Hammour WA. Is COVID-19 multisystem inflammatory syndrome a new variant of Kawasaki Disease? Arch Rheumatol 2022;37(2):230-244.
Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conceptualized and designed the study, designed the data collection instrument, collected data, carried out the initial analyses, drafted the initial manuscript, reviewed and revised the manuscript: K.A.H.; Carried out the initial analyses, drafted the initial manuscript, reviewed and revised the manuscript: R.A.F., Q.M.; Carried out the initial analyses, drafted the initial manuscript, reviewed and revised the manuscript: T.D.; Conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content: W.A.H.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

The authors received no financial support for the research and/or authorship of this article.

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