@article{2999799,
    title = "Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths",
    author = "Bastard, P. and Gervais, A. and Voyer, T.L. and Rosain, J. and Philippot, Q. and Manry, J. and Michailidis, E. and Hoffmann, H.-H. and Eto, S. and Garcia-Prat, M. and Bizien, L. and Parra-Martínez, A. and Yang, R. and Haljasmägi, L. and Migaud, M. and Särekannu, K. and Maslovskaja, J. and De Prost, N. and Tandjaoui-Lambiotte, Y. and Luyt, C.-E. and Amador-Borrero, B. and Gaudet, A. and Poissy, J. and Morel, P. and Richard, P. and Cognasse, F. and Troya, J. and Trouillet-Assant, S. and Belot, A. and Saker, K. and Garçon, P. and Rivière, J.G. and Lagier, J.-C. and Gentile, S. and Rosen, L.B. and Shaw, E. and Morio, T. and Tanaka, J. and Dalmau, D. and Tharaux, P.-L. and Sene, D. and Stepanian, A. and Megarbane, B. and Triantafyllia, V. and Fekkar, A. and Heath, J.R. and Franco, J.L. and Anaya, J.-M. and Solé-Violán, J. and Imberti, L. and Biondi, A. and Bonfanti, P. and Castagnoli, R. and Delmonte, O.M. and Zhang, Y. and Snow, A.L. and Holland, S.M. and Biggs, C.M. and Moncada-Vélez, M. and Arias, A.A. and Lorenzo, L. and Boucherit, S. and Coulibaly, B. and Anglicheau, D. and Planas, A.M. and Haerynck, F. and Duvlis, S. and Nussbaum, R.L. and Ozcelik, T. and Keles, S. and Bousfiha, A.A. and El Bakkouri, J. and Ramirez-Santana, C. and Paul, S. and Pan-Hammarström, Q. and Hammarström, L. and Dupont, A. and Kurolap, A. and Metz, C.N. and Aiuti, A. and Casari, G. and Lampasona, V. and Ciceri, F. and Barreiros, L.A. and Dominguez-Garrido, E. and Vidigal, M. and Zatz, M. and Van De Beek, D. and Sahanic, S. and Tancevski, I. and Stepanovskyy, Y. and Boyarchuk, O. and Nukui, Y. and Tsumura, M. and Vidaur, L. and Tangye, S.G. and Burrel, S. and Duffy, D. and Quintana-Murci, L. and Klocperk, A. and Kann, N.Y. and Shcherbina, A. and Lau, Y.-L. and Leung, D. and Coulongeat, M. and Marlet, J. and Koning, R. and Reyes, L.F. and Chauvineau-Grenier, A. and Venet, F. and Monneret, G. and Nussenzweig, M.C. and Arrestier, R. and Boudhabhay, I. and Baris-Feldman, H. and Hagin, D. and Wauters, J. and Meyts, I. and Dyer, A.H. and Kennelly, S.P. and Bourke, N.M. and Halwani, R. and Sharif-Askari, N.S. and Dorgham, K. and Sallette, J. and Sedkaoui, S.M. and AlKhater, S. and Rigo-Bonnin, R. and Morandeira, F. and Roussel, L. and Vinh, D.C. and Ostrowski, S.R. and Condino-Neto, A. and Prando, C. and Bondarenko, A. and Spaan, A.N. and Gilardin, L. and Fellay, J. and Lyonnet, S. and Bilguvar, K. and Lifton, R.P. and Mane, S. and Anderson, M.S. and Boisson, B. and Béziat, V. and Zhang, S.-Y. and Andreakos, E. and Hermine, O. and Pujol, A. and Peterson, P. and Mogensen, T.H. and Rowen, L. and Mond, J. and Debette, S. and De Lamballerie, X. and Duval, X. and Mentré, F. and Zins, M. and Soler-Palacin, P. and Colobran, R. and Gorochov, G. and Solanich, X. and Susen, S. and Martinez-Picado, J. and Raoult, D. and Vasse, M. and Gregersen, P.K. and Piemonti, L. and Rodríguez-Gallego, C. and Notarangelo, L.D. and Su, H.C. and Kisand, K. and Okada, S. and Puel, A. and Jouanguy, E. and Rice, C.M. and Tiberghien, P. and Zhang, Q. and Cobat, A. and Abel, L. and Casanova, J.-L. and Alavoine, L. and Behillil, S. and Burdet, C. and Charpentier, C. and Dechanet, A. and Descamps, D. and Ecobichon, J.-L. and Enouf, V. and Frezouls, W. and Houhou, N. and Kafif, O. and Lehacaut, J. and Letrou, S. and Lina, B. and Lucet, J.-C. and Manchon, P. and Nouroudine, M. and Piquard, V. and Quintin, C. and Thy, M. and Tubiana, S. and Van Der Werf, S. and Vignali, V. and Visseaux, B. and Yazdanpanah, Y. and Chahine, A. and Waucquier, N. and Migaud, M.-C. and Deplanque, D. and Djossou, F. and Mergeay-Fabre, M. and Lucarelli, A. and Demar, M. and Bruneau, L. and Gerardin, P. and Maillot, A. and Payet, C. and Laviolle, B. and Laine, F. and Paris, C. and Desille-Dugast, M. and Fouchard, J. and Malvy, D. and Nguyen, D. and Pistone, T. and Perreau, P. and Gissot, V. and Le Goas, C. and Montagne, S. and Richard, L. and Chirouze, C. and Bouiller, K. and Desmarets, M. and Meunier, 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Philippe, A. and Picod, A. and De Chambrun, M.P. and Piralla, A. and Planas-Serra, L. and Ploin, D. and Poncelet, G. and Poulakou, G. and Pouletty, M.S. and Pourshahnazari, P. and Qiu-Chen, J.L. and Quentric, P. and Rambaud, T. and Raoult, V. and Rebillat, A.-S. and Redin, C. and Resmini, L. and Ricart, P. and Richard, J.-C. and Rivet, N. and Rocamora-Blanch, G. and Rodero, M.P. and Rodrigo, C. and Rodriguez, L.A. and Rodriguez-Palmero, A. and Romero, C.S. and Rothenbuhler, A. and Roux, D. and Rovina, N. and Rozenberg, F. and Ruch, Y. and Ruiz, M. and Del Prado, M.Y.R. and Ruiz-Rodriguez, J.C. and Sabater-Riera, J. and Saks, K. and Salagianni, M. and Sanchez, O. and Sanchez-Montalva, A. and Sanchez-Ramon, S. and Schidlowski, L. and Schluter, A. and Schmidt, J. and Schmidt, M. and Schuetz, C. and Schweitzer, C.E. and Scolari, F. and Sediva, A. and Seijo, L. and Seminario, A.G. and Seng, P. and Senoglu, S. and Seppanen, M. and Llovich, A.S. and Shahrooei, M. and Siguret, V. and Siouti, E. and Smadja, D.M. and Smith, N. and Sobh, A. and Soler, C. and Sozeri, B. and Stella, G.M. and Stepanovskiy, Y. and Stoclin, A. and Taccone, F. and Taupin, J.-L. and Tavernier, S.J. and Terrier, B. and Thiery, G. and Thorball, C. and Thorn, K. and Thumerelle, C. and Tipu, I. and Tolstrup, M. and Tomasoni, G. and Toubiana, J. and Alvarez, J.T. and Tsang, O.T.Y. and Tserel, L. and Tso, E.Y.K. and Tucci, A. and Oz, Ş.K.T. and Ursini, M.V. and Utsumi, T. and Uzunhan, Y. and Vabres, P. and Valencia-Ramos, J. and Van Den Rym, A.M. and Vandernoot, I. and Velez-Santamaria, V. and Veliz, S.P.Z. and Vidigal, M.C. and Viel, S. and Vilain, C. and Vilaire-Meunier, M.E. and Villar-Garcia, J. and Vincent, A. and Vogt, G. and Voiriot, G. and Volokha, A. and Vuotto, F. and Wauters, E. and Wu, A.K.L. and Wu, T.-C. and Yahşi, A. and Yesilbas, O. and Yildiz, M. and Young, B.E. and Yukselmiş, U. and Zecca, M. and Zuccaro, V. and Van Praet, J. and Lambrecht, B.N. and Van Braeckel, E. and Bosteels, C. and 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Montagna, D. and Licari, A. and Marseglia, G.L. and Storgaard, M. and Jorgensen, S. and Al-Muhsen, S. and Al-Mulla, F. and Arias, A.A. and Bogunovic, D. and Bolze, A. and Brodin, P. and Bryceson, Y. and Bustamante, C.D. and Butte, M.J. and Chakravorty, S. and Christodoulou, J. and Constantinescu, S.N. and Cooper, M.A. and Desai, M. and Drolet, B.A. and El Baghdadi, J. and Espinosa-Padilla, S. and Froidure, A. and Henrickson, S.E. and Hsieh, E.W.Y. and Husebye, E.S. and Imai, K. and Itan, Y. and Jarvis, E.D. and Karamitros, T. and Ku, C.-L. and Ling, Y. and Lucas, C.L. and Maniatis, T. and Marodi, L. and Milner, J.D. and Mironska, K. and Novelli, A. and Novelli, G. and Renia, L. and Resnick, I. and Sancho-Shimizu, V. and Seppanen, M.R.J. and Shahrooei, M. and Slaby, O. and Tayoun, A.A. and Ramaswamy, S. and Turvey, S.E. and Furkan Uddin, K.M. and Uddin, M.J. and Von Bernuth, H. and Zawadzki, P. and Bigio, B. and De La Chapelle, A. and Chen, J. and Chrabieh, M. and Liu, D. and Nemirowskaya, Y. and Cruz, I.M. and Materna, M. and Pelet, S. and Seeleuthner, Y. and Thibault, C. and Liu, Z. and Foti, G. and Bellani, G. and Citerio, G. and Contro, E. and Pesci, A. and Valsecchi, M.G. and Cazzaniga, M. and Batten, I. and Reddy, C. and McElheron, M. and Noonan, C. and Connolly, E. and Fallon, A. and Erikstrup, C. and Pedersen, O.B. and Sorensen, E. and Mikkelsen, S. and Dinh, K.M. and Larsen, M.A.H. and Paulsen, I.W. and Von Stemann, J.H. and Hansen, M.B. and Annereau, J.-P. and Briseno-Roa, L. and Gribouval, O. and Pelet, A. and Alcover, A. and Aschard, H. and Bousso, P. and Bruhns, P. and Cerf-Bensussan, N. and Cumano, A. and D'Enfert, C. and Deriano, L. and Dillies, M.-A. and Di Santo, J. and Dromer, F. and Eberl, G. and Enninga, J. and Gomperts-Boneca, I. and Hasan, M. and Hedestam, G.K. and Hercberg, S. and Ingersoll, M.A. and Lantz, O. and Kenny, R.A. and Menager, M. and Michel, F. and Patin, E. and Pellegrini, S. and Rausell, A. and Rieux-Laucat, F. and Rogge, L. and Fontes, M. and Sakuntabhai, A. and Schwartz, O. and Schwikowski, B. and Shorte, S. and Tangy, F. and Toubert, A. and Touvier, M. and Ungeheuer, M.-N. and Zimmer, C. and Albert, M.L. and Van Agtmael, M. and Algera, A.G. and Appelman, B. and Van Baarle, F. and Bax, D. and Beudel, M. and Bogaard, H.J. and Bomers, M. and Bonta, P. and Bos, L. and Botta, M. and De Brabander, J. and De Bree, G. and De Bruin, S. and Buis, D.T.P. and Bugiani, M. and Bulle, E. and Chouchane, O. and Cloherty, A. and Dijkstra, M. and Dongelmans, D.A. and Dujardin, R.W.G. and Elbers, P. and Fleuren, L. and Geerlings, S. and Geijtenbeek, T. and Girbes, A. and Goorhuis, B. and Grobusch, M.P. and Hafkamp, F. and Hagens, L. and Hamann, J. and Harris, V. and Hemke, R. and Hermans, S.M. and Heunks, L. and Hollmann, M. and Horn, J. and Hovius, J.W. and De Jong, M.D. and Lim, E.H.T. and Van Mourik, N. and Nellen, J. and Nossent, E.J. and Paulus, F. and Peters, E. and Pina-Fuentes, D.A.I. and Van Der Poll, T. and Preckel, B. and Prins, J.M. and Raasveld, J. and Reijnders, T. and De Rotte, M.C.F.J. and Schinkel, M. and Schultz, M.J. and Schrauwen, F.A.P. and Schuurman, A. and Schuurmans, J. and Sigaloff, K. and Slim, M.A. and Smeele, P. and Smit, M. and Stijnis, C.S. and Stilma, W. and Teunissen, C. and Thoral, P. and Tsonas, A.M. and Tuinman, P.R. and Van Der Valk, M. and Veelo, D. and Volleman, C. and De Vries, H. and Vught, L.A. and Van Vugt, M. and Wouters, D. and Zwinderman, A.H. and Brouwer, M.C. and Joost Wiersinga, W. and Vlaar, A.P.J. and Nadif, R. and Goldberg, M. and Ozguler, A. and Henny, J. and Lemonnier, S. and Coeuret-Pellicer, M. and Le Got, S. and Tzourio, C. and Dufouil, C. and Soumare, A. and Lachaize, M. and Fievet, N. and Flaig, A. and Martin, F. and Bonneaudeau, B. and Cannet, D. and Gallian, P. and Jeanne, M. and Perroquin, M. and Hamzeh-Cognasse, H. and CoV-Contact Cohort and St James's Hospital, SARS CoV2 Interest group and COVID Clinicians and French COVID Cohort Study Group and NIAID Immune Response to COVID Group and Danish CHGE and COVID Human Genetic Effort and HGID Lab and COVID-STORM Clinicians and NH-COVAIR Study Group and The Danish Blood Donor Study (DBDS) and Imagine COVID-Group and The Milieu Interieur Consortium and Amsterdam UMC Covid-19 Biobank and CONSTANCES cohort and 3C-Dijon Study and Cerba HealthCare and Etablissement du Sang study group",
    journal = "Science Immunology",
    year = "2021",
    volume = "6",
    number = "62",
    publisher = "American Association for the Advancement of Science",
    issn = "2470-9468",
    doi = "10.1126/sciimmunol.abl4340",
    keywords = "alpha2 interferon;  autoantibody;  interferon;  omega interferon;  alpha interferon;  autoantibody;  immunoglobulin G;  interferon;  interferon omega 1;  neutralizing antibody, adolescent;  adult;  aged;  antibody detection;  Article;  child;  cohort analysis;  controlled study;  coronavirus disease 2019;  critically ill patient;  disease severity;  enzyme linked immunosorbent assay;  fatality;  female;  human;  infant;  major clinical study;  male;  mortality rate;  prevalence;  protein blood level;  virus neutralization;  virus replication;  blood;  case control study;  critical illness;  immunology;  middle aged;  mortality;  newborn;  preschool child;  very elderly;  young adult, Adolescent;  Adult;  Aged;  Aged, 80 and over;  Antibodies, Neutralizing;  Autoantibodies;  Case-Control Studies;  Child;  Child, Preschool;  COVID-19;  Critical Illness;  Humans;  Immunoglobulin G;  Infant;  Infant, Newborn;  Interferon Type I;  Interferon-alpha;  Middle Aged;  Young Adult",
    abstract = "Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 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 1124 deceased patients (aged 20 days to 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-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-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 individuals 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-β 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. © 2021 The Authors, some rights reserved."
}