¹Assistance Publique–Hôpitaux de Paris, Department of General Paediatrics, Paediatric Infectious Disease and Internal Medicine, Robert Debré University Hospital, Université de Paris, Paris, France
²ACTIV, Association Clinique et Thérapeutique Infantile du Val-de-Marne, Créteil, France
³Université de Paris, INSERM UMR 1123, ECEVE, Paris, France
⁴Assistance Publique–Hôpitaux de Paris, Department of General Paediatrics and Paediatric Infectious Diseases, Necker-Enfants-Malades University Hospital, Université de Paris, Paris, France
⁵Institut Pasteur, Biodiversity and Epidemiology of Bacterial Pathogens, Paris, France
⁶Santé Publique France, Agence Nationale de Santé Publique, Saint-Maurice, France
⁷Hospices Civils de Lyon, Paediatric Intensive Care Unit, Hopital Femme, Mère Enfant, University of Lyon, Bron, France
⁸EA 7426 Pathophysiology of Injury-Induced Immunosuppression, University Claude Bernard Lyon 1, Hospices Civils of Lyon, Lyon, France
⁹Centre Hospitalier Intercommunal, Paediatric Department, Université Paris Est, IMRB-GRC GEMINI, Créteil, France
¹⁰Assistance Publique–Hôpitaux de Paris, Department of General Paediatric, Armand Trousseau University Hospital, Sorbonne Université, Paris, France
¹¹Assistance Publique–Hôpitaux de Paris, Paediatric Intensive Care Unit, Armand Trousseau University Hospital, Sorbonne Université, Paris, France
¹²Assistance Publique–Hôpitaux de Paris, Department of Paediatric Rheumatology, Reference Centre for Autoinflammatory Diseases and Amyloidosis (CEREMAIA), Bicêtre University Hospital, Université de Paris Saclay, Le Kremlin-Bicêtre, France
¹³Assistance Publique–Hôpitaux de Paris, Paediatric Intensive Care Unit, Bicêtre University Hospital, Université de Paris Saclay, Le Kremlin-Bicêtre, France
¹⁴Children’s Hospital, University Hospital of Nancy, Paediatric Department, Université de Lorraine, Vandoeuvre les Nancy, France
¹⁵INSERM UMRS 1256 NGERE, Nutrition, Genetics, and Environmental Risk Exposure, National Center of Inborn Errors of Metabolism, Université de Lorraine, Vandoeuvre les Nancy, France
¹⁶Assistance Publique–Hôpitaux de Paris, Paediatric Emergency Departement, Louis Mourier University Hospital, Colombes, France
¹⁷Assistance Publique–Hôpitaux de Marseille, Paediatric and Congenital Cardiology, Timone Hospital Marseille, University Hospital, Marseille, France
¹⁸INSERM, Marseille Medical Genetics, UMR 1251, Aix Marseille Université, Marseille, France
¹⁹Hôpital Femme Enfant Adolescent, Department of Paediatrics and Paediatric Emergency, University Hospital, Nantes, France
²⁰Assistance Publique–Hôpitaux de Paris, Internal Medicine Department, Ambroise Paré University Hospital, Université Versailles-Saint Quentin-en-Yvelines, Boulogne-Billancourt, France
²¹Paediatric Department, Hôpital Delafontaine, Saint Denis, France
²²Hôpital des Enfants, Paediatric Nephrology Department, Purpan University Hospital, Toulouse, France
²³Paediatric Department, Hôpital de Valence, Valence, France
²⁴Strasbourg University Hospital, Paediatric Cardiology Department, Hautepierre University Hospital, Strasbourg, France
²⁵Paediatric Intensive Care Unit, Strasbourg University Hospital, Hautepierre University Hospital, Strasbourg, France
²⁶Assistance Publique–Hôpitaux de Paris, Paediatric Emergency Department, Necker-Enfants Malades University Hospital, Université de Paris, Paris, France
²⁷Assistance Publique–Hôpitaux de Paris, Paediatric Intensive Care Unit, Necker-Enfants Malades University Hospital, EA7323, Université de Paris, Paris, France
²⁸Assistance Publique–Hôpitaux de Paris, M3C Department, Necker-Enfants Malades University Hospital, Université de Paris, Paris, France
²⁹Assistance Publique–Hôpitaux de Paris, Cardiopaediatric Unit, Robert Debré University Hospital, Université de Paris, Paris, France
³⁰Centre for Research on Inflammation, UMR1149, INSERM, Paris, France
³¹Assistance Publique–Hôpitaux de Paris, Paediatric Intensive Care Unit, Robert Debré University Hospital, Université de Paris, Paris, France
³²Hôpital Nord Franche-Comté, Paediatric Department, Trévenans, France
³³Centre Hospitalier Intercommunal, Research Centre, Université Paris Est, IMRB-GRC GEMINI, Créteil, France
³⁴Hospices Civils de Lyon, Paediatric Nephrology, Rheumatology, Dermatology, Hopital Femme, Mère Enfant, Centre International de Recherche en Infectiologie/INSERM U1111, Bron, France
³⁵INSERM, Centre de Recherche des Cordeliers, UMRS 1138, Sorbonne Université, Université de Paris, Paris, France

French Covid-19 Paediatric Inflammation Consortiumfor the

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Original Investigation

Clinical Characteristics of Children With SARS-CoV-2–Associated Pediatric Inflammatory Multisystem Syndrome

Elizabeth Whittaker, MD; Alasdair Bamford, MD; Julia Kenny, MD; Myrsini Kaforou, PhD; Christine E. Jones, MD; Priyen Shah, MD; Padmanabhan Ramnarayan, MD; Alain Fraisse, MD; Owen Miller, MD; Patrick Davies, MD; Filip Kucera, MD; Joe Brierley, MD; Marilyn McDougall, MD; Michael Carter, MD; Adriana Tremoulet, MD; Chisato Shimizu, MD; Jethro Herberg, MD; Jane C. Burns, MD; Hermione Lyall, MD; Michael Levin, MD; for the PIMS-TS Study Group and EUCLIDS and PERFORM Consortia
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Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents

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Race/Ethnicity Among Children With COVID-19–Associated Multisystem Inflammatory Syndrome

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Mucocutaneous Manifestations of Multisystem Inflammatory Syndrome in Children

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Characteristics and Outcomes of US Children and Adolescents With MIS-C Compared With Severe Acute COVID-19

Leora R. Feldstein, PhD; Mark W. Tenforde, MD; Kevin G. Friedman, MD; Margaret Newhams, MPH; Erica Billig Rose, PhD; Heda Dapul, MD; Vijaya L. Soma, MD; Aline B. Maddux, MD; Peter M. Mourani, MD; Cindy Bowens, MD; Mia Maamari, MD; Mark W. Hall, MD; Becky J. Riggs, MD; John S. Giuliano Jr, MD; Aalok R. Singh, MD; Simon Li, MD; Michele Kong, MD; Jennifer E. Schuster, MD; Gwenn E. McLaughlin, MD; Stephanie P. Schwartz, MD; Tracie C. Walker, MD; Laura L. Loftis, MD; Charlotte V. Hobbs, MD; Natasha B. Halasa, MD; Sule Doymaz, MD; Christopher J. Babbitt, MD; Janet R. Hume, MD; Shira J. Gertz, MD; Katherine Irby, MD; Katharine N. Clouser, MD; Natalie Z. Cvijanovich, MD; Tamara T. Bradford, MD; Lincoln S. Smith, MD; Sabrina M. Heidemann, MD; Sheemon P. Zackai, MD; Kari Wellnitz, MD; Ryan A. Nofziger, MD; Steven M. Horwitz, MD; Ryan W. Carroll, MD; Courtney M. Rowan, MD; Keiko M. Tarquinio, MD; Elizabeth H. Mack, MD; Julie C. Fitzgerald, MD; Bria M. Coates, MD; Ashley M. Jackson, MPH; Cameron C. Young; Mary Beth F. Son, MD; Manish M. Patel, MD; Jane W. Newburger, MD; Adrienne G. Randolph, MD; Overcoming COVID-19 Investigators
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Otolaryngologic Manifestations in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With COVID-19

Ryan C. T. Cheong, BSc(Hons), MBBS; Christopher Jephson, MBBS; Claire Frauenfelder, MBBS, MSurg; Lesley Cavalli, BSc(Hons), MSc, MRCSLT; Karyn Moshal, MBChB, DTM&H; Colin R. Butler, PhD, MBBS; Michelle E. Wyatt, MA(Cantab), MBBS(Cantab)
Correction

Addition of Nonauthor Collaborator Names of the French Covid-19 Paediatric Inflammation Consortium
Research Letter

Multisystem Inflammatory Syndrome in Children by COVID-19 Vaccination Status of Adolescents in France

Michael Levy, MD, PhD; Morgan Recher, MD, PhD; Hervé Hubert, MD, PhD; Etienne Javouhey, MD, PhD; Olivier Fléchelles, MD, PhD; Stéphane Leteurtre, MD, PhD; François Angoulvant, MD, PhD

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Key Points

Question Is there an association between treatment with intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone and course of fever in multisystem inflammatory syndrome in children (MIS-C) associated with severe acute respiratory syndrome coronavirus 2?

Findings This retrospective cohort study included 111 children with MIS-C. After propensity score matching, the rate of treatment failure (defined by the persistence of fever 2 days after the introduction of first-line therapy or recrudescence of fever within 7 days) for those who received IVIG plus methylprednisolone vs IVIGs alone was 9% vs 51%, a difference that was statistically significant.

Meaning Combined treatment with methylprednisolone vs IVIG alone was associated with a better course of fever in MIS-C.

Abstract

Importance Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown.

Objective To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C.

Design, Setting, and Participants Retrospective cohort study drawn from a national surveillance system with propensity score–matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021.

Exposures IVIG and methylprednisolone vs IVIG alone.

Main Outcomes and Measures The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1.

Results Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, −0.28 [95% CI, −0.48 to −0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, −0.22 [95% CI, −0.40 to −0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, −0.17 [95% CI, −0.34 to −0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, −0.18 [95% CI, −0.35 to −0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, −2.4 [95% CI, −4.0 to −0.7]).

Conclusions and Relevance Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.

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Article Information

Corresponding Author: François Angoulvant, MD, PhD, Paediatric Emergency Department, Necker-Enfants Malades University Hospital, 149 Rue de Sèvre, 75015 Paris, France (francois.angoulvant@aphp.fr).

Accepted for Publication: January 19, 2021.

Published Online: February 1, 2021. doi:10.1001/jama.2021.0694

Correction: This article was corrected on July 6, 2021, to add the list of nonauthor collaborators as a supplement.

Author Contributions: Drs Ouldali and Angoulvant had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ouldali, Lachaume, M. Levy, C. Levy, Angoulvant.

Acquisition, analysis, or interpretation of data: Ouldali, Toubiana, Antona, Javouhey, Madhi, Lorrot, Léger, Galeotti, Claude, Wiedemann, Ovaert, Dumortier, Kahn, Mandelcwajg, Percheron, Biot, Bordet, Girardin, Yang, Grimaud, Oualha, Allali, Bajolle, Beyler, Meinzer, M. Levy, Paulet, C. Levy, Cohen, Belot, Angoulvant.

Drafting of the manuscript: Ouldali, Mandelcwajg, Yang, Angoulvant.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ouldali, Bordet, Angoulvant.

Obtained funding: C. Levy, Belot.

Administrative, technical, or material support: Toubiana, Antona, Javouhey, Lachaume, Dumortier, Mandelcwajg, Girardin, Allali, Meinzer, Paulet, C. Levy, Belot, Angoulvant.

Supervision: Ouldali, Madhi, Mandelcwajg, Girardin, Bajolle, Beyler, C. Levy, Cohen, Belot, Angoulvant.

Conflict of Interest Disclosures: Dr Javouhey reported receiving grants from CSL Behring. Dr C. Levy reported receiving grants from GlaxoSmithKline, Merck Sharp & Dohme, and Sanofi and personal fees from Pfizer and Merck. Dr Cohen reported receiving personal fees from GlaxoSmithKline, Pfizer, Sanofi, and Merck Sharp & Dohme. No other disclosures were reported.

Funding/Support: This study received an unrestricted grant from Pfizer; the French Covid-19 Paediatric Inflammation Consortium received an unrestricted grant from the Square Foundation (Grandir–Fonds de Solidarité Pour L’enfance).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: A list of members in the French Covid-19 Pediatric Inflammation Consortium is in Supplement 2.

Additional Contributions: We are grateful to Santé Publique France, Société Française de Pédiatrie, Groupe de Paediatrie Generale, Groupe de Pathologie Infectieuse Pédiatrique, Groupe Francophone de Réanimation et d’Urgences Pédiatriques, Société Française de Cardiologie, Filiale de Cardiologie Pédiatrique et Congénitale, Société Francophone Dédiée à L’étude des Maladies Inflammatoires Pédiatriques, and Filière de Santé des Maladies Auto-immunes et Auto-inflammatoires Rares for their participation in the French Covid-19 Paediatric Inflammation Consortium study. We thank Isabelle Ramay, BSc, Claire Prieur, BSc, Marine Borg, Aurore Prieur, BSc, Laura Meyet, LLM, Jéremy Levy, BSc, Stéphane Bechet, MSc, and Sofia Abbou, LLM, from ACTIV (Association Clinique et Thérapeutique Infantile du Val-de-Marne), Créteil, France; Cecile Hoffart, MSc, and Maxime Brussieux, BSc, from Clinical Research Centre, Centre Hospitalier Intercommunal de Créteil, Créteil, France; Daniel Levy-Bruhl, MD, Mireille Allemand, Scarlett Georges, BSc, Valerie Olie, PhD, Nolween Regnault, PhD, and Jerome Naud, PharmD, from Santé Publique France, Agence Nationale de Santé Publique, Saint-Maurice; Murielle Herasse, PhD, from Filière de Santé Des Maladies Auto-immunes et Auto-inflammatoires Rares (FAI2R), Lyon, France; and David Skurnik, PhD, from INSERM U1151-Equipe 11. We are grateful to every microbiological laboratory staff member who performed severe acute respiratory syndrome coronavirus 2 reverse transcriptase–polymerase chain reaction and antibody testing in each center. None of the persons listed here received compensation for their role in the study.

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Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children

Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents

Clinical Characteristics of Children With SARS-CoV-2–Associated Pediatric Inflammatory Multisystem Syndrome

Race/Ethnicity Among Children With COVID-19–Associated Multisystem Inflammatory Syndrome

Mucocutaneous Manifestations of Multisystem Inflammatory Syndrome in Children

Otolaryngologic Manifestations in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With COVID-19

Characteristics and Outcomes of US Children and Adolescents With MIS-C Compared With Severe Acute COVID-19

Addition of Nonauthor Collaborator Names of the French Covid-19 Paediatric Inflammation Consortium

Multisystem Inflammatory Syndrome in Children by COVID-19 Vaccination Status of Adolescents in France

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