Lower risk of multi-system inflammatory syndrome in children (MIS-C) with the omicron variant

Multi-system inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2 (PIMS-TS), is an infrequent but severe post-infectious complication of COVID-19.1Dionne A Son MB Randolph AG. An update on multisystem inflammatory syndrome in children related to SARS-CoV-2.Pediatr Infect Dis J. 2022; 41: e6Crossref PubMed Scopus (13) Google Scholar The Paediatric Active Enhanced Disease Surveillance (PAEDS) network (www.paeds.org.au)2Dinsmore N McRae JE Quinn HE et al.Paediatric active enhanced disease surveillance (PAEDS) 2019: prospective hospital-based surveillance for serious paediatric conditions.Commun Dis Intell (2018). 2021; 45 (Epub 30/9/2021)https://doi.org/10.33321/cdi.2021.45.53Crossref PubMed Scopus (1) Google Scholar initiated sentinel surveillance for MIS-C in May 2020. PAEDS used a case definition for MIS-C modified from the WHO definition (supplementary methods). PAEDS concurrently undertook surveillance for hospitalized COVID-19 and Kawasaki disease.3Wurzel D McMinn A Hoq M et al.Prospective characterisation of SARS-CoV-2 infections among children presenting to tertiary paediatric hospitals across Australia in 2020: a national cohort study.BMJ Open. 2021; 11e054510Crossref PubMed Scopus (6) Google Scholar SARS-CoV-2 infections were classified as occurring during three periods according to the dominant SARS-CoV-2 variant circulating3Wurzel D McMinn A Hoq M et al.Prospective characterisation of SARS-CoV-2 infections among children presenting to tertiary paediatric hospitals across Australia in 2020: a national cohort study.BMJ Open. 2021; 11e054510Crossref PubMed Scopus (6) Google Scholar, 4COVID-19 National Incident Room Surveillance Team. COVID-19 Australia: Epidemiology Report updated 22 Feb 2022, Technical supplement [accessed 9 June 2022; cited 10 June 2022]. Available from: Department of Health | Coronavirus disease 2019 (COVID-19) epidemiology reports, Australia, 2020–2022Google Scholar: Pre-Delta/ancestral strains from March 2020 to May 2021, Delta variant of concern (VoC; B.1.617.2) from June to November 2021 and Omicron (B.1.1.529) variants December 2021 to April 2022. The variant at the time of SARS-CoV-2 infection for each MIS-C case was presumed to be the dominant variant circulating 28 days before symptom onset, assuming an average 4-week lag between infection and MIS-C onset.1Dionne A Son MB Randolph AG. An update on multisystem inflammatory syndrome in children related to SARS-CoV-2.Pediatr Infect Dis J. 2022; 41: e6Crossref PubMed Scopus (13) Google Scholar,2Dinsmore N McRae JE Quinn HE et al.Paediatric active enhanced disease surveillance (PAEDS) 2019: prospective hospital-based surveillance for serious paediatric conditions.Commun Dis Intell (2018). 2021; 45 (Epub 30/9/2021)https://doi.org/10.33321/cdi.2021.45.53Crossref PubMed Scopus (1) Google Scholar A SARS-CoV-2 infection-related incidence rate of MIS-C was calculated in those states with publicly available infection notification data in persons aged 0-<19 years. PAEDS identified 107 cases of MIS-C from 1 May 2020 to 30 April 2022. Of these, 5 (5%) were associated with the pre-Delta period, 30 (28%) with the Delta VoC wave and 72 (67%) with Omicron waves. MIS-C was most frequent in children aged 5-<12years (n = 61, 57%). ICU admission was required in 23 cases (22%); there were no deaths. MIS-C cases peaked 4–8 weeks after peaks in COVID-19 admitted cases in children (Supplementary Figure). During the pre-Delta period, the MIS-C rate was 13 cases per 10,000 (95% confidence interval [CI]: 4–29) SARS-CoV-2 notified infections in those aged 0–19 years (Table 1). This rate reduced to 5 per 10,000 (95% CI: 4–7) during the Delta period and decreased further to 0.8 per 10,000 (95% CI: 0–1) during the Omicron period.Table 1Infection-related incidence of MIS-C among children aged 0-<19 infected with SARS-CoV-2 by dominant variant and jurisdictional notification rates.Pre-DeltaDeltaOmicronJurisdictionMIS-C cases (n)COVID-19 cases (N)Incidence rate per 10,000 notifications (95% CI)aNotifications used as denominator data; in NSW these are aged are 0 to <19 years, PCR and rapid antigen (RAT) tests); in Victoria are 0 to and including 19 years, PCR tests only; and in QLD are 0 to and including 19 years, PCR and RAT tests.,bConfidence intervals are 95% Clopper-Pearson; COVID-19 cases notified from 1 March 2020 to 1 March 2022, PIMS-TS cases from 1 May 2020 to 30st April 2022.MIS-C casesaNotifications used as denominator data; in NSW these are aged are 0 to <19 years, PCR and rapid antigen (RAT) tests); in Victoria are 0 to and including 19 years, PCR tests only; and in QLD are 0 to and including 19 years, PCR and RAT tests. (n)COVID-19 cases (N)Incidence rate per 10,000 notifications (95% CI) aNotifications used as denominator data; in NSW these are aged are 0 to <19 years, PCR and rapid antigen (RAT) tests); in Victoria are 0 to and including 19 years, PCR tests only; and in QLD are 0 to and including 19 years, PCR and RAT tests.,bConfidence intervals are 95% Clopper-Pearson; COVID-19 cases notified from 1 March 2020 to 1 March 2022, PIMS-TS cases from 1 May 2020 to 30st April 2022.MIS-C cases (n)COVID-19 cases (N)Incidence rate per 10,000 notifications (95% CI) aNotifications used as denominator data; in NSW these are aged are 0 to <19 years, PCR and rapid antigen (RAT) tests); in Victoria are 0 to and including 19 years, PCR tests only; and in QLD are 0 to and including 19 years, PCR and RAT tests.,bConfidence intervals are 95% Clopper-Pearson; COVID-19 cases notified from 1 March 2020 to 1 March 2022, PIMS-TS cases from 1 May 2020 to 30st April 2022.NSW256036 (4–128)1025,0724 (2–7)27471,6710.6 (0–1)Victoria333069 (2–26)2033,5626 (4–9)28142,8922 (1–3)QLD01080016805112,1750.4 (0–1)Overall5397413 (4–29)3058,8025 (4–7)60726,7380.8 (0–1)a Notifications used as denominator data; in NSW these are aged are 0 to <19 years, PCR and rapid antigen (RAT) tests); in Victoria are 0 to and including 19 years, PCR tests only; and in QLD are 0 to and including 19 years, PCR and RAT tests.b Confidence intervals are 95% Clopper-Pearson; COVID-19 cases notified from 1 March 2020 to 1 March 2022, PIMS-TS cases from 1 May 2020 to 30st April 2022. Open table in a new tab We provide evidence for a reduction in the infection-related frequency of MIS-C in children across the COVID-19 pandemic in Australia, particularly associated with Omicron variants. These data support a similar finding in the United Kingdom, Israel and Denmark where significantly lower rates of MIS-C relative to SARS-CoV-2 infections have occurred in association with Omicron VoC.5Cohen JM Carter MJ Cheung CR Ladhani S Evelina PIMS-TS Study GroupLower risk of multisystem inflammatory syndrome in children (MIS-C) with the delta and omicron variants of SARS-CoV-2.Clin Infect Dis. 2022; https://doi.org/10.1093/cid/ciac553Crossref Google Scholar, 6Levy N Koppel JH Kaplan O et al.Severity and incidence of multisystem inflammatory syndrome in children during 3 SARS-CoV-2 pandemic waves in Israel.JAMA. 2022; 327: 2452-2454https://doi.org/10.1001/jama.2022.8025Crossref PubMed Scopus (14) Google Scholar, 7Holm M Espenhain L Glenthøj J et al.Risk and phenotype of multisystem inflammatory syndrome in vaccinated and unvaccinated Danish children before and during the omicron wave.JAMA Pediatr. 2022; 176: 821-823https://doi.org/10.1001/jamapediatrics.2022.2206Crossref PubMed Scopus (9) Google Scholar Prior infection-related immunity to SARS-CoV-2 is unlikely to have contributed substantially to the observed reduction in MIS-C rates. Our PAEDS serosurvey showed a very low population rate of infection in Australian children prior to the Delta wave,8Koirala A Gidding HF Vette K Macartney K Serosurvey Group PAEDS The seroprevalence of SARS-CoV-2-specific antibodies in children, Australia, November 2020 - March 2021.Med J Aust. 2022; (Online ahead of print)https://doi.org/10.5694/mja2.51542Crossref Scopus (4) Google Scholar and total Delta wave notifications occurred in only 2% of the child population. The Australian COVID vaccination program for 5–11 year olds began on 10 January 2022; only 36.7% of children in this age group had received two doses by 30th April and children aged <5 years were ineligible.9Australian Government Department of Health. COVID-19 vaccination daily rollout update Available from: https://www.health.gov.au/resources/publications/covid-19-vaccine-rollout-update-30-april-2022. Accessed 9 June 2022; [Cited 10 June 2022].Google Scholar A minority of MIS-C cases (n=20; 19%) were aged >12 years who had an earlier access to vaccination from Quarter 3, 2021. It is therefore also unlikely that vaccination has contributed substantially to the observed change in MIS-C rate during the Omicron waves as most cases occurred prior to high vaccine coverage in this age group. We did not observe any age-specific reduction in PIMS-TS case counts associated with the Omicron variant (Supplementary Table). Our findings support a contention that changes in viral antigens likely contributed to reduction in MIS-C incidence. Potential alteration in super-antigen-like features of the Spike protein is one possibility that requires further investigation.5Cohen JM Carter MJ Cheung CR Ladhani S Evelina PIMS-TS Study GroupLower risk of multisystem inflammatory syndrome in children (MIS-C) with the delta and omicron variants of SARS-CoV-2.Clin Infect Dis. 2022; https://doi.org/10.1093/cid/ciac553Crossref Google Scholar,10Cheng MH Zhang S Porritt RA et al.Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation.Proc Natl Acad Sci. 2020; 117: 25254-25262Crossref PubMed Scopus (126) Google Scholar Our analysis has some limitations. Few cases had individual SARS CoV-2 genomic analysis, but the dominance of the Omicron VoC was evident in early December 2021. Further, PAEDS undertakes sentinel site surveillance. Although our network of hospitals includes >80% of tertiary pediatric beds in Australia, incomplete case ascertainment may impact the numerator in our analysis. We expect a majority of cases would have either presented or been referred to tertiary centres given MIS-C severity, frequent diagnostic uncertainty and need for acute paediatric cardiology assessment. Supporting this, through our wider clinical networks we are aware of only a relatively small number of MIS-C cases that presented outside our hospitals (PAEDS investigators, personal correspondence). Additionally, whilst Australia has had a high population level of SARS-COV-2 infection ascertainment, accuracy of infection notification rates reduced from late 2021. This was due to transiently reduced access to PCR and rapid antigen testing (RAT), changing guidelines regarding testing and voluntary or non-reporting of RAT results depending on jurisdiction, as well as reduced sensitivity of RAT. However, we suggest that increased under-reporting of infections in notification data over time would bias to over-estimation of MIS-C rates in 2022 relative to 2020-21, contrasting with the observed reduction in MIS-C rates. A/Prof Britton and A/Prof Wood conceptualized and designed the study, were PAEDS principle investigators and attended a majority of review panel meetings, drafted the initial manuscript, and reviewed and revised the manuscript. Dr Lopez and Dr Glover conceptualized and designed the study, performed the analysis, drafted the initial manuscript, and reviewed and revised the manuscript. Prof Burgner, Dr Carr, A/Prof Clark, Dr Boast, Dr Vasilunas, Dr McMullan, A/Prof Francis, A/Prof Bowen, A/Prof Blyth, Prof Macartney, A/Prof Crawford were PAEDS principle investigators, attended a majority of review panel meetings and reviewed and revised the manuscript. Ms Carey coordinated and supervised data collection and acted as secretariat for the review panel meetings. All authors critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Dr David Burgner reports an Investigator grant from the National Health and Medical Research Council and voluntary position at the Kawasaki Disease Foundation, Australia. Dr Asha C. Bowen reports an Investigator grant from the National Health and Medical Research Council and is Vice President of the World Society of Pediatric Infectious Diseases. The rest of the authors have no conflicts of interest relevant to this article to disclose. PAEDS network in addition to authors: Prof. Jim Buttery, Prof. Helen Marshall, Prof. Elizabeth Elliott, Prof. Peter Richmond, Dr. Ushma Wadia, Alissa McMinn, Karen Bellamy, Guillian Hunter, Kathryn Meredith, Laura Rost, Nicole Kerly, Sonia Dougherty, Sara Cook, Natasha Doran, Laura Francis, Christine Heath and Carolyn Finucane. Australian Vasculitis Working Group in addition to authors: A/Prof. Davinder Singh-Grewal, Dr Ryan Lucas, and Prof. Lesley Voss. The authors would also like to thank the infectious diseases, rheumatology and immunology fellows and consultants who presented cases to the case review panel, as well as other clinicians who provided medical and nursing care to these children and their families. The Paediatric Active Enhanced Disease Surveillance (PAEDS) network is funded by the Australian Government Department of Health.