The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies
Jérémy Manry, Paul Bastard, Adrian Gervais, Tom Le Voyer, Jérémie Rosain, Quentin Philippot, Eleftherios Michailidis, Hans-Heinrich Hoffmann, Shohei Eto, Marina García-Prat, Lucy Bizien, Alba Parra-Martínez, Rui Yang, Liis Haljasmägi, Mélanie Migaud, Karita Särekannu, Julia Maslovskaja, Nicolas de Prost, Yacine Tandjaoui-Lambiotte, Charles‐Édouard Luyt, Blanca Amador-Borrero, Alexandre Gaudet, Julien Poissy, Pascal Morel, Pascale Richard, Fabrice Cognasse, Jesús Troya, Sophie Trouillet‐Assant, Alexandre Belot, Kahina Saker, Pierre Garçon, Jacques G. Rivière, Jean‐Christophe Lagier, Stéphanie Gentile, Lindsey B. Rosen, Elana Shaw, Tomohiro Morio, Junko Tanaka, David Dalmau, Pierre‐Louis Tharaux, D. Sène, Alain Stépanian, Bruno Mégarbane, Vasiliki Triantafyllia, Arnaud Fekkar, James R. Heath, José Luis Franco, Juan‐Manuel Anaya, Jordi Solé‐Violán, Luisa Imberti, Andrea Biondi, Paolo Bonfanti, Riccardo Castagnoli, Ottavia M. Delmonte, Yu Zhang, Andrew L. Snow, Steven M. Holland, Catherine M. Biggs, Marcela Moncada‐Vélez, Andrés A. Arias, Lazaro Lorenzo, Soraya Boucherit, Dany Anglicheau, Anna M. Planas, Filomeen Haerynck, Sotiriјa Duvlis, Tayfun Özçelık, Sevgi Keleş, Ahmed Aziz Bousfiha, Jalila El Bakkouri, Carolina Ramı́rez-Santana, Stéphane Paul, Qiang Pan‐Hammarström, Lennart Hammarström, Annabelle Dupont, Alina Kurolap, Christine N. Metz, Alessandro Aiuti, Giorgio Casari, Vito Lampasona, Fabio Ciceri, Lucila Akune Barreiros, Elena Domínguez‐Garrido, Mateus Vidigal, Mayana Zatz, Diederik van de Beek, Sabina Sahanic, Ivan Tancevski, Yuriy Stepanovskyy, Oksana Boyarchuk, Yoko Nukui, Miyuki Tsumura, Loreto Vidaur, Stuart G. Tangye, Sonia Burrel, Darragh Duffy, Lluis Quintana-Murci, Adam Klocperk, Nelli Y. Kann, Anna Shcherbina
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y 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, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.