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

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      1 , 2 , 3 , @ , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 4 , 4 , 5 , 6 , 1 , 2 , 6 , 3 , 7 , 1 , 2 , 7 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 19 , 21 , 22 , 23 , 24 , 25 , 26 , 25 , 27 , 6 , 28 , 29 , 30 , 31 , 32 , 32 , 33 , 34 , 35 , 36 , 13 , 37 , 38 , 39 , 1 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 32 , 49 , 32 , 32 , 50 , 51 , 32 , 52 , 3 , 3 , 53 , 54 , 1 , 2 , 1 , 2 , 1 , 2 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 64 , 42 , 43 , 65 , 66 , 66 , 67 , 68 , 69 , 70 , 70 , 71 , 72 , 73 , 74 , 75 , 75 , 76 , 77 , 77 , 78 , 79 , 80 , 5 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 89 , 90 , 90 , 91 , 92 , 93 , 76 , 94 , 95 , 96 , 97 , 98 , 99 , 97 , 99 , 100 , 101 , 8 , 9 , 55 , 68 , 102 , 102 , 103 , 104 , 105 , 106 , 107 , 107 , 108 , 109 , 109 , 110 , 111 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 116 , 117 , 118 , 73 , 119 , 78 , 3 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 127 , 131 , 132 , 128 , HGID Lab, COVID Clinicians, COVID-STORM Clinicians, NIAID Immune Response to COVID Group, NH-COVAIR Study Group, Danish CHGE, Danish Blood Donor Study, St. James’s Hospital, SARS CoV2 Interest group, French COVID Cohort Study Group, Imagine COVID-Group, The Milieu Intérieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank Investigators, COVID Human Genetic Effort, CONSTANCES cohort, 3C-Dijon Study, Cerba Health-Care, Etablissement du Sang study group, 133 , 1 , 2 , 3 , 1 , 2 , 1 , 2 , 3 , 134 , 2 , 135 , 136 , 7 , 137 , 138 , 41 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 143 , 144 , 145 , 147 , 6 , 148 , 110 , 149 , 150 , 67 , 151 , 152 , 153 , 28 , 29 , 154 , 69 , 71 , 155 , 156 , 32 , 32 , 157 , 7 , 5 , 1 , 2 , 3 , 1 , 2 , 3 , 4 , 19 , 20 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , 101 , @
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          Abstract

          Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10ng/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 (100pg/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-β. 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 aged 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-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.

          One-sentence summary

          Autoantibodies neutralizing type I IFNs increase in prevalence over 60 years of age and underlie about 20% of all fatal COVID-19 cases.

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          OpenSAFELY: factors associated with COVID-19 death in 17 million patients

          COVID-19 has rapidly impacted on mortality worldwide. 1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets. Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19 related deaths. COVID-19 related death was associated with: being male (hazard ratio 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared to people with white ethnicity, black and South Asian people were at higher risk even after adjustment for other factors (HR 1.48, 1.29-1.69 and 1.45, 1.32-1.58 respectively). We have quantified a range of clinical risk factors for COVID-19 related death in the largest cohort study conducted by any country to date. OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly.
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            Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

            Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression suggesting diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A unique phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor NF-κB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling. These data suggest that type-I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
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              Autoantibodies against type I IFNs in patients with life-threatening COVID-19

              The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. eabd4585; see also p. 404
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                Author and article information

                Journal
                101688624
                45516
                Sci Immunol
                Sci Immunol
                Science immunology
                2470-9468
                8 October 2021
                19 August 2021
                19 February 2022
                : 6
                : 62
                : eabl4340
                Affiliations
                [1 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
                [2 ]University of Paris, Imagine Institute, Paris, France
                [3 ]St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
                [4 ]Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
                [5 ]Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
                [6 ]Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain
                [7 ]Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
                [8 ]Service de Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP)
                [9 ]Groupe de Recherche Clinique CARMAS, Faculté de Santé de Créteil, Université Paris Est Créteil, 51, Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil Cedex, France
                [10 ]Avicenne Hospital, Assistance Publique Hôpitaux de Paris, Bobigny, INSERM U1272 Hypoxia & Lung, Bobigny, France
                [11 ]Sorbonne Université, Assistance Publique–Hôpitaux de Paris, Hôpital Pitié–Salpêtrière, Médecine Intensive Réanimation, AP-HP, Paris, France
                [12 ]INSERM UMRS_1166-iCAN, Institute of Cardiometabolism and Nutrition, Paris, France
                [13 ]Internal Medicine Department, Lariboisière Hospital, AP-HP, Paris University, Paris, France
                [14 ]University of Lille, U1019-UMR9017-Center for Infection and Immunity of Lille, Lille, France
                [15 ]CNRS, UMR9017, Lille, France
                [16 ]INSERM, U1019, Lille, France
                [17 ]Institut Pasteur de Lille, Lille, France
                [18 ]CHU Lille, Pôle de Réanimation, Hôpital Roger Salengro, Lille, France
                [19 ]Etablissement Français du Sang, La Plaine-St Denis, France
                [20 ]UMR 1098 RIGHT, Inserm, EFS, Université de Franche-Comté, Besançon, France
                [21 ]SAINBIOSE, INSERM U1059, University of Lyon, Université Jean-Monnet-Saint-Etienne
                [22 ]Etablissement Français du Sang, Auvergne Rhône-Alpes, St-Etienne, St-Etienne, France
                [23 ]Department of Internal Medicine, Infanta Leonor University Hospital, Madrid, Spain
                [24 ]Hospices Civils de Lyon, Lyon, France; International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France
                [25 ]Joint Research Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France
                [26 ]CNRS UMR 5308, ENS, UCBL, Lyon, France; National Referee Centre for Rheumatic, and Autoimmune and Systemic Diseases in Children (RAISE), Lyon, France; Lyon; Immunopathology Federation LIFE, Hospices Civils de Lyon, Lyon, France
                [27 ]Intensive Care Unit, Grand Hôpital de l’Est Francilien Site de Marne-la-Vallée, Jossigny, France
                [28 ]Institut Hospitalo-Universitaire Méditerranée Infection , Marseille, France
                [29 ]Aix Marseille Université, IRD, APHM, MEPHI, Marseille, France
                [30 ]Service d’Evaluation Médicale, Hôpitaux Universitaires de Marseille Assistance Publique Hôpitaux de Marseille (APHM), Marseille, France
                [31 ]Aix Marseille University, School of Medicine - La Timone Medical Campus, EA 3279: CEReSS - Health Service Research and Quality of Life Center, Marseille, France
                [32 ]Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
                [33 ]Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
                [34 ]Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
                [35 ]Hospital Universitari Mutua Tarrassa, Tarrasa, Spain
                [36 ]Paris Cardiovascular Center, PARCC, Inserm, Université de Paris, Paris, France
                [37 ]Service d’Hématologie Biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and EA3518, Institut Universitaire d’Hématologie-Hôpital Saint Louis, Université Paris Diderot, Paris, France
                [38 ]Réanimation Médicale et Toxicologique, Hôpital Lariboisière (AP-HP), Université Paris-Diderot, INSERM Unité Mixte de Recherche Scientifique (UMRS) 1144
                [39 ]Laboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
                [40 ]Service de Parasitologie-Mycologie, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France
                [41 ]Institute for Systems Biology, Seattle, WA 98109, USA
                [42 ]Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UDEA, Medellín, Colombia
                [43 ]Center for Autoimmune Disease Research, School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
                [44 ]Critical Care Unit , University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain
                [45 ]CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
                [46 ]CREA Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy
                [47 ]Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy
                [48 ]Department of Infectious Diseases, San Gerardo Hospital–University of Milano-Bicocca, Monza, Italy
                [49 ]Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
                [50 ]NIAID Clinical Genomics Program, National Institutes of Health, Bethesda, USA
                [51 ]Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
                [52 ]Department of Pediatrics, British Columbia Children’s Hospital, The University of British Columbia, Vancouver, BC, Canada
                [53 ]Primary Immunodeficiencies Group, University of Antioquia UdeA, Medellin, Colombia
                [54 ]School of Microbiology, University of Antioquia UdeA, Medellin, Colombia
                [55 ]Department of Nephrology and Transplantation, Necker University Hospital - APHP, Paris, France; INEM INSERM U 1151 - CNRS UMR 8253, Paris University, Paris, France
                [56 ]Institute for Biomedical Research, Spanish Research Council, Barcelona, Spain
                [57 ]Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
                [58 ]Department of Paediatric Immunology and Pulmonology, Center for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, Ghent University Hospital, Ghent, Belgium
                [59 ]Faculty of Medical Sciences, University “Goce Delchev”, Stip, Republic of Northern Macedonia
                [60 ]Institute of public health of Republic of North Macedonia
                [61 ]Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, USA
                [62 ]Department of Molecular Biology and Genetics, Bilkent University, Bilkent - Ankara, Turkey
                [63 ]Meram Medical Faculty, Necmettin Erbakan University, Meram Medical Faculty, Konya, Turkey
                [64 ]Clinical Immunology Unit, Department of Pediatric Infectious Disease, CHU Ibn Rushd and LICIA, Laboratoire d’Immunologie Clinique, Inflammation et Allergie, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
                [65 ]Department of Immunology, CIC1408, GIMAP CIRI INSERM U1111, University Hospital of Saint-Etienne, Saint-Etienne, France
                [66 ]Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
                [67 ]Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
                [68 ]The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
                [69 ]Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
                [70 ]Pathogenesis and Therapy of Primary Immunodeficiencies Unit, San Raffaele, Milano, Italy
                [71 ]Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
                [72 ]Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
                [73 ]Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
                [74 ]Fundación Rioja Salud - Centro de Investigación Biomédica de La Rioja, Logrono, Spain
                [75 ]University of Sao Paulo, Sao Paulo, Brazil
                [76 ]Department of Neurology, Amsterdam Neuroscience, Amsterdam, The Netherlands
                [77 ]Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
                [78 ]Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine
                [79 ]Department of Children’s Diseases and Pediatric Surgery, I.Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
                [80 ]Department of Infection Control and Prevention, Medical Hospital, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
                [81 ]Intensive Care Department, Donostia University Hospital, San Sebastian, Spain
                [82 ]Centro de Investigación en Red de Enfermedades Respiratorias-CIBERES - Instituto de Salud Carlos III, Madrid, España
                [83 ]Garvan Institute of Medical Research, Sydney, Australia
                [84 ]Sorbonne Université, INSERM U1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Pitié Salpêtrière, Service de Virologie, Paris, France
                [85 ]Translational Immunology Lab, Institut Pasteur
                [86 ]Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, Paris, France
                [87 ]Chair of Human Genomics and Evolution, Collège de France, Paris, France
                [88 ]Department of Immunology, 2nd Faculty of Medicine, Charles University and University Hospital in Motol, Prague, Czech Republic
                [89 ]Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
                [90 ]Department of Paediatrics & Adolescent Medicine, The University of Hong Kong, Hong Kong, China
                [91 ]Division of Geriatric Medicine, Tours University Medical Center, Tours, France
                [92 ]INSERM U1259, MAVIVH, Université de Tours, Tours, France
                [93 ]Service de Bactériologie-Virologie-Hygiène, CHU de Tours, Tours, France
                [94 ]Department of Microbiology, Universidad de La Sabana, Chia, Colombia
                [95 ]Department of Critical Care Medicine, Clinica Universidad de La Sabana, Chia, Colombia
                [96 ]Service de Biologie Médicale, CHI Robert Ballanger, Aulnay sous Bois, France
                [97 ]Laboratoire d’Immunologie, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
                [98 ]Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard-Lyon 1, Lyon, France
                [99 ]EA 7426 « Pathophysiology of Injury-Induced Immunosuppression », Université Claude Bernard Lyon 1 - Hospices Civils de Lyon, Hôpital Edouard Herriot - BioMérieux, Lyon, France
                [100 ]Laboratory of Molecular Immunology, Rockefeller University, New York, NY, USA
                [101 ]Howard Hughes Medical Institute, New York, NY, USA
                [102 ]Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                [103 ]Allergy and Clinical Immunology Unit, Department of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
                [104 ]Medical Intensive care Unit, University Hospitals Leuven, Leuven, Belgium
                [105 ]Laboratory of Inborn Errors of Immunity, Department of Immunology, Microbiology and Transplantation, KU Leuven, Leuven, Belgium
                [106 ]Department of Pediatrics, Jeffrey Modell Diagnostic and Research Network Center, University Hospitals Leuven, Leuven, Belgium
                [107 ]Department of Age-Related Healthcare, Tallaght University Hospital & Department of Medical Gerontology, School of Medicine, Trinity College Dublin
                [108 ]Department of Medical Gerontology, School of Medicine, Trinity College Dublin
                [109 ]Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
                [110 ]Sorbonne Université, Inserm, Centre d’Immunologie et des Maladies Infectieuses, (CIMI- Paris), Paris, France
                [111 ]Cerba Health Care, Issy-les-Moulineaux, France
                [112 ]Department of Pediatrics, King Fahad Hospital of the University, Al-Khobar, Saudi Arabia
                [113 ]College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
                [114 ]Department of Clinical Laboratory, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
                [115 ]Department of Immunology, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
                [116 ]Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada
                [117 ]Infectious Disease Susceptibility Program, Research Institute-McGill University Health Centre, Montréal, Québec, Canada
                [118 ]Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
                [119 ]Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil
                [120 ]Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
                [121 ]Service de Médecine Interne, Hôpital universitaire Jean-Verdier, AP-HP, Bondy, France
                [122 ]INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
                [123 ]School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
                [124 ]Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
                [125 ]Swiss Institue of Bioinformatics, Lausanne, Switzerland
                [126 ]Imagine Institute, Université de Paris, INSERM UMR 1163, Paris, France
                [127 ]Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA
                [128 ]Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
                [129 ]Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA
                [130 ]Department of Medical Genetics, Acibadem University School of Medicine, Istanbul, Turkey
                [131 ]Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
                [132 ]Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY
                [133 ]Diabetes Center, University of California, San Francisco, CA, USA
                [134 ]Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
                [135 ]Department of Hematology, Necker Hospital, AP-HP, Paris, France
                [136 ]Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, CIBERER U759, and Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain
                [137 ]Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark
                [138 ]Department of Biomedicine, Aarhus University, Aarhus, Denmark
                [139 ]ADMA Biologics Inc., Ramsey NJ
                [140 ]University of Bordeaux, INSERM, Bordeaux Population Health Center, UMR1219, F-33000 Bordeaux, France
                [141 ]Bordeaux University Hospital, Department of Neurology, Institute of Neurodegenerative Diseases, F-33000 Bordeaux, France
                [142 ]IHU Méditerranée Infection, Unité des Virus Émergents, UVE: Aix Marseille University, IRD 190, INSERM 1207, Marseille, France
                [143 ]Inserm CIC 1425, Paris, France
                [144 ]Université de Paris, IAME UMR-S 1137, INSERM, Paris, France
                [145 ]AP-HP, Département Epidémiologie Biostatistiques et Recherche Clinique, Hôpital Bichat, Paris, France
                [146 ]AP-HP, Bichat Claude Bernard Hospital, Infectious and Tropical Diseases Department, Paris, France
                [147 ]Université de Paris, Université Paris-Saclay, UVSQ, Inserm UMS11, Villejuif, France
                [148 ]Immunology Division, Genetics Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Vall d’Hebron Barcelona Hospital Campus, UAB, Barcelona, Catalonia, Spain
                [149 ]Département d’Immunologie, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpétrière, Paris, France
                [150 ]Department of Internal Medicine, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
                [151 ]IrsiCaixa AIDS Research Institute and Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain
                [152 ]Infectious Diseases and Immunity, Center for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain
                [153 ]Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
                [154 ]Service de Biologie Clinique & UMR-S 1176, Hopital Foch, Suresnes, France
                [155 ]Hospital Universitario de Gran Canaria Dr Negrín, Canarian Health System, Canary Islands, Spain
                [156 ]Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Canary Islands, Spain
                [157 ]Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
                Author notes
                [&]

                These authors contributed equally to this work.

                [#]

                These authors contributed equally to this work.

                [£]

                These authors contributed equally to this work.

                [†]

                These authors contributed equally to this work.

                [‡]

                These authors contributed equally to this work.

                [*]

                These authors contributed equally to this work.

                [§]

                All collaborators and their affiliations appear at the end of this paper.

                Author contributions: P.B., A.G., T.L.V., J.R., Q.P., E.M., H.-H.H., S.E., L.H., M.G.P., L.B., A.P.M., R.Y., M.M., P.P., K.S., J.M., S.T.-A., A.B., K.S., E.S., L.B.R., M.M., A.A., B.C. A.F., S.M.H., O.M.D., Y.Z., B.B., V.B., S.-Y.Z., L.D.N., H.C.S., K.K., S.O., A.P., E.J., C.M.R. and Q.Z. performed or supervised experiments, generated and analyzed data, and contributed to the manuscript by providing figures and tables. J.M., A.C., and L.A. performed computational analyses of data. P.B., N.D.-P., Y.T.L., C.-E.L., B.A.-B., A.G., J.P., P.M., P.R., F.C., J.T., J.R., L.L., J.-C.L., S.G., S.T.-A., A.B., K.S., P.G., D.D., P.-L.T., D.S., A.S., B.M., V.T., J.R.H., J.C.F., J.-M.A., A.C.-N., L.I., A.B., R.C., P.Bo., A.B., A.L.S., A.M.P., F.H., S.D., R.L.N., T.M., A.A.B., T.O., S.K., C.R., S.P., P.Q.H., L.H., A.D., A.K., C.N.M., A.A., G.C., V.L.L, F.C., L.A.B., E.D.-G. L.V., D.V.D.B., S.G.T., S.B., D.D., L.Q.-M., M.C.N., R.A., D.A., I.,B., H.B.-F., J.W., I.M. D.H., N.S.S.-A., R.H., K.D., J.S., S.M.S., L.G., A.K., F.M., Y.N., J.S.-V., A.H.D., S.P.K, N.M.B., S.A.A.A.-K, Y.S., J.T., O.B., N.Y.K., Y.-L.-L, D.L., M.C., J.M., R.K., L.F.R., C.B., M.S.A., R.R.-B., R.M., M.V., M.Z., A.C.G., F.V., G.M., D.C.V., L.R., S.R.O., A.S., E.A., S.S., I.T., J.F., S.L., K.B., R.P.L., S.M., S.B., V.V., O.H., A.P.O., T.H.M., L.R., J.M., S.D., X.D.L., X.D., F.M., M.Z., P.S.-P., R.C., G.G., X.S.M., S.S., J.M.-P., D.R., M.V., P.K.G., L.P., C.R.-G., L.D.N., H.C.S., P.T., Q.Z., and J.-L.C. evaluated and recruited patients to COVID and/or control cohorts of patients, and/or cohorts of individuals from the general population. P.B. and J.-L.C. wrote the manuscript. J.-L.C. supervised the project. All the authors edited the manuscript.

                Article
                NIHMS1744468
                10.1126/sciimmunol.abl4340
                8521484
                34413139
                08227ede-6d5c-4b44-ab8f-7a71f79bbe27

                This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, permitting unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; authorization from the rights holder before using such material. For patients enrolled in the Italian cohort, patient specimens may be available from Monza, subject to approval by their local IRB, through an MTA.

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