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

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.

PMID: 35505833
PMCID: PMC9051933
DOI: 10.1016/j.lanepe.2022.100393

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

Naïm Ouldali et al. Lancet Reg Health Eur. 2022 Jun.

. 2022 Jun:17:100393.

doi: 10.1016/j.lanepe.2022.100393. Epub 2022 Apr 29.

Authors

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.

PMID: 35505833
PMCID: PMC9051933
DOI: 10.1016/j.lanepe.2022.100393

Erratum in

Correction to "Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study".
Ouldali N, Bagheri H, Salvo F, Antona D, Pariente A, Leblanc C, Tebacher M, Micallef J, Levy C, Cohen R, Javouhey E, Bader-Meunier B, Ovaert C, Renolleau S, Hentgen V, Kone-Paut I, Deschamps N, De Pontual L, Iriart X, Guen CG, Angoulvant F, Belot A; French Covid-19 Paediatric Inflammation Consortium; French Pharmacovigilance network. Ouldali N, et al. Lancet Reg Health Eur. 2022 Oct;21:100468. doi: 10.1016/j.lanepe.2022.100468. Epub 2022 Aug 10. Lancet Reg Health Eur. 2022. PMID: 35967266 Free PMC article.

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.

PubMed Disclaimer

Conflict of interest statement

Dr N. Ouldali reports travel grants from GSK, Pfizer, and Sanofi. Dr C. Levy reported receiving grants from Pfizer and personal fees from Pfizer and Merck. Pr R. Cohen reported receiving personal fees from GlaxoSmithKline, Pfizer, Sanofi, and Merck Sharp & Dohme. Dr V. Hentgen reports travel grants from Novartis and Sobi. Pr F. Angoulvant reports receiving personal fees from MSD, Astrazeneca, Sanofi and Pfizer. Pr A. Belot reports receiving personal fees from GlaxoSmithKline, Novartis, Sobi and Pfizer, and grants from Merck Serono and Boehringer Ingelheim. All other authors have no potential conflicts of interest to disclose.

References

1. Riphagen S., Gomez X., Gonzalez-Martinez C., Wilkinson N., Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020 doi: 10.1016/S0140-6736(20)31094-1. published online May 7. - DOI - PMC - PubMed
1. Dufort E.M., Koumans E.H., Chow E.J., et al. Multisystem Inflammatory syndrome in children in New York State. N Engl J Med. 2020;383:347–358. - PMC - PubMed
1. Whittaker E., Bamford A., Kenny J., et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324:259–269. - PMC - PubMed
1. Feldstein L.R., Rose E.B., Horwitz S.M., et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020;383:334–346. - PMC - PubMed
1. Belot A., Levy-Bruhl D., Covid F. 19 Pediatric inflammation consortium. Multisystem inflammatory syndrome in children in the United States. N Engl J Med. 2020;383:1793–1794. - PubMed

LinkOut - more resources

Full Text Sources
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous