Evaluation of Autoantibody Binding to Cardiac Tissue in Multisystem Inflammatory Syndrome in Children and COVID-19 Vaccination–Induced Myocarditis
Authors: Patel Harsita , Sintou Amalia , Chowdhury Rasheda A. , Rothery Stephen , Iacob Alma Octavia , Prasad Sanjay , Rainer Peter P. , Martinón-Torres Federico , Sancho-Shimizu Vanessa , Shimizu Chisato , Dummer Kirsten , Tremoulet Adriana H. , Burns Jane C. , Sattler Susanne , Levin Michael ,   DIAMONDS consortium, Cunnington Aubrey , Herberg Jethro , Kaforou Myrsini , Wright Victoria J. , Bellos Evangelos , Broderick Claire , Channon-Wells Samuel , Cooray Samantha , De Tisham , D’Souza Giselle , Estramiana Elorrieta Leire , Estrada-Rivadeneyra Diego , Galassini Rachel , Habgood-Coote Dominic , Hamilton Shea , Jackson Heather , Kavanagh James , Keren Ilana , Moradi Marjaneh Mahdi , Menikou Stephanie , Nichols Samuel , Nijman Ruud , Pennisi Ivana , Powell Oliver , Reid Ruth , Shah Priyen , Vito Ortensia , Whittaker Elizabeth , Wilson Clare , Womersley Rebecca , Abdulla Amina , Darnell Sarah , Mustafa Sobia , Georgiou Pantelis , Manzano Jesus-Rodriguez , Moser Nicolas , Carter Michael , Tibby Shane , Cohen Jonathan , Davis Francesca , Kenny Julia , Wellman Paul , White Marie , Fish Matthew , Jennings Aislinn , Shankar-Hari Manu , Fidler Katy , Agranoff Dan , Richmond Vivien , Seal Mathhew , Faust Saul , Owen Dan , Ensom Ruth , McKay Sarah , Shaji Mariya , Schranz Rachel , Rughnani Prita , Anpananthar Amutha , Liebeschuetz Susan , Riddell Anna , Divakaran Divya , Han Louise , Khalid Nosheen , Malcolm Ivone Lancoma , Schofield Jessica , Simagan Teresa , Peters Mark , Bamford Alasdair , O’Neill Lauran , Pathan Nazima , Daubney Esther , White Deborah , Heightman Melissa , Eisen Sarah , Segal Terry , Wellings Lucy , B Drysdale Simon , Branch Nicole , Hamzah Lisa , Jarman Heather , Nyirenda Maggie , Capozzi Lisa , Gardiner Emma , Moots Robert , Nasher Magda , Hanson Anita , Linforth Michelle , O’Riordan Sean , Ellis Donna , Deep Akash , Caro Ivan , Shackley Fiona , Bellini Arianna , Gormley Stuart , Neshat Samira , Scholefield Barnaby , Robbins Ceri , Winmill Helen , Paulus Stéphane C , Pollard Andrew J , Anthony Mark , Hopton Sarah , Miller Danielle , Oliver Zoe , Beer Sally , Ward Bryony , Shrestha Shrijana , Gurung Meeru , Amatya Puja , Pokhrel Bhishma , Bijukchhe Sanjeev Man , Gautam Madhav Chandra , Kelly Sarah , O’Reilly Peter , Shrestha Sonu , Martinón-Torres Federico , Salas Antonio , González Fernando Álvez , Gómez Sonia Ares , Bello Xabier , García Mirian Ben , Viña Fernando Caamaño , Carnota Sandra , Curras-Tuala María José , Urbieta Ana Dacosta , Suárez Carlos Durán , Vidal Isabel Ferreiros , Vicente Luisa García , Gómez-Carballa Alberto , Rial Jose Gómez , Iglesias Pilar Leboráns , Mallah Narmeen , Martinón-Torres Nazareth , Martinón José María , Sánchez Belén Mosquera Pérez , Pardo-Seco Jacobo , Pischedda Sara , Vázquez Sara Rey , Calle Irene Rivero , Rodríguez-Tenreiro Carmen , Redondo-Collazo Lorenzo , Fernández Sonia Serén , Iglesias Marisol Vilas , Carrol Enitan D , Cocklin Elizabeth , Beckley Rebecca , Bracken Abbey , Evans Ceri , Khanijau Aakash , Lenihan Rebecca , Lewis-Burke Nadia , Newall Karen , Romaine Sam , Whitbread Jennifer , Tsolia Maria , Eleftheriou Irini , Spyridis Nikos , Tambouratzi Maria , Maritsi Despoina , Marmarinos Antonios , Xagorari Marietta , Panagiota Lourida , Aggelos Pefanis , Karolina Akinosoglou , Charalambos Gogos , Markos Maragos , Michalis Voulgarelis , Ioanna Stergiou , Emonts Marieke , Lim Emma , Isaacs John , Bell Kathryn , Crulley Stephen , Fabian Daniel , Thomson Evelyn , Wallia Diane , Miller Caroline , Bell Ashley , van der Velden Fabian J S , Shenton Geoff , Price Ashley , Treloar Owen , Thomas Daisy , Rojo Pablo , Epalza Cristina , Villaverde Serena , Márquez Sonia , Gijón Manuel , Machín Fátima , Cabello Laura , Hernández Irene , Gutiérrez Lourdes , Manzanares Ángela , Kuijpers Taco W , van de Kuip Martijn , van Furth Marceline , van den Berg Merlijn , Biesbroek Giske , Verkuil Floris , van der Zee Carlijn , Pajkrt Dasja , van Hensbroek Michael Boele , Schonenberg Dieneke , Gruppen Mariken , Nagelkerke Sietse , Jansen MachielH , Goetschalckx Ines , Romani Lorenza , De Luca Maia , Chiurchiù Sara , Tripiciano Costanza , Mercadante Stefania , Vermont Clementien L , Moll Henriëtte A , Borensztajn Dorine M , Hagedoorn Nienke N , Tan Chantal , Zachariasse Joany , Dik W , Shen Ching-Fen , Zavadska Dace , Laivacuma Sniedze , Rudzate Aleksandra , Stoldere Diana , Barzdina Arta , Barzdina Elza , Madelane Monta , Gravele Dagne , Svilz Dace , Basmaci Romain , Lachaume Noémie , Bories Pauline , Tkhayat RajaBen , Chériaux Laura , Davoust Juraté , Ong Kim-Thanh , Cotillon Marie , de Groc Thibault , Le Sébastien , Vergnault Nathalie , Sée Hélène , Cohen Laure , de Tugny Alice , Danekova Nevena , Mommert-Tripon Marine , Brengel-Pesce Karen , Pokorn Marko , Kolnik Mojca , Avčin Tadej , Avramoska Tanja , Bahovec Natalija , Bogovič Petra , Kitanovski Lidija , Nahtigal Mirijam , Papst Lea , Plankar Srovin Tina , Strle Franc , Vincek Katarina , van der Flier Michiel , Tissing Wim J E , Wösten-van Asperen Roelie M , Vastert Sebastiaan J , Vijlbrief Daniel C , Bont Louis J , Beudeker Coco R , Agyeman Philipp , Schlapbach Luregn , Aebi Christoph , Usman Mariama , Schlüchter Stefanie , Wyss Verena , Schöbi Nina , Zimmermann Elisa , Meier Marion , Weber Kathrin , Fink Colin , Voice Marie , Calvo-Bado Leo , Steele Michael , Holden Jennifer , Taylor Andrew , Calvez Ronan , Davies Catherine , Evans Benjamin , Stevens Jake , Matthews Peter , Billing Kyle , Zenz Werner , Binder Alexander , Kohlmaier Benno , Kohlfürst Daniela S , Schweintzger Nina A , Zurl Christoph , Hösele Susanne , Leitner Manuel , Pölz Lena , Rusu Alexandra , Rajic Glorija , Stoiser Bianca , Strempfl Martina , Sagmeister Manfred G , Bauchinger Sebastian , Benesch Martin , Ceolotto Astrid , Eber Ernst , Gallistl Siegfried , Haidl Harald , Hauer Almuthe , Hude Christa , Kapper Andreas , Keldorfer Markus , Löffler Sabine , Niedrist Tobias , Pilch Heidemarie , Pfleger Andreas , Pfurtscheller Klaus , Rödl Siegfried , Skrabl-Baumgartner Andrea , Strenger Volker , Wallner Elmar , Tauchert Maike K , Yeung Shunmay , Dewez Manuel , Bath David , Fitchett Elizabeth , Cresswell Fiona , Usuf Effua , Bojang Kalifa , Roca Anna , Sarr Isatou , Saidykhan Momodou , Ndure Ebrahim , von Both Ulrich , Kolberg Laura , Schmied Patricia , Mavridi Ioanna , Alba-Alejandre Irene , Haas Nikolaus , Maier Esther , Juranek Sabrina , Feuchtinger Tobias , Danhauser Katharina , Griese Matthias , Kappler Matthias , Lurz Eberhard , Schroepf Sebastian , Hoffmann Florian , Reiter Karl , Schoen Carola , Schlapbach Luregn J , Giannoni Eric , Stocker Martin , Posfay-Barbe Klara M , Heininger Ulrich , Bernhard-Stirnemann Sara , Niederer-Loher Anita , Kahlert Christian , Natalucci Giancarlo , Relly Christa , Berger Christoph , Riedel Thomas 
Published: May 2023

ImportanceCardiac dysfunction and myocarditis have emerged as serious complications of multisystem inflammatory syndrome in children (MIS-C) and vaccines against SARS-CoV-2. Understanding the role of autoantibodies in these conditions is essential for guiding MIS-C management and vaccination strategies in children.ObjectiveTo investigate the presence of anticardiac autoantibodies in MIS-C or COVID-19 vaccine-induced myocarditis.Design, Setting, and ParticipantsThis diagnostic study included children with acute MIS-C or acute vaccine myocarditis, adults with myocarditis or inflammatory cardiomyopathy, healthy children prior to the COVID-19 pandemic, and healthy COVID-19 vaccinated adults. Participants were recruited into research studies in the US, United Kingdom, and Austria starting January 2021. Immunoglobulin G (IgG), IgM, and IgA anticardiac autoantibodies were identified with immunofluorescence staining of left ventricular myocardial tissue from 2 human donors treated with sera from patients and controls. Secondary antibodies were fluorescein isothiocyanate–conjugated antihuman IgG, IgM, and IgA. Images were taken for detection of specific IgG, IgM, and IgA deposits and measurement of fluorescein isothiocyanate fluorescence intensity. Data were analyzed through March 10, 2023.Main Outcomes and MeasuresIgG, IgM and IgA antibody binding to cardiac tissue.ResultsBy cohort, there were a total of 10 children with MIS-C (median [IQR] age, 10 [13-14] years; 6 male), 10 with vaccine myocarditis (median age, 15 [14-16] years; 10 male), 8 adults with myocarditis or inflammatory cardiomyopathy (median age, 55 [46-63] years; 6 male), 10 healthy pediatric controls (median age, 8 [13-14] years; 5 male), and 10 healthy vaccinated adults (all older than 21 years, 5 male). No antibody binding above background was observed in human cardiac tissue treated with sera from pediatric patients with MIS-C or vaccine myocarditis. One of the 8 adult patients with myocarditis or cardiomyopathy had positive IgG staining with raised fluorescence intensity (median [IQR] intensity, 11 060 [10 223-11 858] AU). There were no significant differences in median fluorescence intensity in all other patient cohorts compared with controls for IgG (MIS-C, 6033 [5834-6756] AU; vaccine myocarditis, 6392 [5710-6836] AU; adult myocarditis or inflammatory cardiomyopathy, 5688 [5277-5990] AU; healthy pediatric controls, 6235 [5924-6708] AU; healthy vaccinated adults, 7000 [6423-7739] AU), IgM (MIS-C, 3354 [3110-4043] AU; vaccine myocarditis, 3843 [3288-4748] AU; healthy pediatric controls, 3436 [3313-4237] AU; healthy vaccinated adults, 3543 [2997-4607] AU) and IgA (MIS-C, 3559 [2788-4466] AU; vaccine myocarditis, 4389 [2393-4780] AU; healthy pediatric controls, 3436 [2425-4077] AU; healthy vaccinated adults, 4561 [3164-6309] AU).Conclusions and RelevanceThis etiological diagnostic study found no evidence of antibodies from MIS-C and COVID-19 vaccine myocarditis serum binding cardiac tissue, suggesting that the cardiac pathology in both conditions is unlikely to be driven by direct anticardiac antibody–mediated mechanisms.