Multisystemic inflammatory syndrome following COVID-19 mRNA vaccine in children: a national post-authorization pharmacovigilance study

  1. Naïm Ouldali
  2. Haleh Bagheri
  3. Francesco Salvo
  4. Denise Antona
  5. Antoine Pariente
  6. Claire Leblanc
  7. Martine Tebacher
  8. Joëlle Micallef
  9. Corinne Levy
  10. Robert Cohen
  11. Etienne Javouhey
  12. Brigitte Bader-Meunier
  13. Caroline Ovaert
  14. Sylvain Renolleau
  15. Veronique Hentgen
  16. Isabelle Kone-Paut
  17. Nina Deschamps
  18. Loïc De Pontual
  19. Xavier Iriart
  20. Christelle Gras-Le Guen
  21. François Angoulvant
  22. Alexandre Belot
  23. the “French Covid-19 Paediatric Inflammation Consortium”
  24. the “French Pharmacovigilance network”

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Abstract

Importance

Multisystem inflammatory syndrome in children (MIS-C) is the most severe life-threatening clinical entity associated with pediatric SARS-CoV-2 infection. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown.

Objective

To assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children.

Design, Setting, and Participants

Post-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12– 17-year-old children between June 15 th , 2021 and January 1 st , 2022, were reported. Each case was assessed for WHO MIS-C criteria. Causality assessment followed 2019 WHO recommendations.

Exposure

COVID-19 mRNA vaccine.

Main Outcome and Measures

The main outcome was the reporting rate of post-vaccine hyper-inflammatory syndrome per 1,000,000 COVID-19 mRNA vaccine doses in 12–17-year-old children. This reporting rate was compared to the MIS-C rate per 1,000,000 12–17-year-old children infected by SARS-CoV-2. Secondary outcomes included the comparison of clinical features between post-vaccine hyper-inflammatory syndrome and post SARS-CoV-2 MIS-C.

Results

From June 2021 to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12–17-year-old children. Among them, 9 presented a multisystemic hyper-inflammatory syndrome. All cases fulfilled MIS-C WHO criteria. Main clinical features included male predominance (8/9, 89%), cardiac involvement (8/9, 89%), digestive symptoms (7/9, 78%), coagulopathy (5/9, 54%), cytolytic hepatitis (4/9, 46%), and shock (3/9, 33%). 3/9 (33%) required intensive care unit transfer, and 2/9 (22%) hemodynamic support. All cases recovered. Only three cases had evidence of previous SARS-CoV-2 infection. The reporting rate was 1.1 (95%CI [0.5; 2.1]) per 1,000,000 doses injected. As a comparison, 113 MIS-C (95%CI [95; 135]) occurred per 1,000,000 12–17-year-old children infected by SARS-CoV-2. Clinical features (inflammatory parameters, cytopenia) slightly differed from post-SARS-CoV-2 MIS-C, along with short-term outcomes (less PICU transfer than MIS-C).

Conclusion and Relevance

Very few cases of hyper-inflammatory syndromes with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12–17-year-old children. The low reporting rate of this syndrome, compared to the rate of MIS-C among same age children infected by SARS-CoV-2, supports the benefit of SARS-CoV-2 vaccination in children. Further studies are required to explore specific pathways of this entity compared to post-SARS-CoV-2 MIS-C.

Key points

Question

Is COVID-19 mRNA vaccine in 12-17-year-old children associated with subsequent multisystemic hyper-inflammatory syndrome?

Findings

The French national pharmacovigilance system identified 9 children with a hyper-inflammatory syndrome with multi-organ involvement following COVID-19 mRNA vaccination (reporting rate 1.1 [0.5; 2.1] per 1,000,000 doses), of which only three had evidence of previous SARS-CoV-2 infection. All cases fulfilled WHO definition for MIS-C, but clinical and immunological features, along with short-term outcomes, slightly differed from classical post SARS-CoV-2 MIS-C.

Meaning

Very rare cases of hyper-inflammatory syndrome can occur following COVID-19 mRNA vaccine in 12-17-year-old children. The very low rate of this entity, compared to classical post-SARS-CoV-2 MIS-C, supports the benefit of SARS-CoV-2 vaccination in children.

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  1. ScreenIT

    SciScore for 10.1101/2022.01.17.22269263: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: For the MIS-C following SARS-CoV-2 infection surveillance system, the study was approved by the INSERM ethics committee for evaluation (IRB00003888).
    Consent: Oral consent was obtained from study participants; no family members or participants refused to participate.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Several limitations should be discussed. First the causality of COVID-19 mRNA vaccines assessment was mainly based on investigation for previous SARS-CoV-2 infection. However, pauci or asymptomatic infections are frequent in children, and may not have been documented. Furthermore, false negatives can be observed for anti-Nucleocapsid serology.41 Thus, we cannot exclude that some of the cases reported here could be related to undiagnosed SARS-CoV-2 infections. Second, because this entity has not been previously described in healthy populations, we could not have a control population to estimate the expected incidence of this disease in unvaccinated children, which would help in elucidating the vaccine causality.16 Third, we cannot rule out under reporting of adverse drug events in our population, which may have biased the estimated rate of hyper-inflammatory syndrome. However, following the implementation of COVID-19 mRNA vaccine, a major effort has been made by all pharmacovigilance centers to publicize that the reporting of any suspected adverse drug reaction following these vaccines was mandatory.26 The impressive number of suspected adverse drug reaction reports (>80,000 between January 2021 and January 2022 in France) suggest that underreporting may have been very rare, especially for serious adverse drug reactions.26 Fourth, given the very low proportion of 12-17-year-old children vaccinated by mRNA-1273 (<5%), we could not conduct subgroup analysis to compare the risk o...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2022.01.17.22269263v1 on medRxiv