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

Naïm Ouldali; Haleh Bagheri; Francesco Salvo; Denise Antona; Antoine Pariente; Claire Leblanc; Martine Tebacher; Joëlle Micallef; Corinne Levy; Robert Cohen; Etienne Javouhey; Brigitte Bader-Meunier; Caroline Ovaert; Sylvain Renolleau; Veronique Hentgen; Isabelle Kone-Paut; Nina Deschamps; Loïc De Pontual; Xavier Iriart; Christelle Gras-Le Guen; François Angoulvant; Alexandre Belot; “French Covid-19 Paediatric Inflammation Consortium”£ and the “French Pharmacovigilance network”*

doi:10.1016/j.lanepe.2022.100393

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

Lancet Reg Health Eur. 2022 Jun:17:100393. doi: 10.1016/j.lanepe.2022.100393. Epub 2022 Apr 29.

Authors

Naïm Ouldali^{1

2

3

4}, Haleh Bagheri⁵, Francesco Salvo^{6

7}, Denise Antona⁸, Antoine Pariente⁹, Claire Leblanc¹, Martine Tebacher¹⁰, Joëlle Micallef^{11

12}, Corinne Levy^{3

13}, Robert Cohen^{3

13}, Etienne Javouhey^{14

15}, Brigitte Bader-Meunier^{16

17}, Caroline Ovaert^{18

19}, Sylvain Renolleau^{20

21}, Veronique Hentgen^{22

23}, Isabelle Kone-Paut^{23

24}, Nina Deschamps²⁵, Loïc De Pontual²⁶, Xavier Iriart^{27

28

29}, Christelle Gras-Le Guen^{30

31

32}, François Angoulvant^{1

33}, Alexandre Belot^{34

35

36}; “French Covid-19 Paediatric Inflammation Consortium”£ and the “French Pharmacovigilance network”*

Affiliations

¹ Assistance Publique-Hôpitaux de Paris, Department of general paediatrics, paediatric infectious disease and internal medicine, Robert Debré university hospital, Université de Paris, Paris, France.
² Infectious Diseases Division, CHU Sainte Justine - Montreal University, Montreal, Quebec, Canada.
³ ACTIV, Association Clinique et Thérapeutique Infantile du Val-de-Marne, Créteil, France.
⁴ Université de Paris, INSERM UMR 1123, ECEVE, Paris, France.
⁵ Department of Medical and Clinical Pharmacology, Regional Pharmacovigilance Center, CIC 1436, Toulouse University Hospital, France.
⁶ INSERM, BPH, U1219, Team Pharmacoepidemiology, Université de Bordeaux, 33000 Bordeaux, France.
⁷ Pole de Santé Publique, Service de Pharmacologie Médicale, Regional pharmacovigilance center of Bordeaux, CHU de Bordeaux, 33000 Bordeaux, France.
⁸ Santé Publique France, Agence nationale de Santé publique, Saint-Maurice, France.
⁹ Team Pharmacoepidemiology, U1219 BPH Research Center, Bordeaux University, INSERM, Bordeaux, France.
¹⁰ Regional pharmacovigilance center of Strasbourg, HUS, Strasbourg, France.
¹¹ Marseille University hospital, Clinical pharmacology department Regional Pharmacovigilance Center of Marseille, France.
¹² Aix-Marseille University, INSERM UMR 1106, Marseille, France.
¹³ Centre Hospitalier Intercommunal, Research Center, Université Paris Est, IMRB-GRC GEMINI, Créteil, France.
¹⁴ Hospices Civils de Lyon, Paediatric Intensive Care Unit, Hopital Femme, Mère Enfant, University of Lyon, Bron, France.
¹⁵ EA 7426 "Pathophysiology of Injury-Induced Immunosuppression", University Claude Bernard Lyon 1, Hospices Civils of Lyon, Lyon, France.
¹⁶ Department of Paediatric Hematology-Immunology and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France.
¹⁷ Laboratory of Immunogenetics of Paediatric Autoimmunity, Imagine Institute, Paris University, Inserm U 1163, Paris, France.
¹⁸ Department of Pediatric Cardiology, Hôpital Timone Enfant, AP-HM, Marseille, France.
¹⁹ Aix-Marseille University, MMG, INSERM, Marseille, France.
²⁰ Pediatric Intensive Care Unit, Necker Hospital, AP-HP, Paris University, Paris, France.
²¹ Paris University, Paris EA7323, France.
²² General Pediatrics department, Versailles Hospital, Paris, France.
²³ CEREMAIA (French reference center for auto-inflammatory diseases and inflammatory amyloidosis), Paris, France.
²⁴ Pediatric Rheumatology Department, Bicêtre Hospital, APHP, University of Paris Saclay, Kremlin Bicêtre, France.
²⁵ General Pediatrics department, Saint-Malo Hospital, Saint-Malo, France.
²⁶ General Pediatrics and Pediatric emergency department, Jean Verdier Hospital, Bondy, France.
²⁷ Department of Pediatric and Adult Congenital Cardiology, Bordeaux University Hospital, Pessac, France.
²⁸ Institut Hospitalo-Universitaire Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, Bordeaux, Pessac, France.
²⁹ INSERM, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.
³⁰ Department of Pediatric Emergency Care, Nantes University Hospital, Nantes F-44000, France.
³¹ Obstetrical, Perinatal and Pediatric Epidemiology Research team, Center of Research in Epidemiology and Statistics, Université de Paris, INSERM, Paris F-75004, France.
³² Inserm CIC 1413, Nantes University Hospital, Nantes F-44000, France.
³³ INSERM, Centre de Recherche des Cordeliers, UMRS 1138, Sorbonne Université, Université de Paris, Paris, France.
³⁴ Hospices Civils de Lyon, Paediatric Nephrology, Rheumatology, Dermatology, Hopital Femme, Mère Enfant and Centre International de Recherche en Infectiologie / INSERM U1111, Bron, France.
³⁵ National Reference Center for Rheumatic and AutoImmune and Systemic Diseases in Children (RAISE), Lyon, France.
³⁶ International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, 69007 Lyon, France.

Abstract

Background: Multisystem inflammatory syndrome in children (MIS-C) is the most severe clinical entity associated with pediatric SARS-CoV-2 infection with a putative role of the spike protein into the immune system activation. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. We aimed to assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children.

Methods: We conducted a 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. Cases were reviewed according to WHO criteria for MIS-C. The reporting rate of this syndrome was compared to the MIS-C rate per 1,000,000 12-17-year-old children infected by SARS-CoV-2.

Findings: Up to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12-17-year-old children. Among them, 12 presented a hyper-inflammatory syndrome with multisystemic involvement. Main clinical features included male predominance (10/12, 83%), cardiac involvement (10/12, 83%), digestive symptoms (10/12, 83%), coagulopathy (7/12, 58%), cytolytic hepatitis (6/12, 50%), and shock (5/12, 42%). 4/12 (33%) required intensive care unit transfer, and 3/12 (25%) hemodynamic support. All cases recovered. In eight cases, no evidence of previous SARS-CoV-2 infection was found. The reporting rate was 1.5 (95%CI [0.8; 2.6]) per 1,000,000 doses injected, i.e. 2.9 (95%CI [1.5; 5.1]) per 1,000,000 12-17-year-old vaccinated children. 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.

Interpretation: Very few cases of hyper-inflammatory syndrome 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 post-SARS-CoV-2 MIS-C in the same age-group, largely supports the vaccination in a context of an important circulation of SARS-CoV-2.

Funding: ESPID Fellowship Award; Grandir-Fonds de Solidarité Pour L'enfance.

Keywords: BNT162b2; COVID-19 mRNA vaccine; Hyper-inflammatory syndrome; Multisystem inflammatory syndrome in children; SARS-COV-2; child.