Risk and Phenotype of Multisystem Inflammatory Syndrome in Vaccinated and Unvaccinated Danish Children Before and During the Omicron Wave

Multisystem inflammatory syndrome in children (MIS-C) is a severe manifestation of SARS-CoV-2 in children and adolescents.¹ We aimed to estimate the risk of MIS-C after SARS-CoV-2 infection in vaccinated and unvaccinated individuals during the Omicron wave. Further, we aimed to compare the risk and clinical characteristics of MIS-C with the pre-Omicron waves.

This population-based cohort study prospectively included patients aged 0 to 17 years with MIS-C from all 18 Danish pediatric departments. Patients were diagnosed from January 1, 2022, to March 15, 2022, after SARS-CoV-2 infection between January 1 and February 1, 2022, when Omicron constituted more than 95% of variants. We followed the STROBE reporting guidelines for cohort studies. We used previously reported data to compare MIS-C during Omicron with the pre-Omicron waves.^1,2

We calculated the risk of MIS-C per 1 million estimated SARS-CoV-2 infections in children and adolescents. We estimated the number of infections by applying multipliers of 1.5 to 2.1 to laboratory-confirmed infections obtained from the Danish COVID-19 surveillance registries (Table 1). All 95% CIs were calculated using an exact method for binomial proportions. We compared risks of MIS-C in risk ratios (RRs) using Fisher exact test. Two-tailed Mann-Whitney U or χ² tests were used to compare patient characteristics. Permission to disclose patient data was obtained by oral and written parental consent or by a waiver of requirement.

We identified 1 vaccinated and 11 unvaccinated patients with MIS-C among 583 618 estimated infected children and adolescents, including 267 086 vaccinated individuals (Table 1). No MIS-C cases occurred among 31 516 estimated individuals with reinfections.

During the Omicron wave, the risk of MIS-C after SARS-CoV-2 infection was significantly lower among vaccinated vs unvaccinated individuals (RR, 0.11; 95% CI, 0.01-0.83; P = .007) (Table 1). The risk of MIS-C among unvaccinated individuals during the Omicron wave was significantly lower than during the Delta wave (RR, 0.12; 95% CI, 0.06-0.23; P < .001) and wild-type wave (RR, 0.14; 95% CI, 0.07-0.29; P < .001). The phenotype of MIS-C was similar in Omicron and pre-Omicron waves (Table 2).

We found the risk of MIS-C after SARS-CoV-2 infection during the Omicron wave substantially lower compared with previous SARS-CoV-2 variants. This could be explained by a reduced ability of Omicron to trigger hyperinflammation as it is phylogenetically different and associated with an increased immune escape.³ The lower risk could also partly be explained by a reduced risk after reinfection, although only 6% of our included infected individuals had confirmed reinfection, and such a reduced risk after reinfection has not yet been reported.

The risk of MIS-C during the Omicron wave was found to be significantly lower after breakthrough infection in vaccinated compared with unvaccinated children and adolescents. A high vaccine effectiveness against MIS-C has previously been found during the Delta wave, primarily explained by a high effectiveness against the Delta variant.^1,4,5 The present study suggests a direct vaccine effectiveness against MIS-C after breakthrough infection. This may be caused by vaccine-induced modulation of the immune system rendering it less prone to cause hyperinflammation after SARS-CoV-2 infection.

The main limitation of this study was the small population size resulting in few MIS-C cases, making our estimates vulnerable to fluctuations. The multipliers of 1.5 to 2.1 used to estimate the true number of infected individuals were encumbered with uncertainty and lower than those previously used for the US population⁶; our multipliers were low owing to thorough test capacity in Denmark with biweekly screening tests in schools. In this Danish population-based cohort study, we found a substantially decreased risk of MIS-C after infection with Omicron compared with pre-Omicron variants and a lower risk of MIS-C after breakthrough infections in vaccinated individuals.

Accepted for Publication: May 4, 2022.

Published Online: June 8, 2022. doi:10.1001/jamapediatrics.2022.2206

Correction: This article was corrected on August 1, 2022, to add reference citations and a multiplier to footnote a in Table 1.

Corresponding Author: Ulrikka Nygaard, MD, MPhil, PhD, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark (ulrikka.nygaard@regionh.dk).

Author Contributions: Dr Nygaard and Ms Espenhain had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Holm, Glenthoej, Schmidt, Brit Nordly, Hartling, Nygaard.

Acquisition, analysis, or interpretation of data: Holm, Espenhain, Glenthoej, Brit Nordly, Hartling, Nygaard.

Drafting of the manuscript: Holm, Espenhain, Glenthoej, Nygaard.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Holm, Espenhain, Nygaard.

Obtained funding: Nygaard.

Administrative, technical, or material support: Holm, Glenthoej, Schmidt, Nygaard.

Supervision: Brit Nordly, Hartling.

Conflict of Interest Disclosures: None reported.

Funding/Support: The study was supported by COVID-19 grant 0237-00004B from the National Ministry of Higher Education and Science and grant 0176-00020B from Innovation Fund Denmark.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.