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-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 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.

ADMA Biologics Inc Ramsey NJ

Aix Marseille Université IRD APHM MEPHI Marseille France

Aix Marseille University School of Medicine La Timone Medical Campus EA 3279 CEReSS Health Service Research and Quality of Life Center Marseille France

Allergy and Clinical Immunology Unit Department of Medicine Tel Aviv Sourasky Medical Center Tel Aviv Israel

AP HP Bichat Claude Bernard Hospital Infectious and Tropical Diseases Department Paris France

AP HP Département Epidémiologie Biostatistiques et Recherche Clinique Hôpital Bichat Paris France

Avicenne Hospital Assistance Publique Hôpitaux de Paris Bobigny INSERM U1272 Hypoxia and Lung Bobigny France

Bordeaux University Hospital Department of Neurology Institute of Neurodegenerative Diseases F 33000 Bordeaux France

Cancer Genetics and Prevention Program University of California San Francisco San Francisco USA

Catalan Institution for Research and Advanced Studies Barcelona Spain

Center for Autoimmune Disease Research School of Medicine and Health Sciences Universidad del Rosario Bogota Colombia

Center for Clinical Experimental Surgery and Translational Research Biomedical Research Foundation of the Academy of Athens Athens Greece

Centro de Investigación en Red de Enfermedades Respiratorias CIBERES Instituto de Salud Carlos 3 Madrid España

Cerba Health Care Issy les Moulineaux France

Chair of Human Genomics and Evolution Collège de France Paris France

CHU Lille Pôle de Réanimation Hôpital Roger Salengro Lille France

CIBER de Enfermedades Respiratorias Instituto de Salud Carlos 3 Madrid Spain

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 2 University Casablanca Morocco

CNRS UMR 5308 ENS UCBL Lyon France; National Referee Centre for Rheumatic and Autoimmune and Systemic Diseases in Children Lyon France; Lyon; Immunopathology Federation LIFE Hospices Civils de Lyon Lyon France

CNRS UMR9017 Lille France

College of Medicine Imam Abdulrahman Bin Faisal University Dammam Saudi Arabia

CREA Laboratory Diagnostic Department ASST Spedali Civili di Brescia Brescia Italy

Critical Care Unit University Hospital of Gran Canaria Dr Negrín Canarian Health System Las Palmas de Gran Canaria Canary Islands Spain

Département d'Immunologie Assistance Publique Hôpitaux de Paris Hôpital Pitié Salpétrière Paris France

Department of Age Related Healthcare Tallaght University Hospital and Department of Medical Gerontology School of Medicine Trinity College Dublin

Department of Biomedicine Aarhus University Aarhus Denmark

Department of Biosciences and Nutrition Karolinska Institutet Stockholm Sweden

Department of Children's Diseases and Pediatric Surgery 1 Horbachevsky Ternopil National Medical University Ternopil Ukraine

Department of Clinical Immunology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Laboratory Hospital Universitari de Bellvitge IDIBELL Barcelona Spain

Department of Clinical Sciences University Fernando Pessoa Canarias Las Palmas de Gran Canaria Canary Islands Spain

Department of Critical Care Medicine Clinica Universidad de La Sabana Chia Colombia

Department of Epidemiology Infectious Disease Control and Prevention Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan

Department of Genetics Yale University School of Medicine New Haven CT USA

Department of Hematology Necker Hospital AP HP Paris France

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital in Motol Prague Czech Republic

Department of Immunology CIC1408 GIMAP CIRI INSERM U1111 University Hospital of Saint Etienne Saint Etienne France

Department of Immunology Hospital Universitari de Bellvitge IDIBELL Barcelona Spain

Department of Immunology Institute of Biomedical Sciences University of Sao Paulo Sao Paulo Brazil

Department of Infection Control and Prevention Medical Hospital Tokyo Medical and Dental University Tokyo Japan

Department of Infectious Diseases Aarhus University Hospital Skejby Denmark

Department of Infectious Diseases San Gerardo Hospital University of Milano Bicocca Monza Italy

Department of Internal Medicine 2 Medical University of Innsbruck Innsbruck Austria

Department of Internal Medicine Hospital Universitari de Bellvitge IDIBELL Barcelona Spain

Department of Internal Medicine Infanta Leonor University Hospital Madrid Spain

Department of Medical Genetics Acibadem University School of Medicine Istanbul Turkey

Department of Medical Gerontology School of Medicine Trinity College Dublin

Department of Medical Microbiology University Medical Center Utrecht Utrecht Netherlands

Department of Medicine Division of Infectious Diseases McGill University Health Centre Montréal Québec Canada

Department of Microbiology Universidad de La Sabana Chia Colombia

Department of Molecular Biology and Genetics Bilkent University Bilkent Ankara Turkey

Department of Nephrology and Transplantation Necker University Hospital APHP Paris France; INEM INSERM U 1151 CNRS UMR 8253 Paris University Paris France

Department of Neurology Amsterdam Neuroscience Amsterdam Netherlands

Department of Neurosurgery Yale University School of Medicine New Haven CT USA

Department of Paediatric Immunology and Pulmonology Center for Primary Immunodeficiency Ghent Jeffrey Modell Diagnosis and Research Center Ghent University Hospital Ghent Belgium

Department of Paediatrics and Adolescent Medicine The University of Hong Kong Hong Kong China

Department of Pathology and Laboratory Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA

Department of Pediatrics and Developmental Biology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan

Department of Pediatrics British Columbia Children's Hospital The University of British Columbia Vancouver BC Canada

Department of Pediatrics Fondazione IRCCS Policlinico San Matteo University of Pavia Pavia Italy

Department of Pediatrics Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan

Department of Pediatrics Jeffrey Modell Diagnostic and Research Network Center University Hospitals Leuven Leuven Belgium

Department of Pediatrics King Fahad Hospital of the University Al Khobar Saudi Arabia

Department of Pharmacology and Molecular Therapeutics Uniformed Services University of the Health Sciences Bethesda MD USA

Diabetes Center University of California San Francisco CA USA

Diabetes Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

Division of Geriatric Medicine Tours University Medical Center Tours France

Dmitry Rogachev National Medical Research Center of Pediatric Hematology Oncology and Immunology Moscow Russia

EA 7426 « Pathophysiology of Injury Induced Immunosuppression » Université Claude Bernard Lyon 1 Hospices Civils de Lyon Hôpital Edouard Herriot BioMérieux Lyon France

Etablissement Français du Sang Auvergne Rhône Alpes St Etienne St Etienne France

Etablissement Français du Sang La Plaine St Denis France

Faculdades Pequeno Príncipe Instituto de Pesquisa Pelé Pequeno Príncipe Curitiba Brazil

Faculty of Medical Sciences University Goce Delchev Stip Republic of Northern Macedonia

Feinstein Institutes for Medical Research Northwell Health Manhasset NY USA

Fundación Rioja Salud Centro de Investigación Biomédica de La Rioja Logrono Spain

Garvan Institute of Medical Research Sydney Australia

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

Hematology and Bone Marrow Transplantation Unit IRCCS San Raffaele Scientific Institute Milano Italy

Hospices Civils de Lyon Lyon France; International Center of Research in Infectiology Lyon University INSERM U1111 CNRS UMR 5308 ENS UCBL Lyon France

Hospital Universitari Mutua Tarrassa Tarrasa Spain

Hospital Universitario de Gran Canaria Dr Negrín Canarian Health System Canary Islands Spain

Howard Hughes Medical Institute New York NY USA

Human Evolutionary Genetics Unit Institut Pasteur CNRS UMR 2000 Paris France

IHU Méditerranée Infection Unité des Virus Émergents UVE Aix Marseille University IRD 190 INSERM 1207 Marseille France

Imagine Institute Université de Paris INSERM UMR 1163 Paris France

Immunology Division Genetics Department Hospital Universitari Vall d'Hebron Vall d'Hebron Research Institute Vall d'Hebron Barcelona Hospital Campus UAB Barcelona Catalonia Spain

Infectious Disease Susceptibility Program Research Institute McGill University Health Centre Montréal Québec Canada

Infectious Diseases and Immunity Center for Health and Social Care Research Vic Spain

Inserm CIC 1425 Paris France

INSERM U1019 Lille France

INSERM U1138 Centre de Recherche des Cordeliers Paris France

INSERM U1259 MAVIVH Université de Tours Tours France

INSERM UMRS_1166 iCAN Institute of Cardiometabolism and Nutrition Paris France

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Institut Hospitalo Universitaire Méditerranée Infection Marseille France

Institut Pasteur de Lille Lille France

Institute for Biomedical Research Spanish Research Council Barcelona Spain

Institute for Systems Biology Seattle WA 98109 USA

Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia

Institute of public health of Republic of North Macedonia

Intensive Care Department Donostia University Hospital San Sebastian Spain

Intensive Care Unit Grand Hôpital de l'Est Francilien Site de Marne la Vallée Jossigny France

Internal Medicine Department Lariboisière Hospital AP HP Paris University Paris France

IrsiCaixa AIDS Research Institute and Institute for Health Science Research Germans Trias i Pujol Badalona Spain

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

Laboratoire d'Immunologie Hospices Civils de Lyon Hôpital Edouard Herriot Lyon France

Laboratory of Clinical Immunology and Microbiology Division of Intramural Research NIAID NIH Bethesda MD USA

Laboratory of Human Genetics and Genomics The Rockefeller University New York NY

Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM U1163 Necker Hospital for Sick Children Paris France

Laboratory of Immunobiology Center for Clinical Experimental Surgery and Translational Research Biomedical Research Foundation of the Academy of Athens 11527 Athens Greece

Laboratory of Inborn Errors of Immunity Department of Immunology Microbiology and Transplantation KU Leuven Leuven Belgium

Laboratory of Molecular Immunology Rockefeller University New York NY USA

Laboratory of Virology and Infectious Disease The Rockefeller University New York NY USA

Medical Intensive care Unit University Hospitals Leuven Leuven Belgium

Meram Medical Faculty Necmettin Erbakan University Meram Medical Faculty Konya Turkey

Neurometabolic Diseases Laboratory IDIBELL Hospital Duran i Reynals CIBERER U759 and Catalan Institution of Research and Advanced Studies Barcelona Spain

NIAID Clinical Genomics Program National Institutes of Health Bethesda USA

Paris Cardiovascular Center PARCC Inserm Université de Paris Paris France

Pathogenesis and Therapy of Primary Immunodeficiencies Unit San Raffaele Milano Italy

Pediatric Department and Centro Tettamanti European Reference Network PaedCan EuroBloodNet MetabERN University of Milano Bicocca Fondazione MBBM Ospedale San Gerardo Monza Italy

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 Barcelona Catalonia Spain

Precision Medicine Unit Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Primary Immunodeficiencies Group Department of Microbiology and Parasitology School of Medicine University of Antioquia UDEA Medellín Colombia

Primary Immunodeficiencies Group University of Antioquia UdeA Medellin Colombia

Réanimation Médicale et Toxicologique Hôpital Lariboisière 1144

Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

SAINBIOSE INSERM U1059 University of Lyon Université Jean Monnet Saint Etienne

School of Life Sciences Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland

School of Microbiology University of Antioquia UdeA Medellin Colombia

Service d'Evaluation Médicale Hôpitaux Universitaires de Marseille Assistance Publique Hôpitaux de Marseille Marseille France

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

Service de Bactériologie Virologie Hygiène CHU de Tours Tours France

Service de Biologie Clinique and UMR S 1176 Hopital Foch Suresnes France

Service de Biologie Médicale CHI Robert Ballanger Aulnay sous Bois France

Service de Médecine Intensive Réanimation Hôpitaux Universitaires Henri Mondor Assistance Publique Hôpitaux de Paris

Service de Médecine Interne Hôpital universitaire Jean Verdier AP HP Bondy France

Service de Parasitologie Mycologie Groupe Hospitalier Pitié Salpêtrière AP HP Paris France

Sharjah Institute for Medical Research College of Medicine University of Sharjah Sharjah United Arab Emirates

Shupyk National Healthcare University of Ukraine Kyiv Ukraine

Sorbonne Université Assistance Publique Hôpitaux de Paris Hôpital Pitié Salpêtrière Médecine Intensive Réanimation AP HP Paris France

Sorbonne Université Inserm Centre d'Immunologie et des Maladies Infectieuses Paris France

Sorbonne Université INSERM U1136 Institut Pierre Louis d'Epidémiologie et de Santé Publique AP HP Hôpital Pitié Salpêtrière Service de Virologie Paris France

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY USA

Swiss Institue of Bioinformatics Lausanne Switzerland

The Genetics Institute Tel Aviv Sourasky Medical Center Tel Aviv University Tel Aviv Israel

Translational Immunology Lab Institut Pasteur

UMR 1098 RIGHT Inserm EFS Université de Franche Comté Besançon France

Université de Lille Inserm CHU Lille Institut Pasteur de Lille U1011 EGID F 59000 Lille France

Université de Paris IAME UMR S 1137 INSERM Paris France

Université de Paris Université Paris Saclay UVSQ Inserm UMS11 Villejuif France

University of Bordeaux INSERM Bordeaux Population Health Center UMR1219 F 33000 Bordeaux France

University of Lille U1019 UMR9017 Center for Infection and Immunity of Lille Lille France

University of Paris Imagine Institute Paris France

University of Sao Paulo Sao Paulo Brazil

Yale Center for Genome Analysis Yale School of Medicine New Haven CT USA

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Nature. 2021 Sep;597(7875):162. doi: 10.1038/d41586-021-02337-5. PubMed

Comment In

J Clin Immunol. 2022 May;42(4):742-745. doi: 10.1007/s10875-022-01235-3. PubMed

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Immun Inflamm Dis. 2023 Nov;11(11):e1056. doi: 10.1002/iid3.1056. PubMed

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Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ∼10% of patients

Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency

Autoimmunity and Immunodeficiency in Severe SARS-CoV-2 Infection and Prolonged COVID-19

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies