Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Bastard, Paul; Orlova, Elizaveta; Sozaeva, Leila; Lévy, Romain; James, Alyssa; Schmitt, Monica M.; Ochoa, Sebastian; Kareva, Maria; Rodina, Yulia; Gervais, Adrian; Le Voyer, Tom; Rosain, Jérémie; Philippot, Quentin; Neehus, Anna-Lena; Shaw, Elana; Migaud, Mélanie; Bizien, Lucy; Ekwall, Olov; Berg, Stefan; Beccuti, Guglielmo; Ghizzoni, Lucia; Thiriez, Gérard; Pavot, Arthur; Goujard, Cécile; Frémond, Marie-Louise; Carter, Edwin; Rothenbuhler, Anya; Linglart, Agnès; Mignot, Brigite; Comte, Aurélie; Cheikh, Nathalie; Hermine, Olivier; Breivik, Lars; Husebye, Eystein S.; Humbert, Sébastien; Rohrlich, Pierre; Coaquette, Alain; Vuoto, Fanny; Faure, Karine; Mahlaoui, Nizar; Kotnik, Primož; Battelino, Tadej; Trebušak Podkrajšek, Katarina; Kisand, Kai; Ferré, Elise M.N.; DiMaggio, Thomas; Rosen, Lindsey B.; Burbelo, Peter D.; McIntyre, Martin; Kann, Nelli Y.; Shcherbina, Anna; Pavlova, Maria; Kolodkina, Anna; Holland, Steven M.; Zhang, Shen-Ying; Crow, Yanick J.; Notarangelo, Luigi D.; Su, Helen C.; Abel, Laurent; Anderson, Mark S.; Jouanguy, Emmanuelle; Neven, Bénédicte; Puel, Anne; Casanova, Jean-Laurent; Lionakis, Michail S.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.