Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study
Samuel Channon‐Wells, Ortensia Vito, Andrew McArdle, Eleanor G. Seaby, Harsita Patel, Priyen Shah, Ekaterina Pazukhina, Clare Wilson, Claire Broderick, Giselle D’Souza, Ilana Keren, Ruud Nijman, Adriana Tremoulet, Daniel Munblit, Rolando Ulloa‐Gutiérrez, Michael J. Carter, Padmanabhan Ramnarayan, Tisham De, Clive Hoggart, Elizabeth Whittaker, Jethro Herberg, Myrsini Kaforou, Aubrey J. Cunnington, Oleg Blyuss, Michael Levin, Mohamed Chouli, N Hamadouche, Mohamed Samir Ladj, Jorge Agrimbau Vázquez, Rodrigo Carmona, Adrián Collia, Alejandro Ellis, Diego Natta, Laura Pérez, Mayra Rubiños, Natalia Veliz, Silvana Yori, Philip N Britton, David Burgner, Emma Carey, Nigel W. Crawford, H Giuliano, Alissa McMinn, Shirley Wong, Nicholas Wood, Wolfgang Holter, Matthias Krainz, Raphael Ulreich, Christoph Zurl, Joke Dehoorne, Filomeen Haerynck, Levi Hoste, Petra Schelstraete, Kristof Vandekerckhove, Jef Willems, Camila Giuliana Almeida Farias, Flávia Jacqueline Almeida, Izabel Alves Leal, André Ricardo Araújo da Silva, Anna Esther Araújo e Silva, Sabrina T.A. Barreiro, Daniella Gregoria Bomfim Prado da Silva, Maria Célia Cervi, Mirian Viviane dos Santos Naja Cardoso, Cristiane Henriques Teixeira, Daniel Jarovsky, Juliènne Martins Araújo, Eitan Naaman Berezin, Marco Aurélio Palazzi Sáfadi, Rolando Andres Paternina-de la Ossa, Cristina Souza Vieira, Anna Dimitrova, Margarita Ganeva, Stefan Stefanov, Albena Telcharova-Mihaylovska, Catherine M. Biggs, Alison Lopez, Rosie Scuccimarri, Ryan Tan, Sam Wasserman, Davinia E. Withington, Camila Ampuero, Javiera Aravena, Raúl Bustos, Daniel Casanova, Pablo Cruces, Franco Díaz, Tamara García‐Salum, Loreto Godoy, Rafael Medina, Gonzalo Valenzuela Galaz, Germán Camacho-Moreno, María L. Ávila-Agüero, Helena Brenes-Chacón, Kattia Camacho-Badilla, Gabriela Ivankovich‐Escoto, Gabriela Naranjo-Zuñiga, Alejandra Soriano‐Fallas, Rolando Ulloa‐Gutiérrez, Adriana Yock‐Corrales
Abstract
Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health.