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The changing epidemiology of PIMS-TS across COVID-19 waves: prospective national surveillance, January 2021 to July 2022, England

Published:October 19, 2022DOI:https://doi.org/10.1016/j.jinf.2022.10.017

      Author contributions

      JS wrote the original draft, developed the modelling methodology, produced the figures, and performed all data analysis. HW helped to develop the modelling methodology. SL conceptualized the study and reviewed and edited the draft. TW-K curated all PIMS-TS data. SK, NG, MA, AP, and GO reviewed and edited the draft.
      In April 2020, a rare but serious paediatric Multisystem Inflammatory Syndrome (PIMS-TS, also known as MIS-C) was identified, which was temporally and geographically associated with SARS-CoV-2. [
      • Flood J.
      • Shingleton J.
      • Bennett E.
      • Walker B.
      Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS): prospective, national surveillance, United Kingdom and Ireland.
      ] In England, we estimated a PIMS-TS risk of 0·045% (95% credible interval, 0·035–0·068%) after SARS-CoV-2 infection in <15 year-olds, with a lag of 2–6 weeks. [
      • Shingleton J.
      • Williams H.
      • Burton L.
      Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) during the SARS-CoV-2 Alpha and Delta variant waves: national observational study, 2020-21, England,”.
      ] These results were used to parameterise a model to predict new PIMS-TS cases based on estimated childhood SARS-CoV-2 infection. [
      • Shingleton J.
      • Williams H.
      • Burton L.
      Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) during the SARS-CoV-2 Alpha and Delta variant waves: national observational study, 2020-21, England,”.
      ] SARS-CoV-2 infection rates were derived using the PHE-Cambridge real-time model, which uses multiple data sources to estimate national incidence in addition to laboratory-confirmed cases, which likely significantly underestimates true infection rates. [
      • Shingleton J.
      • Williams H.
      • Burton L.
      Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) during the SARS-CoV-2 Alpha and Delta variant waves: national observational study, 2020-21, England,”.
      ] PIMS-TS cases during the first pandemic wave were derived from national surveillance, [
      • Flood J.
      • Shingleton J.
      • Bennett E.
      • Walker B.
      Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS): prospective, national surveillance, United Kingdom and Ireland.
      ] and, from November 2020, using a new emergency ICD-10 code (U07.5, Multisystem inflammatory syndrome associated with COVID-19)in Secondary Uses Services (SUS, NHS Digital, Leeds, UK), a national administrative database used by National Health Service hospitals to record all admissions, emergency department attendances and outpatient appointments in England. [
      • Shingleton J.
      • Williams H.
      • Burton L.
      Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) during the SARS-CoV-2 Alpha and Delta variant waves: national observational study, 2020-21, England,”.
      ] The outputs of this model were used to direct healthcare resources and inform policy during late 2020 and early 2021.
      After the alpha wave in England (November 2020 to April 2021), the model's performance was re-parameterised using data over a longer time-period. The re-parameterisation estimated a slightly lower PIMS-TS risk after SARS-CoV-2 infection of 0·038% (95%CI, 0·037–0·041%). During the subsequent delta wave, the model significantly over-predicted the risk of PIMS-TS by 53%, with 450 (436–472) estimated versus 212 observed cases during June-October 2021 (median risk, 0·026%; 95%CI, 0·025–0·029%). These results and the modelling methodology are reported elsewhere. [
      • Shingleton J.
      • Williams H.
      • Burton L.
      Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) during the SARS-CoV-2 Alpha and Delta variant waves: national observational study, 2020-21, England,”.
      ]
      The emergence of the highly transmissible omicron in late 2021, which was able to evade natural and vaccine-induced immunity [
      • Moshin M.
      • Mahmud S.
      Omicron SARS-CoV-2 variant of concern: a review on its transmissibility, immune evasion, reinfection, and severity.
      ], raised concerns about further increases in PIMS-TS cases. Early reports, however, indicated an even lower risk of PIMS-TS with the new variant. [
      • Cohen J.M.
      • J C.M.
      • Cheung R.C.
      Lower risk of Multisystem Inflamatory Syndrome in Children (MIS-C) with the Delta and Omicron variants of SARS-CoV-2.
      ]
      Using the same methodology, [
      • Shingleton J.
      • Williams H.
      • Burton L.
      Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) during the SARS-CoV-2 Alpha and Delta variant waves: national observational study, 2020-21, England,”.
      ] our model also identified further divergence between predicted and observed PIMS-TS with omicron compared to alpha. Between 15 December 2021, when omicron became dominant, and 01 August 2022, which encompassed infection waves due to omicron subvariants BA.1, BA.2, BA.4 and BA.5, [

      UK Health Security Agency, “SARS-CoV-2 variants of concern and variant under investigation in England,” UK Government, 2022.

      ] the model predicted 3165 (95%CI, 2855–3459) compared to 570 observed PIMS-TS cases, 82% (95%CI, 80–84%) lower (Fig. 1a). Notably, PIMS-TS cases declined rapidly after the BA.1 wave and have remained very low, despite large BA.2 waves from 15 February 2022 and BA.4/BA.5 waves since June 2022 (Fig. 1b). The model predicted 795 (717–867) compared to 446 observed cases (56% (51–62%) lower) during BA.1 (15 December 2021 to 14 February 2022), and 2352 (2122–2571) compared to 158 observed cases (93% (92- 94%) lower) during subsequent waves (15 February to 01 August 2022).
      Fig 1:
      Fig. 1(a) Forecasted PIMS-TS admissions based on a model fitted to the Alpha variant wave of COVID-19, alongside observed PIMS-TS admissions. (b) SARS-CoV-2 variant prevalence using available sequenced strains for England from 1 February 2021 as of 20 June 2022.
      [

      UK Health Security Agency, “SARS-CoV-2 variants of concern and variant under investigation in England,” UK Government, 2022.

      ]
      (c) Mean age of children with by week since December 2020. A Lowess filter with window size 1/3rd was fitted to identify the general trend in the data. Confidence intervals were produced by applying the filter 1000 times to a random subset of 50% of the data.
      Using a combination of surveillance data, modelled estimates between the first pandemic and alpha waves and SUS coding, we estimated 2105 PIMS-TS cases since the start of the pandemic until 01 August 2022. The model trained on the Alpha wave predicted 6034 (95% CI, 5841–6234) cases over the same period.
      Our findings add to the growing evidence of decreasing PIMS-TS risk with each SARS-CoV-2 wave. [
      • Cohen J.M.
      • J C.M.
      • Cheung R.C.
      Lower risk of Multisystem Inflamatory Syndrome in Children (MIS-C) with the Delta and Omicron variants of SARS-CoV-2.
      ,

      UK Health Security Agency, “SARS-CoV-2 variants of concern and variant under investigation in England,” UK Government, 2022.

      ,
      • Whittaker R.
      • Greve-Isdahl M.
      • Bøås H.
      COVID-19 Hospitalization Among Children <18 Years by Variant Wave in Norway.
      ] Reasons for this decoupling include critical mutations in the virus superantigen motifs speculated to trigger the hyperinflammatory response. [
      • Shingleton J.
      • Williams H.
      • Burton L.
      Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) during the SARS-CoV-2 Alpha and Delta variant waves: national observational study, 2020-21, England,”.
      ] Additionally, if, as is currently speculated, PIMS-TS is associated with an aberrant immune response to primary SARS-CoV-2 infection, then high immunity levels through infection and COVID-19 vaccination in children may be a significant contributing factor. By 24 July 2022, 10·6% of 5–11 and 58·3% of 12–15 year-olds had received ≥1 vaccine dose. [

      N.H.S. England, “COVID-19 Vaccination Statistics,” 24 7 2022. [Online]. Available: https://www.england.nhs.uk/statistics/wp-content/uploads/sites/2/2022/07/COVID-19-weekly-announced-vaccinations-28-July-2022.pdf. [Accessed 6 9 2022].

      ] COVID-19 vaccination is currently not recommended for <5 year-olds in England, but this age-group had very high infection rates during the BA.1 wave. [

      UK Health Security Agency, “Weekly national influenze and COVI-19 surveillance report: week 13,” UK Government, 2022.

      ] Over time, PIMS-TS epidemiology could follow the related Kawasaki disease, with most cases occurring in infants and toddlers, the only age group likely to remain susceptible to the virus in the future. Our analysis shows a declining trend in the age of children diagnosed with PIMS-TS since the start of the pandemic, albeit with large confidence intervals in recent months because of low case numbers (Fig. 1c). In conclusion, the very low risk of PIMS-TS despite large rates of SARS-CoV-2 infections due to the BA.2, BA.4 and BA.5 subvariants in children will be reassuring to parents, clinicians and policy makers. On-going surveillance, however, is critical, particularly in the event of newly emerging variants.

      References

        • Flood J.
        • Shingleton J.
        • Bennett E.
        • Walker B.
        Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS): prospective, national surveillance, United Kingdom and Ireland.
        Lancet Reg Health Eur. 2020; 3 (2021): 75-86
        • Shingleton J.
        • Williams H.
        • Burton L.
        Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) during the SARS-CoV-2 Alpha and Delta variant waves: national observational study, 2020-21, England,”.
        SSRN. 2022;
        • Moshin M.
        • Mahmud S.
        Omicron SARS-CoV-2 variant of concern: a review on its transmissibility, immune evasion, reinfection, and severity.
        Medicine (Baltimore). 2022; 101 (e29165)
        • Cohen J.M.
        • J C.M.
        • Cheung R.C.
        Lower risk of Multisystem Inflamatory Syndrome in Children (MIS-C) with the Delta and Omicron variants of SARS-CoV-2.
        Clin Infect Dis. 2022;
      1. UK Health Security Agency, “SARS-CoV-2 variants of concern and variant under investigation in England,” UK Government, 2022.

        • Whittaker R.
        • Greve-Isdahl M.
        • Bøås H.
        COVID-19 Hospitalization Among Children <18 Years by Variant Wave in Norway.
        Pediatrics. 2022; 150
      2. N.H.S. England, “COVID-19 Vaccination Statistics,” 24 7 2022. [Online]. Available: https://www.england.nhs.uk/statistics/wp-content/uploads/sites/2/2022/07/COVID-19-weekly-announced-vaccinations-28-July-2022.pdf. [Accessed 6 9 2022].

      3. UK Health Security Agency, “Weekly national influenze and COVI-19 surveillance report: week 13,” UK Government, 2022.