Abstract
This cohort study investigates the risk of multisystem inflammatory syndrome after SARS-CoV-2 infection in vaccinated and unvaccinated children before and during the Omicron wave in Denmark.
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.
Methods
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.
Table 1. The Risk of MIS-C Among Children and Adolescents in Denmark Infected With SARS-CoV-2 by Vaccination Status and SARS-CoV-2 Variant.
| Viral agent | Age, y | No. of MIS-C casesa | No. of PCR-confirmed SARS-CoV-2 infections | Estimated No. of SARS-CoV-2 infectionsa | Risk of MIS-C per 1 million estimated infected children and adolescents (95% CI) |
|---|---|---|---|---|---|
| Omicron | |||||
| Unvaccinated | Total | 11 | 187 894 | 315 532 | 34.9 (17.4-62.4) |
| 0-4 | 3 | 56 355 | 118 223 | 25.4 (5.2-74.2) | |
| 5-11 | 7 | 103 266 | 154 899 | 45.2 (18.2-93.1) | |
| 12-17 | 1 | 28 273 | 42 410 | 23.6 (0.6-131.4) | |
| Vaccinatedb | Total | 1 | 178 057 | 267 086 | 3.7 (0.1-20.9) |
| 0-4 | NA | NA | NA | NA | |
| 5-11 | 0 | 44 283 | 66 425 | NA | |
| 12-17 | 1 | 133 774 | 200 661 | 5.0 (0.1-27.8) | |
| Delta | |||||
| Unvaccinated | Total | 51 | 85 947 | 175 458 | 290.7 (216.4-382.2) |
| Vaccinatedb | 12-17 | 1 | 6570 | 9855 | 101.5 (2.6-565.2) |
| Wild type | |||||
| Unvaccinated | Total | 23 | 38 974 | 93 397 | 245.6 (155.7-368.5) |
Abbreviations: MIS-C, multisystem inflammatory syndrome in children; NA, not applicable; PCR, polymerase chain reaction.
Estimated SARS-CoV-2 infections were calculated from laboratory-confirmed SARS-CoV-2 infections using a multiplier to avoid underestimation of actual infected individuals as not all infected individuals are tested. During the Omicron wave, a multiplier of 1.5 (5-17 years) was applied based on seroprevalence in adult blood donors to PCR-confirmed SARS-CoV-2 infections in February 2022, and a multiplier of 2.1 (0-4 years) was applied assuming the cumulated SARS-CoV-2 incidence in the age group 0 to 4 years was similar to individuals aged 5 to 11 years during the Omicron wave. During the Delta wave, a multiplier of 1.5 (5-17 years) and 6.1 (0-4 years) was used.1 During the wild-type wave, a multiplier of 2.4 was used.2
Breakthrough infections were defined as SARS-CoV-2 infections occurring in vaccinated individuals at least 14 days after the second vaccine (SARS-CoV-2 test results and vaccination dates of each individual were obtained from the Danish COVID-19 surveillance database).
Results
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).
Table 2. Clinical Characteristics of MIS-C During the Omicron, Delta, and Wild-Type Waves of COVID-19.
| Phenotype of patients with MIS-C | No. (%)a | ||
|---|---|---|---|
| Omicron (n = 12) | Delta (n = 51)b | Wild type (n = 23)c | |
| Sex | |||
| Male | 9 (75) | 37 (73) | 14 (61) |
| Female | 3 (25) | 14 (27) | 9 (39) |
| Age, median (IQR), y | 8 (4-10) | 8 (7-11) | 8 (5-14) |
| Interval between SARS-CoV-2 infection and hospital admission, median (IQR), wk | 4.4 (2.3-5.3) | 5.4 (4.4–6.1) | 5.3 (3.4-6.0) |
| Clinical characteristicsc | |||
| Hypotension | 6 (50) | 26 (51) | 13 (57) |
| Cardiac involvement | 11 (92) | 46 (90) | 23 (100 |
| Gastrointestinal involvement | 12 (100) | 50 (98) | 23 (100 |
| Hematologic involvement | 7 (58) | 36 (71) | 21 (91) |
| Dermatologic involvement | 11 (92) | 44 (86) | 19 (83) |
| Neurologic involvement | 0d | 0d | 0d |
| Respiratory involvement | 0 | 6 (12) | 6 (26) |
| Kidney involvement | 2 (17) | 12 (24) | 7 (23) |
| Intensive care unit admission | 6 (50) | 28 (55) | 12 (52) |
| Length of hospital stay, median (IQR), d | 5.0 (3.0-5.0) | 5.0 (4.0-7.0) | 8.0 (6.0-9.0) |
Abbreviation: MIS-C, multisystem inflammatory syndrome in children.
Continuous variables are presented as median (IQR) and categorical variables as No. (%). Two-tailed Mann-Whitney U or χ2 tests were used to compare continuous and categorial variables.
MIS-C cases after infection with the Delta variant were included in the period August to December 2021.
MIS-C cases included in the period dominated by the wild-type variant March 2020 to February 2022.
Organ system involvement was defined according to the US Centers for Disease Control and Prevention, eg, neurological involvement if seizure, stroke, or aseptic meningitis. No patients had seizures or were investigated for stroke or aseptic meningitis, but headache was reported in 50%, 50%, and 46% of cases in the Omicron, Delta, and wild-type periods, respectively.
Discussion
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.
References
- 1.Nygaard U, Holm M, Hartling UB, et al. Incidence and clinical phenotype of multisystem inflammatory syndrome in children after infection with the SARS-CoV-2 delta variant by vaccination status: a Danish nationwide prospective cohort study. Lancet Child Adolesc Health. Published online May 5, 2022. doi: 10.1016/S2352-4642(22)00100-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Holm M, Hartling UB, Schmidt LS, et al. Multisystem inflammatory syndrome in children occurred in 1 of 4000 children with severe acute respiratory syndrome coronavirus 2. Acta Paediatr. 2021;110(9):2581-2583. doi: 10.1111/apa.15985 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Garcia-Beltran WF, St Denis KJ, Hoelzemer A, et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2022;185(3):457-466.e4. doi: 10.1016/j.cell.2021.12.033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.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(3):281-283. doi: 10.1001/jama.2021.23262 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Zambrano LD, Newhams MM, Olson SM, et al. ; Overcoming COVID-19 Investigators . Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA vaccination against multisystem inflammatory syndrome in children among persons aged 12 to 18 years—US, July-December 2021. MMWR Morb Mortal Wkly Rep. 2022;71(2):52-58. doi: 10.15585/mmwr.mm7102e1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Reese H, Iuliano AD, Patel NN, et al. Estimated incidence of coronavirus disease 2019 (COVID-19) illness and hospitalization—US, February-September 2020. Clin Infect Dis. 2021;72(12):e1010-e1017. doi: 10.1093/cid/ciaa1780 [DOI] [PMC free article] [PubMed] [Google Scholar]