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Vol. 98. Issue 4.
Pages 338-349 (July - August 2022)
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Vol. 98. Issue 4.
Pages 338-349 (July - August 2022)
Review article
Open Access
Multisystem inflammatory syndrome (MIS-C): a systematic review and meta-analysis of clinical characteristics, treatment, and outcomes
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Mônica O. Santosa,
Corresponding author
, Lucas C. Gonçalvesb, Paulo A.N. Silvab, André L.E. Moreirac, Célia R.M. Itoc, Fernanda A.O. Peixotod, Isabela J. Wastowskie, Lilian C. Carneiroc, Melissa A.G. Avelinod
a Universidade Federal de Goiás, Patologia Clínica e Medicina, Goiânia, GO, Brazil
b Universidade Federal de Goiás, Faculdade de Medicina, Goiânia, GO, Brazil
c Universidade Federal de Goiás, Instituto de Patologia Tropical e Saúde Pública, Goiânia, GO, Brazil
d Universidade Federal de Goiás, Departamento de Pediatria, Goiânia, GO, Brazil
e Universidade Federal de Goiás, Laboratório de Imunologia Molecular, Goiânia, GO, Brazil
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Abstract
Objective

The clinical cases of patients with multisystem inflammatory syndrome (MIS-C) were analyzed via a systematic review and meta-analysis of the clinical findings, treatments, and possible outcomes of articles retrieved via database searches.

Sources

The authors searched the PubMed, Scielo, Web of Science, Science Direct, EMBASA, EBSCO, and Scopus databases for articles containing the keywords “multisystem inflammatory syndrome in children” or “MIS-C” or “PIMS-TS” or “SIMP” and “COVID-19” or “SARS-CoV-2” published between December 1st, 2019 and July 10th, 2021. Patient characteristics, tissue and organ comorbidities, the incidence of symptoms after COVID-19 infection, treatment, and patient evolution in the articles found were evaluated. The data were abstracted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Newcastle-Ottawa Scale (NOS).

Findings

In total, 98 articles (2275 patients) were selected for demographics, clinical treatment, and outcomes of patients diagnosed with MIS-C. The average age of children with MIS-C, 56.8% of whom were male, was of nine years. Fever (100%), gastrointestinal (GI) (82%), and abdominal pain (68%) were the decisive symptoms for the diagnosis of MIS-C. Shock and/or hypotension were common in patients with MIS-C. Cardiac symptoms (66%) predominated over respiratory (39%) and neurological (28%) symptoms. MIS-C treatment followed the common guidelines for treating children with septic shock and Kawasaki disease (KD) and proved to be effective.

Conclusions

This meta-analysis highlights the main clinical symptoms used for the diagnosis of MIS-C, the differences between MIS-C and KD, and the severity of the inflammatory process and urgency for hospital care.

Keywords:
MIS-C
PIMS-TS
COVID-19
SARS-CoV-2
Children
Full Text
Introduction

In April 2020, during the peak of the coronavirus disease (COVID-19) pandemic in Europe, reports on children in England with hyperinflammatory shock, the characteristics of which are similar to those of Kawasaki disease (KD) and toxic shock syndrome (TSS), were published. The Royal College of Pediatrics and Child Health referred to this acute condition as pediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS).1 As more cases emerged worldwide, the disease was called multisystem inflammatory syndrome in children (MIS-C) by the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).2,3

An initial challenge faced by physicians was differentiating patients with MIS-C due to KD and TSS from patients with MIS-C related to COVID-19. Several questions about the symptoms and the possibilities of treatment have been raised.1-3

At the beginning of the pandemic, children were not at high risk for serious manifestations of COVID-19, such as severe acute respiratory syndrome (SARS). However, as the pandemic evolved, more serious complications, including thrombotic events, myocardial dysfunction, and coronary artery disease or aneurysms, manifested in the pediatric age group with MIS-C.

The aim of this systematic review was to describe the main symptoms of MIS-C and characterize its treatment and possible outcomes.

MethodsLiterature search and selection criteria

The authors conducted an online search of the PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Scielo (http://www.scielo.br/), Web of Science (https://clarivate.com/products/web‐of‐science/), Science Direct (https://www.sciencedirect.com/), Embase (www.elsevier.com/embase), EBSCO (https://www.ebscohost.com), and Scopus (https://www.scopus.com/) databases using the keywords “multisystem inflammatory syndrome in children” or “MIS-C” or “PIMS-TS” (pediatric inflammatory multisystem syndrome temporally associated with COVID-19) or “SIMP” (síndrome inflammatory multissistêmica pediátrica) and “COVID-19” or “SARS-CoV-2” to identify relevant studies published between December 1st, 2019 and July 10th, 2021. Before starting our search, the authors searched the Cochrane Library (https://www.cochranelibrary.com) and the National Institute for Health Research database (https://www.crd.york.ac.uk/prospero/) for systematic reviews and meta-analyses on a similar subject, but no articles were found (registration: PROSPERO CRD42020204774).

The risk of bias and the quality of the systematic review was assessed using a quality assessment tool published by the National Institutes of Health. The items included in this systematic review (Supplemental information) were evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and the Newcastle-

Ottawa scale (NOS)

To find additional eligible studies, the authors checked the reference lists of the papers found by our search. Additional studies were included in our review if they presented (1) systemic inflammatory syndrome in children or adolescents with COVID-19 and (2) clinical information and outcomes for children and adolescents.

Studies were included in our quantitative analysis if they had a sample size ≥6. The authors did not exclude any article because of language. The series of cases and studies that investigated the pathological characteristics of tissues and organs were evaluated using qualitative analysis.

Some retrieved articles were excluded from this systematic review because (1) the author of the study made the diagnosis of KD and did not consider the possibility of MIS-C related to COVID-19 or PIMS-TS. (2) The study did not present any confirmation that the patient had contact with people infected with COVID-19 or that the RT-PCR test for SARS-CoV-2 and the serological tests were negative. (3) The study was on children who required intensive care before MIS-C and PIMS were identified; however, if the study did not meet the inclusion criteria, it was excluded to avoid bias. (4) The study used the same patient database as another study, so the information overlapped. (5) The article was opinion, editorial, or comment; review article; or health guidelines. These articles were excluded because they did not contain basic patient data.

Data selection was in accordance with the PRISMA and NOS guidelines.

Statistical analysis

The present research is characterized as a systematic review and meta-analysis. Research of this type is carried out by systematically selecting data and later applying statistical tests. The systematic review was carried out in accordance with the PRISMA guidelines.4

Determination of heterogeneity

To assess the heterogeneity of our meta-analysis, the authors used the Higgins and Thompson test (I²), with the following interpretation of the results: 25% = low heterogeneity, 50% = moderate heterogeneity, and ≥ 75% = high heterogeneity. A heterogeneity of ≥ 50% indicates significant differences among the results of the studies used in the meta-analysis; thus, the randomized effect was used. On the other hand, when the heterogeneity was < 50%, the fixed effect was used, which considers the heterogeneity as insignificant. This interpretation and statistical application are extremely important for assertive results.5

Proportion transformation models and methods

When the heterogeneity among the survey data showed results without significance, the inverse model was used, allowing for the return of the transformation of proportions. This model is associated with the Freeman-Tukey double sine transformation (PFT) for the exact probability transformation. However, when the surveys plotted on the graph had several similar, and some discrepant data, the inverse model, associated with the arcsine transformation (PAS) was used for approximate likelihood transformations. When the heterogeneity among the survey data was significant, the mixed generalized linear model (GLMM), associated with the logistic transformation (PLOGIT), was used for the approximate likelihood transformations.

Determination of bias

The bias in our search results was determined by analyzing funnel plot graphs, which was feasible only when the number of plotted surveys was ≥ 10. This takes into account the inefficiency of the graph when the sample size is small.6

Sample significance

For all statistical analyses, an alpha level of 5% was previously defined as significant; thus, P < 0.05 was considered statistically significant. Statistical analyses were performed using the RStudio® version 4.0.2, and STATA® statistical software ver. 16.0 (StataCorp LLC, College Station, TX, USA).

ResultsStudy selection and characteristics

The inclusion and exclusion criteria for articles followed the guidelines of the Royal College of Pediatrics and Child Health (RCPCH), the CDC, and the WHO (Supplementary Table 1). The search of the databases yielded 1312 articles, of which 252 were examined in full, and 98 were selected for systematic review (Figure 1 and Supplementary Tables 2 and 3).

Figure 1.

PRISMA flow diagram of the search of databases. The diagram contains the steps of identification, screening, eligibility, and inclusion.

(0.42MB).

The articles included in the systematic review included 26 case series, 35 observational cohort studies, and 37 case reports (Table 1). The authors divided the analysis into qualitative studies with five or fewer patients and quantitative studies with six or more patients (Figure 1 and Supplementary Table 2). The number of patients in the quantitative meta-analysis articles was 2197 children, adolescents, and young adults. All data, forest plot graphs, and bias analysis (funnel plot) are provided in the Supplementary Figures.

Table 1.

Characteristics of the studies selected in the systematic review and meta-analysis.

Articles (2020/2021)  Country  Study  Total cases  Age in years  Total male 
Abdel-Haq et al. 20217  USA  Observational  33  6 (0.3-17)  15 
Abdel-Mannan et al. 20208  UK  Case series  12 (8-15) 
Acharrya et al. 20209  India  Case report  0.3 
Alkan et al. 202110  Turkey  Observational  36  7.8 (1.7-17)  19 
Bahrami et al. 202011  Iran  Case report 
Balasubramanian et al. 202012  India  Case report 
Bapst et al. 202013  Switzerland  Case report  13 
Bektaş et al. 202114  Turkey  Case report  10.5 
Belhadjer et al. 202015  France/Switzerland  Observational  35  10 (2–16)  18 
Belot et al. 202016  France  Observational  108  8 (5–11)  53 
Blondiaux et al. 202017  France  Case series  9 (6–12) 
Blumfield et al. 202118  USA  Observational  16  10 (1-20)  10 
Buonsenso et al. 202019  Italy  Case report  11 
Capone et al. 202020  USA  Observational  33  8.6 (5.5–12.6)  20 
Carter et al. 202021  UK  Observational  25  12,5 (7.7-14.4)  15 
Cattalini et al. 202122  Italy  Observational  53  7 (4.5-11)  31 
Cheung et al. 202023  USA  Observational  17  8 (1.8–16) 
Chiotos et al. 202024  USA  Case series  7.5 (5–14) 
Cogan et al. 202025  Belgium  Case report  19 
Dallan et al. 202026  Switzerland  Case series  11 (10-12) 
Dasgupta and Finch 202027  USA  Case report 
Davies et al. 202028  UK  Observational  78  11 (8-14)  52 
De Paulis et al. 202029  Brazil  Case report 
Deza Leon et al. 202030  USA  Case report 
Dhanalakshmi et al. 202031  India  Case series  19  6 (1-16) 
Dionne et al. 202032  USA  Observational  25  9.5 (2.7 – 15)  15 
Diorio et al. 202033  USA  Case series  6 (5-7) 
Dolhnikoff et al. 202034  Brazil  Case report  11 
Dolinger et al. 202035  USA  Case report  14 
Domico et al. 202036  USA  Case report  11 
Dufort et al. 202037  USA  Observational  99  (0–20)  53 
Farias et al. 202038  Brazil  Case series  11  4.9 (0.7-11) 
Farias et al. 202039  Brazil  Case report  0.7 
Feldstein et al. 202040  USA  Observational  186  8.3 (3.3–12.5)  115 
Flood et al. 202141  UK and Ireland  Observational  268  8.2 (4-12.1)  161 
Giannattasio et al. 202142  Italy  Case report 
Godfred-Cato et al. 202043  USA  Observational  570  8 (4-12)  316 
Greene et al. 202044  USA  Case report  11 
Grimaud et al. 202045  France  Observational  20  10 (2.9–15)  10 
Gruber et al. 202046  USA  Case series  11.5 (3-20) 
Gupta et al. 202047  India  Case report 
Hameed et al. 202048  UK  Observational  35  11  27 
Heidemann et al. 202049  USA  Case series  6 (5-7) 
Hutchison et al. 202050  USA  Case report  14 
Jain et al. 202051  India  Observational  23  7.2 (0.8-14)  11 
Joshi et al. 202052  USA  Case series  10.6 (6-13) 
Kashyap et al. 202153  India  Observational  12  6.5 
Kaushik et al. 202054  USA  Observational  33  10 (6–13)  20 
Kest et al. 202055  USA  Case series  8 (6-10) 
Khesrani et al. 202056  Algeria  Case report 
Klocperk et al. 202057  Czechia  Case report 
Lang et al. 202058  Germany  Case report  (10-13) 
Lee and Margolskee 202059  USA  Case report 
Lee et al. 202060  USA  Observational  28  9 (0.1-17)  15 
Lee et al. 202061  USA  Case report  17 
Licciardi et al. 202062  Italy  Case series  12, 7 
Lin et al. 202063  USA  Case report  13 
Mamishi et al. 202064  Iran  Observational  45  7 (4–9.9)  24 
Mehler et al. 202165  Germany  Case series  12.1 (1-16) 
Meredith et al. 202166  UK  Case report  10 
Miller et al. 202067  USA  Observational  44  7.3 (0.6–20)  20 
Mills et al. 202168  USA  Case series  9.5 
Moghadam et al. 202069  France  Case report  21 
Moraleda et al. 202070  Spain  Observational  31  7.6 (4.5-11-5)  18 
Nathan et al. 202071  France  Case series  5.5 (5-11) 
Ng et al. 202072  UK  Case series  16, 17, 13 
Nguyen et al. 202073  USA  Case report  10 
Okarska-Napierala et al. 202074  Poland  Case report  14 
Paolino and Wlillians 202075  USA  Case series  7.6 (6-9) 
Patnaik et al. 202176  India  Observational  21  8.5 (2-16)  13 
Penner et al. 202177  UK  Observational  46  10.2 (8.8-13.3)  30 
Pereira et al. 202078  Brazil  Case series  7.78 (0.01-17.6) 
Perez-Toledo et al. 202079  UK  Case series  9 (7–14) 
Pouletty et al. 202080  France  Observational  16  10 (4.7–12.5) 
Prata-Barbosa et al. 202081  Brazil  Case series  10  5.2 (1.5−8.4) 
Prieto et al. 202182  Spain  Case series  7 (5-12) 
Ramcharan et al. 202083  UK  Observational  15  8.8 (6.4–11.2)  11 
Rauf et al. 202084  India  Case report 
Regev et al. 202085  Israel  Case report  16 
Riollano-Cruz et al. 202086  USA  Observational  15  12 (3–20)  11 
Riphagen et al. 202087  UK  Case series  8.9 (4–14) 
Roberts et al. 202188  USA  Observational  50  9.6 (6.2-14)  33 
Rodriguez-Gonzalez 202089  Spain  Case report  0.6 
Rogo et al. 202090  USA  Case series  11.2 (3-20) 
Sadiq et al. 202091  Pakistan  Case series  9.5 (8-10.5) 
Saeed and Shorafa 202092  Iran  Case report 
Sandoval et al. 202193  Chile  Case series  5.4 (1.5-12) 
Schupper et al. 202094  Germany  Case report 
Shenker et al. 202095  USA  Case report  12 
Torres et al. 202096  Chile  Observational  27  6 (0-14)  14 
Toubiana et al. 202097  France  Observational  21  7.9 (3.7–16.6) 
Vari et al. 202098  USA  Case report  14 
Verdoni et al. 202099  Italy  Case series  10  7.5 (2.9–16) 
Verkuil et al. 2020100  USA  Case report  14 
Webb et al. 2020101  South Africa  Observational  23  6.6 (4.7-8.4)  17 
Whittaker et al. 2020102  UK  Observational  58  9 (5.7–14)  25 
Yonker et al. 2020103  USA  Observational  18  7.7  14 
Yozgat et al. 2020104  Turkey  Case report 
Demographic characteristics and comorbidities

Meta-analysis showed that 0.58 (0.55 - 0.61) of the children with MIS-C were male, and the median age of all children was 8.9 years (range = 0.1 days to 20 years old).

Only 23 articles included in the meta-analysis reported the race/ethnicity of the patients. Approximately 0.33 (0.26−0.42) of the children were Hispanic, 0.29 (0.24−0.34) were Black, 0.32 (0.24−0.40) were White, 0.05 (0.02−0.13) were Asian, 0.11 (0.07−0.16) were multiracial or other, and 0.13 (0.07−0.21) had no ethnicity specified in the study (Table 2).

Table 2.

Meta-analysis of pooled demographic and clinical characteristics of MIS-C or PIMS-TS patients.

Characteristics  Total  Events  Pooled mean proportion %(95%CI)  Heterogeneity I2 (%)  Combined 
Demographics      Prop CI95%     
Sex Male  2.144  1.234  0.58 [0.55-0.61]  31%, p = 0.03  Random 
Ethnicity           
White  1627  338  0.19 [0.13-0.26]  84%, p < 0.01  Random 
Multiracial or outhers  1.514  139  0.11 [0.07-0.16]  77%, p < 0.01  Random 
Black or Afrodescendents  1.627  477  0.32 [0.24-0.40]  74%, p < 0.01  Random 
Asian  1.627  158  0.05 [0.02-0.13]  79%, p < 0.01  Random 
Hipanic  1.043  340  0.33 [0.26-0.42]  55%, p < 0.02  Random 
Not declared  1.134  175  0.13 [0.07-0.21]  82%, p < 0.01  Random 
Clinical features           
Fever  2.144  2.067  1.00 [0.98-1.00]  78%, p < 0.01  Random 
Cough  1.388  535  0.41 [0.28-0.55]  93%, p < 0.01  Random 
Headache  1.173  280  0.28 [0.21-0.37]  70%, p < 0.01  Random 
Dyspnea  874  235  0.29 [0.21-0.38]  65%, p < 0.01  Random 
Conjunctivitis  978  541  0.54 [0.47-0.61]  58%, p < 0.01  Random 
Sore throat  279  57  0.20 [0.12-0.31]  71%, p < 0.01  Random 
Diarrhoea  1.542  655  0.58 [0.49-0.67]  76%, p < 0.01  Random 
Vomiting  1.541  736  0.66 [0.56-0.75]  73%, p < 0.01  Random 
Abdominal pain  1.598  763  0.68 [0.62-0.74]  24%, p < 0.12  Random 
GI symptoms (not specifics)  1.228  986  0.82 [0.71-0.89]  87%, p < 0.01  Random 
Erythema  1.724  814  0.59 [0.53-0.65]  51%, p < 0.01  Random 
Shock  1.544  675  0.60 [0.51-0.69]  84%, p < 0.01  Random 
Hypotension  1.697  890  0.59 [0.53-0.65]  62%, p < 0.01  Random 
Cardiac symptoms  1.837  1.251  0.66 [0.58-0.74]  87%, p < 0.01  Random 
Neurologic symptoms  1.494  488  0.28 [0.20-0.38]  83%, p < 0.01  Random 
Respiratory symptoms  1.695  869  0.39 [0.30-0.49]  88%, p < 0.01  Random 
Comorbidity  1.805  604  0.33 [0.27-0.40]  80%, p < 0.01  Random 
Laboratory features           
Serological test confirmation  2.044  2.102  0.69 [0.60-0.77]  84%, p < 0.01  Random 
RT-PCR  2.102  588  0.31 [0.24-0.38]  76%, p < 0.01  Random 
Treatment           
Inotropics  1.965  913  0.54 [0.47-0.60]  77%, p < 0.01  Random 
Steroids  1.973  1.145  0.64 [0.52-0.74]  68%, p < 0.01  Random 
Antibiotics  777  395  0.77 [0.54-0.95]  97%, p < 0.01  Random 
IVIG  1.963  1.501  0.84 [0.79-0.88]  79%, p < 0.01  Random 
Antiplatelet  1.625  1.116  0.78 [0.63-0.89]  97%, p < 0.01  Random 
Biological Immunodulation  1.401  355  0.27 [0.16-0.42]  77%, p < 0.01  Random 
Antiviral therapy  295  45  0.16 [0.08-0.29]  67%, p < 0.01  Random 
ICU  1.973  1.294  0.76 [0.67-0.84]  77%, p < 0.01  Random 
(MV/NIV/ HFNC)  1.919  731  0.50 [0.39-0.62]  82%, p < 0.01  Random 
ECMO  641  36  0.06 [0.03-0.10]  65%, p < 0.01  Random 
Outcomes           
Recoverd  1.973  1.935  1.00 [0.99-1.00]  13%, p < 0.24  Random 
Death  1.973  38  0.01 [0.01-0.03]  22%, p = 0.11  Random 

PICU, pediatric intensive care unit; MV, mechanical ventilation; NIV, noninvasive ventilation; HFNC, high-flow nasal cannula; ECMO, extracorporeal membrane oxygenation.

Only 41 studies reported specific comorbidities and were included in the meta-analysis. Of the 1973 children and adolescents in whom MIS-C was diagnosed, approximately 0.33 (0.27 ± 0.40) had a comorbidity. Several comorbidities were mentioned in the articles evaluated in the qualitative analysis. The most cited comorbidities were asthma, obesity and diabetes. Other less frequent comorbidities were associated with cardiac, renal, neurological, dermatological, and hematological disorders.7-104 The analysis of some comorbidities was discussed in specific studies.105-117

Clinical manifestations

The analysis of the symptom data and clinical characteristics of all patients with MIS-C (Table 2 and Figure 2) showed that the most common symptoms were fever, 1.00 (0.98−1.00); gastrointestinal symptoms, 0.82 (0.71−0.89); abdominal pain, 0.68 (0, 62−0.74); erythema and rash, 0.59 (0.53−0.65); and non-purulent conjunctivitis, 0.54 (0.47−0.61). Cough [0.41 (0.28−0.55)], dyspnea [0.29 (0.21−0.38)], and sore throat [0.20 (0.12−0.31)] also were reported. In contrast with adults, respiratory symptoms in children [0.39 (0.30−0.49)] were less prevalent. Cardiac comorbidities were commonly observed in children with MIS-C [0.66 (0.58−0.74)].

Figure 2.

Summary of the size of the effect of proportions on all the variables studied in the meta-analysis.

(0.69MB).
Treatment of patients with MIS-C

Thirty-three articles that met the inclusion criteria presented clinical characteristics and the complete outcome of the treatment of patients with MIS-C (Table 2). The treatment offered to these patients involved the WHO protocols for treating patients with septic shock and KD.2

Of the 1294 patients with MIS-C, 0.76 (0.67−0.84) needed intensive hospitalization. Because of the rapid and progressive instability caused by the inflammatory process, 0.54 (0.47−0.60) of the patients needed stabilization and inotropic agents. Shock or hypotension was reported in 0.60 (0.51−0.69) and 0.59 (0.53−0.65) of the patients, respectively.

The authors observed the following variations in the treatment of patients with MIS-C: intravenous immunoglobulin (IVIG), 0.84 (0.79−0.88); antiplatelet or anticoagulant, 0.78 (0.63−0.89); steroid, 0.64 (0.52−0.74); biological immunomodulator, 0.27 (0.16−0.42); and antiviral, 0.16 (0.08−0.29). Approximately 0.50 (0.39−0.62) of the patients with COVID-19-related MIS-C required some respiratory support, and 0.06 (0.03−0.10) eventually needed membrane oxygenation cardiopulmonary bypass (extracorporeal membrane oxygenation [ECMO]).

Some studies reported the use of broad-spectrum antibiotics in the first days of hospitalization; however, once the diagnosis of MIS-C was confirmed, the antibiotics were suspended. Only 0.02 (0.01−0.05) of the patients died despite the severity of the clinical symptoms of MIS-C.

To determine the statistical significance of all the characteristics studied, the authors performed a size test on the effect of proportions on all the variables studied in the meta-analysis (Figure 2).

Discussion

This systematic review analyzed and summarized 98 publications that included case reports, case series, and broader observational studies of patients with MIS-C. All the criteria were followed, and all information was noted for statistical analysis and evaluation. The results of this review confirm that there is a new multisystem inflammatory syndrome related to SARS-CoV-2.

In April 2020, alarming news emerged about children with evidence of recent SARS-CoV-2 infection and who developed a severe multisystem disease with fever, severe abdominal pain, hypotension and/or shock, and myocardial dysfunction with markedly elevated damage markers. This syndrome is called pediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS) in Europe and multisystem inflammatory syndrome in children (MIS-C) by the CDC.2 Although the symptoms and characteristics of MIS-C are similar to those of KD, several studies have presented significant differences that distinguish the two diseases.1,2,3,87,88,95,105 Studies have shown that MIS-C occurs in children and adolescents, where the average age of those studied was 08−11 years.11,14-24,32,36,41,46,52,85-87 In our systematic review, the mean age of the children with MIS-C was nine years. This contrasts with studies on the incidence of KD in children with an average age of 5 years.8,21,24,61,79,83,96,98,105,107,108,116

Despite the incidence of COVID-19 in Asian countries, the prevalence of MIS-C there is lower, although cases have been registered worldwide according to the WHO (2020). Our systematic review, which included studies from 18 countries, found there was no statistically significant difference in the incidence of MIS-C in Asian children. This contrasts with studies that showed a predominance of KD in children of Asian origin.105-108 In addition, children with MIS-C had significant abdominal pain that required advanced imaging and surgical consultation, whereas abdominal pain rarely occurs with KD.95-98,105,108,109

Children with MIS-C have gastrointestinal symptoms more often than do adults with COVID-19.93,108,109 As most children with gastrointestinal symptoms are not severely ill, the authors can conclude that children are more vulnerable to gastrointestinal involvement than to respiratory involvement than are adults.73,93,94,108-110 Some children had abdominal pain so severe that they underwent surgery for suspected peritonitis or appendicitis that resulted in the diagnosis of MIS-C.50,60,107-109 The most common conditions associated with abdominal pain include ascites and mesenteric lymphadenitis.13,65,73,107-109

Cardiac involvement was commonly observed in children with MIS-C (Table 2). Fever, skin rashes, and gastrointestinal symptoms also were common. Case report studies showed that the symptoms of patients hospitalized with MIS-C quickly became acute. Placement in the intensive care unit, treatment for shock and hypotension, fluid resuscitation, and ventilatory support were necessary in most cases. Many patients with MIS-C develop cardiac symptoms, including mild coronary artery dilation or, rarely, aneurysms.11,16,26,28,32,36,55,81,82,89,111-117

That mild transient coronary artery dilation can develop as a result of a cytokine storm with high IL-6 levels has been demonstrated in systemic-onset juvenile idiopathic arthritis, and it could result from a similar cytokine storm in MIS-C.86,96,97,111-113 However, persistent coronary artery aneurysms and their complications have been previously attributed to only KD in pediatric patients.83,98,104-110,112-117

Another theory about the cause of cardiac injury is that a direct viral infection causes myocarditis. SARS-CoV-2 may directly cause myocardial damage by entering cardiomyocytes via the angiotensin-converting enzyme 2 (ACE2) receptor. The virus is also capable of activating CD8+ T lymphocyte migration to cardiomyocytes and causing myocardial inflammation through cell-mediated cytotoxicity.113-116 Endomyocardial biopsies from patients with COVID-19 have shown viral particles, and inflammatory infiltrates in the myocardium.111-117 All patients in the articles reviewed who had cardiac symptoms were followed up for a longer period, and the total regression of their cardiac symptoms was observed.

Our systematic review found that the immediate medical support offered to patients with MIS-C that was associated with treatment proved effective toward their recovery [1.00 (0.99−1.00)]. In addition, the treatment of patients with MIS-C correlated with that of patients with KD and with the control of the systemic inflammatory process and cardiac injury as reported in other studies.45,100,101,102

The successful use of steroids, in addition to IL-1 receptor antagonists (Anakinra) and IVIG, to control KD has been described. The anti-IL-6 receptor monoclonal antibody tocilizumab has been used successfully in treating chronic inflammatory processes such as juvenile idiopathic arthritis.67 The authors observed the use of preventive treatment that included the use of antiplatelet drugs or anticoagulants as well as broad-spectrum antibiotics initially until severe inflammation was contained, and then the diagnosis of MIS-C was confirmed.

Limitations

This systematic review has some limitations. Because the authors are still working within the situation of a global pandemic, we believe that patient overload and the need for urgent care have prevented hospitals and researchers from providing more detailed information about symptoms, examinations, and outcomes. In addition, several studies included in this review have points of bias resulting from the type of case, the absence of statistical analysis, patient data in more than one article, or difficulty in separating the data of children from that of adults. The authors believe that the inclusion and exclusion criteria used to obtain articles for this review, as well as the attention paid in analyzing the data and statistics, minimized the observed biases.

Conclusions

The results of this systematic review show MIS-C as a severe inflammatory syndrome that affects older children, in contrast to DK. Many organs are affected, and children need hospitalization and fluid and respiratory support. The treatments proposed by the health guidelines (WHO and RCPCH) were followed and proved to be effective in the total recovery of patients.

Funding

Dr. Melissa AG Avelino coordinates the project: "Differential diagnosis and pediatric clinical evolution of COVID-19 in the context of the seasonality of respiratory viruses in a capital of the Midwest Brazil."/CAPES. Dra. Mônica O. Santos, Dr. Paulo A. N Silva, Dr. André L. E Moreira and Dr. Célia RM Ito were supported by grant (CNPJ Capes: 00.889.834 / 0001-08).

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