Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Bastard, Paul; Gervais, Adrian; Le Voyer, Tom; Rosain, Jérémie; Philippot, Quentin; Manry, Jérémy; 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 B; Shaw, Elana; Morio, Tomohiro; Tanaka, Junko; Dalmau, David; Tharaux, Pierre-Louis; Sene, Damien; Stepanian, Alain; Megarbane, Bruno; Triantafyllia, Vasiliki; Fekkar, Arnaud; Heath, James R; Franco, José Luis; Anaya, Juan-Manuel; Solé-Violán, Jordi; Imberti, Luisa

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-ß. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-ß do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.