Abstract
In this nationwide retrospective study, a substantial decline in the incidence of multisystem inflammatory syndrome in children over 3 successive pandemic waves characterized by different severe acute respiratory syndrome coronavirus 2 variants was documented—from 3.4 of 1000 to 1.1 of 1000 and finally to 0.25 of 1000 confirmed severe acute respiratory syndrome coronavirus 2 positive cases (P < 0.0001), respectively, whereas clinical findings and severity did not significantly vary.
Keywords: incidence, multisystem inflammatory syndrome in children, severe acute respiratory syndrome coronavirus 2 variants
Unlike mild or asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in most children, multisystem inflammatory syndrome in children (MIS-C) is a potentially severe clinical entity requiring pediatric intensive care unit admission in a great proportion of the cases.1 Despite increased awareness, diagnostic approach and treatment strategies are challenging, whereas factors contributing to the pathogenesis of MIS-C remain largely unknown.2 Genetic predisposition has been hypothesized and is already being studied.3 On the other hand, studies about the impact of different SARS-CoV-2 variants on triggering MIS-C at different times of the pandemic are lacking.
The aim of this study was to compare the impact of different SARS-CoV-2 variants on the incidence of MIS-C as well as the epidemiologic and clinical characteristics of patients hospitalized with MIS-C.
MATERIALS AND METHODS
In this nationwide study, we examined the incidence, clinical characteristics and outcome of MIS-C among children and young people (CYP) <18 years of age admitted during 3 successive pandemic waves. During each period, the predominant variant accounted for at least 80% of the strains sequenced according to data provided by the National Public Health Organization, and the onset of each period was at least 8 weeks apart from the peak of the previous wave. The following periods were included, which were characterized by different SARS-CoV-2 variants: (1) from August 1, 2020, to January 31, 2021 (EU1-B.1.177), (2) from February 1, 2021, to July 31, 2021 (Alpha-B.1.1.7) and (3) from August 1, 2021, to December 31, 2021 (Delta-B.1.617.2). The study was conducted with the participation of 10 reference tertiary care centers throughout the country. Patients’ demographic, clinical and laboratory data were retrospectively collected. SARS-CoV-2 reverse transcription polymerase chain reaction and serology were available in all participating institutions throughout the study period. A common protocol on the management of CYP hospitalized with MIS-C was provided by the Hellenic Society of Paediatric Infectious Diseases (available at https://elepl.gr/diaheirisi-paidion-me-mis-c/). Patients were admitted to intensive care unit if cardiovascular or respiratory support or continuous monitoring in deteriorating patients were required.
Age and sex are described by using median values and interquartile ranges and compared by using a nonparametric Kruskal-Wallis test. Clinical data are presented as proportions and percentages and compared with proportion χ2 test. The incidence rate of MIS-C was calculated using as a denominator the total number of SARS-CoV-2 infections in children and adolescents ≤18 years old reported by the National Public Health Organization during the 3 study periods. Testing for SARS-CoV-2 by reverse transcription polymerase chain reaction or rapid antigen detection tests was available in public and private health services across the country throughout the study period. There was also a community surveillance network where RADTs were performed irrespective of symptom status. Since April 13, 2020, a centralized reporting system has been established and remained unchanged for the entire study period. For the confidence interval (CI) of the difference between 2 rates, we used the test-based method. The P value is obtained using the χ2 statistic. For the CI of the incidence rate ratio, we used exact Poisson method. The P value is the exact mid-P double-sided P value.
Statistical significance was set at P < 0.05 and analyses were conducted using STATA (version 17.0), StataCorp Lakeway Drive College Station, TX.
The study was approved by the Ethics Committees of all participating hospitals.
RESULTS
In total, 119 patients were included of which 91.6% (109/119) met the World Health Organization criteria of MIS-C diagnosis; the remaining had not serologic evidence of previous SARS-CoV-2 infection but all reported either COVID-19 in the 6 past weeks (n = 4) or exposure to the virus (n = 6). Their clinical presentation resembled incomplete Kawasaki, and all received the same treatment as the rest of the cohort. Of all children diagnosed with MIS-C, 26.9% (32/119), 39.5% (47/119) and 33.6% (40/119) were hospitalized during the 1st (EU1-B.1.177), 2nd (Alpha-B.1.1.7) and 3rd (Delta-B.1.617.2) study period, respectively. Demographic and clinical characteristics are shown in Table 1. The peak of MIS-C cases followed the peak SARS-CoV-2 infections by 4–6 weeks in all 3 pandemic periods. Notably, no cases were found before October 2020 as Greece experienced a mild first pandemic wave in spring 2020 mainly due to school closures and other strict quarantine measures that were implemented. Three peaks of MIS-C cases were observed following the peaks of SARS-CoV-2 infections by 4–6 weeks. The incidence of MIS-C significantly decreased over the 3 waves from 3.4 of 1000 (95% CI: 2.3–4.7) to 1.1 of 1000 (95% CI: 0.8–1.5) and finally to 0.25 of 1000 (95% CI: 0.18–0.35) confirmed SARS-CoV-2 positive cases (P < 0.0001), respectively. The proportion of males and patients with myocarditis were increasing overtime, while the rate of mucocutaneous and gastrointestinal manifestations were permanently high throughout the study period. The proportion of children admitted to intensive care unit was higher during the second study period. All of them received intravenous immunoglobulin and steroids: 32.1% (9/28) received a second dose of intravenous immunoglobulin and 46.4% (13/28) received pulse steroid therapy. Half of them required inotropes, whereas mechanical ventilation was needed in 14.3% (4/28). One patient required extracorporeal membrane oxygenation (3.5%, 1/28). Nevertheless, no significant difference was observed in the clinical findings and disease severity or outcome of children hospitalized with MIS-C over the 3 waves (Table 1).
TABLE 1.
Characteristics of Children Hospitalized With MIS-C During 3 Pandemic Waves
| Number of cases/Clinical characteristics | August 2020 to January 2021 (EU1-B.1.177) | February 2021 to July 2021 (Alpha-B.1.1.7) | July 2021 to December 2021 (Delta-B.1.617.2) | P |
|---|---|---|---|---|
| Number of SARS-CoV-2 infections* | 9506 | 41,803 | 156,953 | |
| Number of MIS-C cases | 32 | 47 | 40 | |
| Sex, male/female (ratio) | 14:18 (0.8) | 32:15 (2.1) | 30:10 (3) | † |
| Median age (Q1–Q3) | 7.3 (3.4–10.2) | 8.8 (3.8–12.9) | 8.2 (5.4–13.9) | † |
| Cardiac involvement (%) | 20 (62.5) | 32 (68.1) | 25 (62.5) | † |
| Myocarditis (%) | 9 (28.1) | 19 (40.4) | 16 (40.0) | † |
| Pericarditis (%) | 8 (25.0) | 10 (21.3) | 8 (20.0) | † |
| Aneurysms (%) | 3 (9.4) | 3 (6.4) | 1 (2.5) | † |
| Mucocutaneous manifestations (%) | 23 (71.9) | 29 (61.7) | 24 (6.90) | † |
| Gastrointestinal symptoms (%) | 25 (78.1) | 36 (76.6) | 33 (82.5) | † |
| Respiratory symptoms (%) | 9 (28.1) | 16 (34) | 13 (32.5) | † |
| Acute kidney injury (%) | 3 (9.4) | 7 (14.9) | 7 (17.5) | † |
| ICU admission (%) | 7 (21.9) | 14 (29.8) | 7 (17.5) | † |
| IVIG | 7 (21.9) | 14 (29.8) | 7 (17.5) | † |
| Steroids | 7 (21.9) | 14 (29.8) | 4 (10.0) | † |
| Anti-IL-1 | 4 (12.5) | 3 (6.4) | 4 (10.0) | † |
| Inotropes | 3 (9.4) | 7 (14.9) | 4 (10.0) | † |
| Mechanical ventilation | 1 (3.1) | 2 (4.3) | 1 (2.5) | † |
| Death (%) | 1 | 0 | 0 |
Confirmed cases in children and young people <18 years old available from NPHO.
P > 0.05.
ICU indicates intensive care unit; IL-1, interleukin-1; IVIG, intravenous immunoglobulin; NPHO, National Public Health Organization.
DISCUSSION
This nationwide study provides evidence that the incidence of MIS-C may vary according to the predominant variant. Recent research suggests that SARS-CoV-2 contains at least 1 unique superantigen (or superantigen-like) motif and a superantigenic host response has been implicated in patients with MIS-C.4,5 As new variants emerge, the substantial decline in the incidence of MIS-C suggests that mutations in key SARS-CoV-2 epitopes play a central role in triggering the hyper-inflammation and cytokine storm that characterize MIS-C.
In our study, no significant difference was observed in the demographics, clinical presentation and severity or outcome in patients with MIS-C over the 3 pandemic waves, most probably due to small sample. Although the proportions of males and patients with myocarditis were increasing, the findings were not statistically significant. Miller et al6 reported that median age and male predominance significantly increased, whereas several clinical manifestations and outcomes varied over time in CYP with MIS-C onset on or before July 31, 2021.
Our study has some limitations. Due to lack of individual SARS-CoV-2 sequencing data, the definition of the 3 study periods that reflect equal pandemic waves was based on publicly available data on the relative incidence of SARS-CoV-2 variants. Trying to ensure that most if not all MIS-C cases attributed to each variant would be correctly classified, the onset of each period was set 8 weeks apart from the peak of the previous pandemic wave. Although some patients might have not been infected by the predominant variant, our finding of decreasing incidence of MIS-C over 3 pandemic waves cannot be disputed. In addition, comparing different pandemic periods is challenging. The massive SARS-CoV-2 screening applied in schools probably led to the identification of more asymptomatic cases during the third period, although it cannot justify the observed 16-fold increase in pediatric infections. Increased transmissibility of the predominant Delta-B.1.617.2 variant and less restrictive measures, including schools’ reopening, have contributed to the increase of pediatric SARS-CoV-2 infections. In addition, the incidence of MIS-C was significantly lower during the second study period compared with the first, although no systematic SARS-CoV-2 testing was performed in children at that time.
Recent studies suggest that vaccination plays a protective role against MIS-C.7,8 Adolescents ≥12 years of age were eligible for vaccination during the third study period as the BNT162b2-mRNA COVID-19 vaccine was released on July 15, 2021, for this age group. By the end of December 2021, less than 40% of adolescents were fully vaccinated. Nevertheless, the proportion of adolescents among MIS-C cases was not significantly different before and after August 2021—16 of 79 (20.3%) versus 14 of 40 (35%), P = 0.08, respectively. For children 5–11 years old, the BNT162b2-mRNA COVID-19 vaccine was released on December 15, 2021. Up to now no MIS-C case on a fully vaccinated child has been documented in the country.
Finally, immunity following SARS-CoV-2 infection is unlikely to have influenced the incidence of MIS-C at least until Delta variant predominated. By the end of August 2021, pediatric SARS-CoV-2 infections accounted for 12% of total cases and seropositivity was low in both primary and secondary-school age children, 14.4% and 16.1%, respectively.9
Our findings suggest that the incidence of MIS-C may vary according to the predominant variant. This is despite the early hypothesis that highly transmissible emerging variants would contribute to increasing incidence of MIS-C following the higher number of SARS-CoV-2 infections.6 These data serve as a baseline for monitoring future trends associated with SARS-CoV-2 B.1.1.529 (Omicron) or upcoming variants. With MIS-C becoming even rarer and the majority of children being infected and reinfected by SARS-CoV-2, the diagnosis of MIS-C may get more challenging over time. As new variants evolve, MIS-C will still occur in genetically susceptible and immunologically naive CYP. Public health strategies may need to be reviewed and research should focus on accurate diagnostics and optimal management strategies for patients with MIS-C.
Footnotes
The authors have no funding or conflicts of interest to disclose.
I.E. conceptualized the study, designed the data collection instrument, carried out the initial analyses, drafted the initial article and reviewed and revised the article. S.L. designed the data collection instrument, collected data, conducted the initial analyses and reviewed and revised the article. K.C., P.V., K.S., F.F., I.A., D.D. and K.P.-L. collected and interpreted data and reviewed and revised the article. P.K., P.K., E.P.-A., L.F., E.V., D.G., E.F., V.P., E.G., I.N.G., G.A.S., V.S. and A.M. coordinated and supervised data collection, reviewed and revised the article. N.S. coordinated and supervised data collection and critically reviewed and revised the article for important intellectual content. D.M., E.R. and M.N.T. conceptualized and designed the study, coordinated and supervised data collection and critically reviewed the article for important intellectual content. All authors approved the final version of the article to be published.
The study was approved by the Ethics Committees of all participating hospitals.
The dataset analyzed during the current study is available from the corresponding author on reasonable request.
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REFERENCES
- 1.Ward JL, Harwood R, Smith C, et al. Risk factors for PICU admission and death among children and young people hospitalized with COVID-19 and PIMS-TS in England during the first pandemic year. Nat Med. 2022;28:193–200. [DOI] [PubMed] [Google Scholar]
- 2.Bukulmez H. Current understanding of multisystem inflammatory syndrome (MIS-C) following COVID-19 and its distinction from Kawasaki disease. Curr Rheumatol Rep. 2021;23:58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Schulert GS, Blum SA, Cron RQ. Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children. Curr Opin Pediatr. 2021;33:549–555. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Morita A, Hosaka S, Imagawa K, et al. Time course of peripheral immunophenotypes of multisystem inflammatory syndrome in children. Clin Immunol. 2022;236:108955. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Porritt RA, Binek A, Paschold L, et al. The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children. J Clin Invest. 2021;131:e151520. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Miller AD, Zambrano LD, Yousaf AR, et al. Multisystem inflammatory syndrome in children-United States, February 2020-July 2021. Clin Infect Dis. 2022;75:e1165–e1175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zambrano LD, Newhams MM, Olson SM, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA vaccination against multisystem inflammatory syndrome in children among persons aged 12-18 years - United States, July-December 2021. MMWR Morb Mortal Wkly Rep. 2022;71:52–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Levy M, Recher M, Hubert H, et al. Multisystem inflammatory syndrome in children by COVID-19 vaccination status of adolescents in France. JAMA. 2022;327:281–283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Filippatos F, Tatsi EB, Dellis C, et al. Seroepidemiology of SARS-CoV-2 in pediatric population during a 16-month period prior to vaccination. J Med Virol. 2022;94:2174–2180. [DOI] [PMC free article] [PubMed] [Google Scholar]