The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies
Authors: Manry Jeremy , Bastard Paul , Gervais Adrian , Voyer Tom Le , Rosain Jérémie , Philippot Quentin , Michailidis Eleftherios , Hoffmann Hans-Heinrich , Eto Shohei , Garcia-Prat Marina , Bizien Lucy , Parra-Martínez Alba , Yang Rui , Haljasmägi Liis , Migaud Mélanie , Särekannu Karita , Maslovskaja Julia , de Prost Nicolas , Tandjaoui-Lambiotte Yacine , Luyt Charles-Edouard , Amador-Borrero Blanca , Gaudet Alexandre , Poissy Julien , Morel Pascal , Richard Pascale , Cognasse Fabrice , Troya Jesus , Trouillet-Assant Sophie , Belot Alexandre , Saker Kahina , Garçon Pierre , Rivière Jacques G. , Lagier Jean-Christophe , Gentile Stéphanie , Rosen Lindsey , Shaw Elana , Morio Tomohiro , Tanaka Junko , Dalmau David , Tharaux Pierre-Louis , Sene Damien , Stepanian Alain , Mégarbane Bruno , Triantafyllia Vasiliki , Fekkar Arnaud , Heath James , Franco Jose , Anaya Juan-Manuel , Solé-Violán Jordi , Imberti Luisa , Biondi Andrea , Bonfanti Paolo , Castagnoli Riccardo , Delmonte Ottavia , Zhang Yu , Snow Andrew , Holland Steve , Biggs Catherine , Moncada-Vélez Marcela , Arias Andrés , Lorenzo Lazaro , Boucherit Soraya , Anglicheau Dany , Planas Anna , Haerynck Filomeen , Duvlis Sotirija , Nussbaum Robert , Ozcelik Tayfun , Keles Sevgi , Bousfiha Aziz , Bakkouri Jalila El , Ramirez-Santana Carolina , Paul Stéphane , Pan-Hammarstrom Qiang , Hammarstrom Lennart , Dupont Annabelle , Kurolap Alina , Metz Christine , Aiuti Alessandro , Casari Giorgio , Lampasona Vito , Ciceri Fabio , Barreiros Lucila , Dominguez-Garrido Elena , Vidigal Mateus , Zatz Mayana , de Beek Diederik van , Sahanic Sabina , Tancevski Ivan , Stepanovskyy Yurii , Boyarchuk Oksana , Nukui Yoko , Tsumura Miyuki , Vidaur Loreto , Tangye Stuart , Burrel Sonia , Duffy Darragh , Quintana-Murci Lluis , Klocperk Adam , Kann Nelli , Shcherbina Anna , Lau Yu-Lung , Leung Daniel , Coulongeat Matthieu , Marlet Julien , Koning Rutger , Reyes Luis , Chauvineau-Grenier Angélique , Venet Fabienne , monneret guillaume , Nussenzweig Michel , Arrestier Romain , Boudhabhay Idris , Baris-Feldman Hagit , Hagin David , Wauters Joost , Meyts Isabelle , Dyer Adam , Kennelly Sean , Bourke Nollaig , Halwani Rabih , Sharif-Askari Fatemeh , Dorgham Karim , Sallette Jérôme , Mehlal-Sedkaoui Souad , AlKhater Suzan , Rigo-Bonnin Raúl , Morandeira Francisco , Roussel Lucie , Vinh Donald , Erikstrup Christian , Condino-Neto Antonio , Prando Carolina , Bondarenko Anastasiia , Spaan András , Gilardin Laurent , Fellay Jacques , Lyonnet Stanislas , Bilguvar Kaya , Lifton Richard , Mane Shrikant , Anderson Mark , Boisson Bertrand , Béziat Vivien , Zhang Shen-Ying , Andreakos Evangelos , Hermine Olivier , Pujol Aurora , Peterson Pärt , Mogensen Trine Hyrup , Rowen Lee , Mond James , Debette Stéphanie , deLamballerie Xavier , Burdet Charles , Bouadma Lila , Zins Marie , Soler-Palacin Pere , Colobran Roger , Gorochov Guy , Solanich Xavier , Susen Sophie , Martinez-Picado Javier , Raoult Didier , Vasse Marc , Gregersen Peter , Rodríguez-Gallego Carlos , Piemonti Lorenzo , Notarangelo Luigi , Su Helen , Kisand Kai , Okada Satoshi , Puel Anne , Jouanguy Emmanuelle , Rice Charles , Tiberghien Pierre , Zhang Qian , Casanova Jean-Laurent , Abel Laurent , Cobat Aurélie 
Published: January 2022

Abstract
SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.