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

Jeremy Manry (1) , Paul Bastard (1) , Adrian Gervais , Tom Le Voyer (1) , Jérémie Rosain (1) , Quentin Philippot (1) , Eleftherios Michailidis (2) , Hans-Heinrich Hoffmann (2) , Shohei Eto (3) , Marina Garcia-Prat (4) , Lucy Bizien (1) , Alba Parra-Martínez (4) , Rui Yang (2) , Liis Haljasmägi (5) , Mélanie Migaud (1) , Karita Särekannu (5) , Julia Maslovskaja (5) , Nicolas de Prost (6) , Yacine Tandjaoui-Lambiotte (7) , Charles-Edouard Luyt (8) , Blanca Amador-Borrero (9) , Alexandre Gaudet (10) , Julien Poissy (10) , Pascal Morel (11) , Pascale Richard (11) , Fabrice Cognasse (12) , Jesus Troya (13) , Sophie Trouillet-Assant (14) , Alexandre Belot (14) , Kahina Saker (14) , Pierre Garçon (15) , Jacques Rivière (16) , Jean-Christophe Lagier (17) , Stéphanie Gentile (18) , Lindsey Rosen (19) , Elana Shaw (19) , Tomohiro Morio (20) , Junko Tanaka (3) , David Dalmau (21) , Pierre-Louis Tharaux (22) , Damien Sene (9) , Alain Stepanian (9) , Bruno Mégarbane (9, 22) , Vasiliki Triantafyllia (23) , Arnaud Fekkar (22) , James Heath (24) , Jose Franco (25) , Juan-Manuel Anaya (26) , Jordi Solé-Violán (27) , Luisa Imberti (28) , Andrea Biondi , Paolo Bonfanti (29) , Riccardo Castagnoli (19) , Ottavia Delmonte (19) , Yu Zhang (30) , Andrew Snow (31) , Steve Holland (30) , Catherine Biggs (32) , Marcela Moncada-Vélez (2) , Andrés Arias (2) , Lazaro Lorenzo (33) , Soraya Boucherit (33) , Dany Anglicheau (33) , Anna Planas (34) , Filomeen Haerynck (35) , Sotirija Duvlis (36) , Robert Nussbaum (37) , Tayfun Ozcelik (38) , Sevgi Keles (39) , Aziz Bousfiha (40) , Jalila El Bakkouri (41) , Carolina Ramirez-Santana (26) , Stéphane Paul (42) , Qiang Pan-Hammarstrom (43) , Lennart Hammarstrom (43) , Annabelle Dupont (44, 22) , Alina Kurolap (45) , Christine Metz (46) , Alessandro Aiuti (47) , Giorgio Casari (48) , Vito Lampasona (48) , Fabio Ciceri (47) , Lucila Barreiros (49) , Elena Dominguez-Garrido (50) , Mateus Vidigal (49) , Mayana Zatz (49) , Diederik van de Beek (51) , Sabina Sahanic (52) , Ivan Tancevski (52) , Yurii Stepanovskyy (53) , Oksana Boyarchuk (54) , Yoko Nukui (20) , Miyuki Tsumura (3) , Loreto Vidaur (55) , Stuart Tangye (56) , Sonia Burrel (57) , Darragh Duffy (58) , Lluis Quintana-Murci (59) , Adam Klocperk (60, 61) , Nelli Kann (62) , Anna Shcherbina (62) , Yu-Lung Lau (63) , Daniel Leung (63) , Matthieu Coulongeat (64) , Julien Marlet (65) , Rutger Koning (51) , Luis Reyes (66) , Angélique Chauvineau-Grenier (67) , Fabienne Venet (14) , Guillaume Monneret (14) , Michel Nussenzweig (2) , Romain Arrestier (6) , Idris Boudhabhay (33, 22) , Hagit Baris-Feldman (45) , David Hagin (68) , Joost Wauters (69) , Isabelle Meyts (70) , Adam Dyer (71) , Sean Kennelly (71) , Nollaig Bourke (72) , Rabih Halwani , Fatemeh Sharif-Askari (73) , Karim Dorgham (74) , Jérôme Sallette (75) , Souad Mehlal-Sedkaoui (75) , Suzan Alkhater (76) , Raúl Rigo-Bonnin (77) , Francisco Morandeira (77) , Lucie Roussel (78) , Donald Vinh (78) , Christian Erikstrup (79) , Antonio Condino-Neto (49) , Carolina Prando (80) , Anastasiia Bondarenko (53) , András Spaan (2) , Laurent Gilardin (81) , Jacques Fellay (82) , Stanislas Lyonnet (33) , Kaya Bilguvar (83) , Richard Lifton (2) , Shrikant Mane (83) , Mark Anderson (84) , Bertrand Boisson (2) , Vivien Béziat (22) , Shen-Ying Zhang , Evangelos Andreakos (85) , Olivier Hermine (22) , Aurora Pujol (86) , Pärt Peterson (5) , Trine Hyrup Mogensen (79) , Lee Rowen (24) , James Mond , Stéphanie Debette (87) , Xavier Delamballerie (88) , Charles Burdet (89) , Lila Bouadma (90) , Marie Zins (91, 92, 22) , Pere Soler-Palacin (16) , Roger Colobran (16) , Guy Gorochov (57, 93) , Xavier Solanich (77) , Sophie Susen (94) , Javier Martinez-Picado (95) , Didier Raoult (88, 17) , Marc Vasse (96) , Peter Gregersen (46) , Carlos Rodríguez-Gallego (27) , Lorenzo Piemonti (48) , Luigi Notarangelo (30) , Helen Su (30) , Kai Kisand (5) , Satoshi Okada (3) , Anne Puel (22) , Emmanuelle Jouanguy (2) , Charles Rice (2) , Pierre Tiberghien (97) , Qian Zhang (2) , Jean-Laurent Casanova , Laurent Abel (98) , Aurélie Cobat (22)

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 Rockefeller University [New York]
3 Hiroshima University
4 VHIR - Vall d’Hebron Research Institute
5 University of Tartu
6 CHU Henri Mondor
7 Hôpital Avicenne [AP-HP]
8 Institut de cardiologie [CHU Pitié-Salpêtrière]
9 Hôpital Lariboisière-Fernand-Widal [APHP]
10 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
11 EFS - Etablissement Français du Sang [La Plaine Saint-Denis]
12 EFS - Etablissement français du sang - Auvergne-Rhône-Alpes
13 Hospital Universitario Infanta Leonor [Madrid]
14 HCL - Hospices Civils de Lyon
15 GHEF - Grand Hôpital de l'Est Francilien
16 Vall d'Hebron University Hospital [Barcelona]
17 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
18 APHM - Assistance Publique - Hôpitaux de Marseille
19 NIH - National Institutes of Health [Bethesda]
20 TMDU - Tokyo Medical and Dental University [Japan]
21 UB - Universitat de Barcelona
22 INSERM - Institut National de la Santé et de la Recherche Médicale
23 BRFAA - Biomedical Research Foundation of the Academy of Athens
24 ISB - Institute for Systems Biology [Seattle]
25 Universidad de Antioquia = University of Antioquia [Medellín, Colombia]
26 Universidad del Rosario [Bogota]
27 Hospital Universitario de Gran Canaria Dr Negrin
28 Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia]
29 UNIMIB - Università degli Studi di Milano-Bicocca = University of Milano-Bicocca
30 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
31 USUHS - Uniformed Services University of the Health Sciences
32 UBC - University of British Columbia
33 CHU Necker - Enfants Malades [AP-HP]
34 CSIC - Spanish National Research Council
35 Ghent University Hospital
36 UGD - Goce Delchev University
37 Invitae Corporation
38 Bilkent University [Ankara]
39 Necmettin Erbakan University [Konya, Turquie]
40 CHU HII - Centre Hospitalier Universitaire Hassan II
41 CHU Ibn Rochd [Casablanca]
42 CIRI - Centre International de Recherche en Infectiologie - UMR
43 Karolinska Institute
44 Institut Pasteur de Lille
45 Tel Aviv Sourasky Medical Center [Te Aviv]
46 The Feinstein Institute for Medical Research
47 IRCCS San Raffaele Scientific Institute [Milan, Italie]
48 IRCCS Ospedale San Raffaele [Milan, Italy]
49 USP - Universidade de São Paulo = University of São Paulo
50 Fundacion Rioja Salud
51 Amsterdam Neuroscience [Pays-Bas]
52 IMU - Innsbruck Medical University [Austria]
53 SNMAPE - Shupyk National Medical Academy of Postgraduate Education [Kiev]
54 I.Horbachevsky Ternopil State Medical University, Ternopil, Ukraine
55 Hospital Donostia
56 Garvan Institute of medical research
57 SU - Sorbonne Université
58 Immunologie Translationnelle - Translational Immunology lab
59 Institut Pasteur [Paris]
60 CU - Charles University [Prague]
61 University Hospital Motol [Prague]
62 Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology [Moscow, Russia]
63 HKU - The University of Hong Kong
64 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
65 MAVIVH - U1259 Inserm - CHRU Tours - Morphogénèse et antigénicité du VIH et du virus des Hépatites
66 University of La Sabana = Universitad de la Sabana
67 Hôpital Robert Ballanger [Aulnay-sous-Bois]
68 Sackler Faculty of Medicine
69 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
70 University Hospitals Leuven [Leuven]
71 Tallaght Hospital
72 Trinity College Dublin
73 UoS - University of Sharjah
74 CIMI - Centre d'Immunologie et des Maladies Infectieuses
75 Laboratoire CERBA [Saint Ouen l'Aumône]
76 King Fahad University
77 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge [Barcelone]
78 McGill University = Université McGill [Montréal, Canada]
79 Aarhus University [Aarhus]
80 Instituto de Pesquisa Pelé Pequeno Principe
81 Hôpital Jean Verdier [AP-HP]
82 EPFL - Ecole Polytechnique Fédérale de Lausanne
83 Yale University [New Haven]
84 UC San Francisco - University of California [San Francisco]
85 Academy of Athens
86 ICREA - Institució Catalana de Recerca i Estudis Avançats
87 BPH - Bordeaux population health
88 AMU - Aix Marseille Université
89 CIC 1425 - Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique
90 CIC Hôpital Bichat
91 Université Paris-Saclay
92 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
93 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
94 EGID - European Genomic Institute for Diabetes - FR 3508
95 IrsiCaixa (Institut de Recerca de la Sida)
96 Hôpital Foch [Suresnes]
97 Etablissement Français du Sang
98 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades

SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.

Domains: Life Sciences [q-bio]; Immunology

Jeremy Manry, Paul Bastard, Adrian Gervais, Tom Le Voyer, Jérémie Rosain, et al.. The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies. 2022. ⟨pasteur-03610523⟩