key: cord-0962096-vc4tl05v
authors: Yasuhara, Jun; Watanabe, Kae; Takagi, Hisato; Sumitomo, Naokata; Kuno, Toshiki
title: COVID‐19 and multisystem inflammatory syndrome in children: A systematic review and meta‐analysis
date: 2021-01-11
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.25245
sha: 6df1f2fd98d9df05563388b573e9108515d10836
doc_id: 962096
cord_uid: vc4tl05v

BACKGROUND: Multisystem inflammatory syndrome in children (MIS‐C) associated with coronavirus disease 2019 has been increasingly recognized. However, the clinical features of MIS‐C and the differences from Kawasaki disease remain unknown. The study aims to investigate the epidemiology and clinical course of MIS‐C. METHODS: PubMed and EMBASE were searched through August 30, 2020. Observational studies describing MIS‐C were included. Data regarding demographic features, clinical symptoms, laboratory, echocardiography and radiology findings, treatments, and outcomes were extracted. Study‐specific estimates were combined using one‐group meta‐analysis in a random‐effects model. RESULTS: A total of 27 studies were identified including 917 MIS‐C patients. The mean age was 9.3 (95% confidence interval [CI], 8.4–10.1). The pooled proportions of Hispanic and Black cases were 34.6% (95% CI, 28.3–40.9) and 31.5% (95% CI, 24.8–38.1), respectively. The common manifestations were gastrointestinal symptoms (87.3%; 95% CI, 82.9–91.6) and cardiovascular involvement such as myocardial dysfunction (55.3%; 95% CI, 42.4–68.2), coronary artery aneurysms (21.7%; 95% CI, 12.8–30.1) and shock (65.8%; 95% CI, 51.1–80.4), with marked elevated inflammatory and cardiac markers. The majority of patients received intravenous immunoglobulin (81.0%; 95% CI, 75.0–86.9), aspirin (67.3%; 95% CI, 48.8–85.7), and corticosteroids (63.6%; 95% CI, 53.4–73.8) with a variety of anti‐inflammatory agents. Although myocardial dysfunction improved in 55.1% (95% CI, 33.4–76.8) at discharge, the rate of extracorporeal membrane oxygenation use was 6.3% (95% CI, 2.8–9.8) and the mortality was 1.9% (95% CI, 1.0–2.8). CONCLUSION: Our findings suggest that MIS‐C leads to multiple organ failure, including gastrointestinal manifestations, myocardial dysfunction and coronary abnormalities, and has distinct features from Kawasaki disease.

Coronavirus disease 2019 , caused by a novel coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic since December 2019. Initial studies indicated that children with SARS-CoV-2 infection generally present with mild symptoms or are asymptomatic. [1] [2] [3] However, in late April 2020, the United Kingdom reported a newly recognized syndrome related to SARS-CoV-2 infection characterized by hyperinflammation and multiorgan involvement in children, presenting with clinical features similar to Kawasaki disease (KD) and toxic shock syndrome. 4 This syndrome has been named multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 by the Centers for Disease Control and Prevention 5 and pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 in Europe.

Since this new syndrome was identified, several reports have revealed the clinical features of MIS-C, however, there is no large study to date which can clarify the nature and course of MIS-C, including the epidemiology, pathogenesis, clinical spectrum, laboratory features, potential optimal management, and long-term outcomes. Therefore, we conducted a systematic review and metaanalysis aimed to investigate the characteristics of MIS-C, to provide insights into further understanding and the clinical practice of MIS-C.

All observational studies and case series reporting patients with MIS-C were searched using a two-level search strategy. First, PubMed, and EMBASE were searched through August 10, 2020.

Second, relevant studies were identified through a manual search of secondary sources including references of initially identified articles, reviews, and commentaries. All references were downloaded for consolidation, elimination of duplicates, and further analyses ( Figure 1 ).

The search terms included "COVID-19" OR "SARS-CoV-2"

OR "coronavirus", "MIS-C" OR "multisystem inflammatory syndrome in children" OR "multisystem", "inflammatory" OR "Kawasaki disease", "pediatrics" OR "child" OR "children". Two independent and blinded authors (J.Y. and T.K.) reviewed the search results separately to select the studies based on the inclusion and exclusion criteria. Any discrepancies were resolved by discussion and consensus. There were no language restrictions. This study was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses reporting guidelines. 6 F I G U R E 1 PRISMA flow diagram for the study selection. MIS-C, multisystem inflammatory syndrome in children. PRISMA, preferred reporting items for systematic reviews and meta-analyses 2.2 | Study selection and risk of bias assessment Studies which met the following criteria were included: (1) the study design was an observational study or a case series, (2) the study population included children and adolescents (age <21 years old) who met the diagnostic criteria for MIS-C with confirmed SARS-CoV-2 infection through a reverse transcriptase-polymerase chain reaction or serological tests. The diagnosis of MIS-C was confirmed using the case definition established by the Centers for Disease Control and Prevention and World Health Organization. 5, 7 Case reports including one patient, studies not containing original data of the patients such as clinical guidelines, consensus documents, clinical trials, editorials, letters, reviews, systematic reviews and meta-analyses, and articles on other types of coronavirus were excluded from the secondary review. The risk of bias in the individual studies was reviewed using an assessment of the risk of bias in prevalence studies. 8 

The following information was extracted: author, year of publication, country of the study, sample size, age, sex, race/ethnicity, comorbidities, clinical symptoms, laboratory data, echocardiography, and chest X-ray findings, treatments, and outcomes. Disagreements regarding the extracted data were resolved through discussion and consensus of a third author (H.T.).

We performed one-group meta-analysis in a random effects model using the DerSimonian-Laird method for continuous values and Wald method for discrete values with the OpenMetaAnalyst version 12.11.14 (available from http://www.cebm.brown.edu/openmeta/). Continuous variables are expressed as the means ± standard deviations or medians (interquartile range), as appropriate for the data distribution. Categorical variables are expressed as frequencies and percentages.

Our search identified 372 articles that were reviewed based on the title and abstract, and of those, 307 articles were excluded. Sixty-five full texts were assessed for eligibility and 38 articles were excluded based on the article type (case reports, clinical guidelines, consensus documents, clinical trials, editorials, letters, reviews, systematic reviews, and meta-analyses), population (adult patients with COVID-19, cases without meeting the case definition for MIS-C) and topic (other viruses). Twenty-seven articles met the inclusion and exclusion criteria and were analyzed for the systemic review and meta-analysis ( Figure 1 ). 4, The study and patient characteristics of the included studies are shown in Table S1 and Table S2 . The results of the pooled analysis are summarized in Table 1 . A summary of the risk of bias assessment for the prevalence studies for each retrospective cohort study is shown in Table S3 .

All the included articles were published between May 2020 and July 2020. Twelve studies were conducted in the United States, 11,12,15,17,21,22,24,27-29,32,33 7 in the United Kingdom, 4, 16, 20, 23, 26, 30, 31 6 in France, 10, 13, 14, 18, 19, 25 and 1 each in Italy 9 and Spain. 34 Overall, the studies included 917 patients with MIS-C associated with SARS-CoV-2 infections.

The mean age was 9. 

The most common symptom was fever (99.3%; 95% CI, 98. 8 

Laboratory findings are shown in Figure 3 , Table 1 , and Figure S1 .

Inflammatory biomarkers, such as C-reactive protein, procalcitonin, ferritin, erythrocyte sedimentation rate, interleukin-6 (IL-6) and fibrinogen, were significantly elevated ( Figure 3 and Figure S1 ).

In addition, cardiac markers were elevated with marked elevations in B-type natriuretic peptide, N-terminal proB-type natriuretic peptide, and troponin ( Figure 3 ). The majority of patients had elevated levels of D-dimer, elevated neutrophils, reduced lymphocytes, and low albumin ( Figure 3 and Figure S1 ). 

According to the echocardiography findings, cardiovascular involvement was common ( 

The pooled proportions of the therapeutic management and outcomes are shown in Table 1 previously reported, we confirmed that MIS-C affects older children and adolescents, which is in a marked contrast to the epidemiology of KD, occurring predominantly in children 5 years of age or younger and with a peak incidence at 9-11 months of age. 45 Interestingly, the proportions of Hispanic and Black cases were high for MIS-C with few cases reported in children of Asian descent or in Asian countries in contrast to KD. 46 This might be associated with the socioeconomic disparities as the rates of COVID-19 were shown to be higher among racial/ethnic minorities and socioeconomically disadvantaged children. 47 In addition, we noted that MIS-C manifests with a higher incidence of myocardial dysfunction and gastrointestinal symptoms compared to KD. 16 Furthermore, the extent of the elevation of inflammatory biomarkers and cardiac markers in MIS-C are significantly higher than in KD. 9, 16 These marked differences in the epidemiology and clinical and laboratory findings suggest that MIS-C and KD are two distinct disease with overlapping clinical characteristics.

Kawasaki disease shock syndrome (KDSS), a rare form of KD, has many similarities to MIS-C. The incidence of KDSS is 1.5% to 7.0% of KD patients and is higher in Western countries than Asian countries. 48 KDSS is previously found to be associated with an older age and is characterized as hyperinflammation with higher C-reactive protein, procalcitonin, erythrocyte sedimentation rate, IL-6, and D-dimer as compared to KD. 48 In addition, KDSS is often associated with myocarditis and prolonged myocardial dysfunction. 49 

The authors declare that there are no conflict of interests.

Jun Yasuhara: conceptualization (lead); data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); project administration (lead); resources (lead); software (lead); validation (lead); 

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