Multisystem inflammatory syndrome in children related to COVID-19: a systematic review

Abstract

An association between a novel pediatric hyperinflammatory condition and SARS-CoV-2 was recently published and termed pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2 (PIMS-TS) or multisystem inflammatory syndrome (in children) (MIS(-C)). We performed a systematic review and describe the epidemiological, clinical, and prognostic characteristics of 953 PIMS-TS/MIS(-C) cases in 68 records. Additionally, we studied the sensitivity of different case definitions that are currently applied. PIMS-TS/MIS(-C) presents at a median age of 8 years. Epidemiological enrichment for males (58.9%) and ethnic minorities (37.0% Black) is present. Apart from obesity (25.3%), comorbidities are rare. PIMS-TS/MIS(-C) is characterized by fever (99.4%), gastrointestinal (85.6%) and cardiocirculatory manifestations (79.3%), and increased inflammatory biomarkers. Nevertheless, 50.3% present respiratory symptoms as well. Over half of patients (56.3%) present with shock. The majority of the patients (73.3%) need intensive care treatment, including extracorporal membrane oxygenation (ECMO) in 3.8%. Despite severe disease, mortality is rather low (1.9%). Of the currently used case definitions, the WHO definition is preferred, as it is more precise, while encompassing most cases.Conclusion: PIMS-TS/MIS(-C) is a severe, heterogeneous disease with epidemiological enrichment for males, adolescents, and racial and ethnic minorities. However, mortality rate is low and short-term outcome favorable. Long-term follow-up of chronic complications and additional clinical research to elucidate the underlying pathogenesis is crucial. What is Known: • A novel pediatric inflammatory syndrome with multisystem involvement has been described in association with SARS-CoV-2. • To date, the scattered reporting of cases and use of different case definitions provides insufficient insight in the full clinical spectrum, epidemiological and immunological features, and prognosis. What is New: • This systematic review illustrates the heterogeneous spectrum of PIMS-TS/MIS(-C) and its epidemiological enrichment for males, adolescents, and racial and ethnic minorities. • Despite its severe presentation, overall short-term outcome is good. • The WHO MIS definition is preferred, as it is more precise, while encompassing most cases.

Keywords: COVID-19; MIS-C; PIMS-TS; SARS-CoV-2.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram

Fig. 2

Cumulative number of published PIMS-TS/MIS(-C) cases (bars) in relation to total worldwide reported COVID-19 cases, according to data from Johns Hopkins Coronavirus Resource Center (lines; 7-day rolling average)

Fig. 3

Demographic characteristics of all included studies. a Age distribution. b Fraction of males and females in each study. IQR, interquartile range. “Control” corresponds to the control populations with Kawasaki disease as described by Pouletty et al. [64] and Whittaker et al. [15] and non-PIMS-TS/MIS(-C) pediatric COVID-19 by Swann et al. [23]. Data from Swann et al. [23], Rostad et al. [26], and Weisberg et al. [25] was extracted from pre-print publications and these references and have subsequently been published in the peer-reviewed literature [–29]

Fig. 4

Laboratory tests values and distribution for each study. Error bars correspond to the interquartile range. Dashed vertical line equals the upper limit of normal (CRP, white blood cells, ferritin, d-dimers, IL6, and troponin) or the lower limit of normal (sodium, lymphocytes, and platelets). For studies that report multiple values for the same test, the maximum (CRP, white blood cells, ferritin, d-dimers, IL6, and troponin) or the minimum (sodium, lymphocytes, platelets) was used. “Covid” (red line) equals values corresponding to the COVID-19-related hyperinflammatory syndrome; “control” (gray line) equal values corresponding to the control populations with Kawasaki disease described by Pouletty et al. [64] and Whittaker et al. [15] and (orange line) non-PIMS-TS/MIS(-C) pediatric COVID-19 by Swann et al. [23]. Data from Swann et al. [23], Rostad et al. [26], and Weisberg et al [25]. was extracted from pre-print publications and these references have subsequently been published in the peer-reviewed literature [–29]

Fig. 5

Summary figure presenting the findings of this systematic review on the clinical spectrum of PIMS-TS/MIS(-C). Comparison of the clinical picture is made, based on relevant differences with control populations such as published on Kawasaki disease (KD) by Pouletty et al. [64] and Whittaker et al. [15] (*), and non-PIMS-TS/MIS(-C) pediatric COVID-19 by Swann et al. [23] (°). For each variable, the percentage denoting the fraction of included cases is displayed. PIMS-TS/MIS(-C) disease severity is assessed as described in the “Methods” section. Arrows pointing upwards mean that a higher proportion of cases display one of the mentioned symptoms or that higher values for the laboratory markers are found. Arrows pointing down denote lower values or frequencies