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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?
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.
Combined treatment with methylprednisolone vs IVIG alone was associated with a better course of fever in MIS-C.
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.
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.
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.
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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Corresponding Author: François Angoulvant, MD, PhD, Paediatric Emergency Department, Necker-Enfants Malades University Hospital, 149 Rue de Sèvre, 75015 Paris, France (email@example.com).
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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