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

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dc.contributor.authorManry, Jeremy
dc.contributor.authorBastard, Paul
dc.contributor.authorGervais, Adrian
dc.contributor.authorLe Voyer, Tom
dc.contributor.authorRosain, Jeremie
dc.contributor.authorPhilippot, Quentin
dc.contributor.authorMichailidis, Eleftherios
dc.date.accessioned2024-02-23T14:17:06Z
dc.date.available2024-02-23T14:17:06Z
dc.date.issued2022
dc.departmentNEÜen_US
dc.description.abstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-alpha, IFN-omega, and/or IFN-beta are found in similar to 20% of deceased patients across age groups, and in similar to 1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-alpha 2 or IFN-omega, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and >= 70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those >= 80 y old for autoantibodies neutralizing IFN-alpha 2 or IFN-omega, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-alpha 2 and IFN-omega. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.en_US
dc.description.sponsorshipHoward Hughes Medical Institute; Rockefeller University; St. Giles Foundation; NIH [R01AI088364, R01AI163029]; National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program [UL1 TR001866]; Emergent Ventures; Mercatus Center at George Mason University; Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center - National Human Genome Research Institute [UM1HG006504, U24HG008956]; Yale High Performance Computing Center [S10OD018521]; Fisher Center for Alzheimer's Research Foundation; Meyer Foundation; JPB Foundation; French National Research Agency (ANR) under the Investments for the Future program [ANR-10-IAHU-01]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]; French Foundation for Medical Research (FRM) [EQU201903007798]; French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud [ANRS-COV05]; ANR GENVIR [ANR-20-CE93-003]; AABIFNCOV [ANR-20-CO11-0001]; CNSVIRGEN [ANR-19-CE15-0009-01]; GenMIS-C [ANR-21-COVR-0039]; Square Foundation; Grandir-Fonds de solidarite pour l'Enfance; Fondation du Souffle; SCOR Corporate Foundation for Science; French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Sante et de la Recherche Medicale (INSERM); REACTing-INSERM; University Paris Cite; FRM [EA20170638020]; MD-PhD program of the Imagine Institute (Fondation Bettencourt Schueller); Centre for Biomedical Research on Rare Diseases (CIBERER) [ACCI20-767]; European Union's Horizon 2020 research and innovation program [824110]; George Mason University Fast Grant; G. Harold and Leila Y. Mathers Charitable Foundation; Department of Internal Medicine and Allergology; INSERM; REACTing consortium; French Ministry of Health [PHRC 20-0424]; French Ministry of Health; European Commission [RECOVER WP 6]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research, NIH [ZIA AI001270, 1ZIAAI001265]; Agence Nationale de la Recherche [ANR-10-LABX-69-01]; Estonian Research Council [PRG117, PRG377]; Al Jalila Foundation Seed Grant, Dubai, United Arab Emirates [AJF202019]; University of Sharjah, United Arab Emirates [CoV19-0307]; National Health and Medical Research Council of Australia; University of New South Wales COVID Rapid Response Initiative Grant; Regione Lombardia, Italy (project Risposta immune in pazienti con COVID-19 e co-morbidita); Instituto de Salud Carlos III [COV20/0968]; Biomedical Advanced Research and Development Authority [HHSO10201600031C]; Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development [JP20fk0108531]; ANR Flash COVID-19 program; SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID program; Fondation pour la Recherche Medicale; Caisse Nationale d'Assurance Maladie des Travailleurs Salaries; Direction generale de la Sante, Mutuelle Generale de l'Education Nationale; Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne; Fondation de France; Ministry of Research-INSERM Program Cohortes et collections de donnees biologiques; University of Bordeaux Initiative of Excellence; National Cancer Institute, NIH [75N91019D00024, 75N91021F00001]; Research Foundation -Flanders (FWO) Fundamental Clinical Mandate [1833317N]; Instituto de Salud Carlos III Grant - European Regional Development Fund (ERDF/FEDER) [PI17/00660]; Spanish Ministry for Science and Innovation (AEI/FEDER, European Union) [RTC-2017-6471-1]; Fundacion DISA [OA18/017, OA20/024]; Cabildo Insular de Tenerife [CGIEU0000219140]; Novo Nordisk Foundation [NNF20OC0064890, NNF21OC0067157]; Michael Smith Foundation for Health Research Health ProfessionalInvestigator Award; European Union's Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium) [101003650]; Society for the Relief of Disabled Children; Croucher Foundation; Evaluation-Orientation de la Coop~eration Scientifique (ECOS) Nord -Cooperation Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/C [806-2018]; Colciencias [713-2016, 111574455633]; Czech Health Research Council [NU20-05-00282, NV18-05-00162]; Ministry of Health, Czech Republic; Program Project COVID-19 OSRUniSR; Ministero della Salute [COVID-2020-12371617]; CSL Behring Chair of Primary Immunodeficiencies (PID); Katholieke Universiteit Leuven C1 Grant [C16/18/007]; Flanders Institute for Biotechnology-Grand Challenges-PID grant; FWO [G0C8517N, G0B5120N, G0E8420N]; Jeffrey Modell Foundation; Hellenic Foundation for Research and Innovation [INTERFLU 1574]; Sao Paulo Research Foundation [2020/097021]; JBS SA [69004]; Meath Foundationen_US
dc.description.sponsorshipWe thank the patients and their families for placing their trust in us. We thank the members of both branches of the Laboratory of Human Genetics of Infectious Diseases. We thank Y. Nemirovskaya, M. Woollett, D. Liu, S. Boucherit, C. Rivalain, M. Chrabieh, and L. Lorenzo for administrative assistance. We also thank the staff of the Imagine facilities: C. Bureau, L. Colonna, S. Paillet, N. Ghouas, and M. Sy. We are also grateful to the legal team and technology transfer staff of the Imagine Institute: M. Pilorges, R. Marlanges, E. Rubino, W. Loewen, D. Beudin, and N. Wuylens. We thank all the staff of the Imagine Institute, Necker Hospital, and Necker sorting center for help. We thank S. Nagashima (Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller University; the St. Giles Foundation; the NIH (Grants R01AI088364 and R01AI163029); the National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956); the Yale High Performance Computing Center (Grant S10OD018521); the Fisher Center for Alzheimer's Research Foundation; the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the Investments for the Future program (Grant ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (Grant EQU201903007798); the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects; the Square Foundation; Grandir-Fonds de solidarite pour l'Enfance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Sante et de la Recherche Medicale (INSERM), REACTing-INSERM; and the University Paris Cite. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424).; The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.'s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project Risposta immune in pazienti con COVID-19 e co-morbidita). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d'Assurance Maladie des Travailleurs Salaries, Direction generale de la Sante, Mutuelle Generale de l'Education Nationale, Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research-INSERM Program Cohortes et collections de donnees biologiques. S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation -Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d'Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundacion DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and Apuestas cient~ificas del ITER para colaborar en la lucha contra la COVID-19). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health ProfessionalInvestigator Award. P.Q.H. and L.; Hammarstr_om were funded by the European Union's Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.'s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coop~eration Scientifique (ECOS) Nord -Cooperation Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSRUniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation-Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID); by the Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for Biotechnology-Grand Challenges -PID grant; by the FWO Grants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union's Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the Sao Paulo Research Foundation (Grant 2020/097021) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.en_US
dc.identifier.doi10.1073/pnas.2200413119
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.issue21en_US
dc.identifier.pmid35576468en_US
dc.identifier.scopus2-s2.0-85131944795en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1073/pnas.2200413119
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12948
dc.identifier.volume119en_US
dc.identifier.wosWOS:000841027100010en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherNatl Acad Sciencesen_US
dc.relation.ispartofProceedings Of The National Academy Of Sciences Of The United States Of Americaen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectCovid-19en_US
dc.subjectType I Ifnsen_US
dc.subjectAutoantibodiesen_US
dc.subjectRelative Risken_US
dc.subjectInfection Fatality Rateen_US
dc.titleThe risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodiesen_US
dc.typeArticleen_US

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