Department of Clinical Medicine

TY - JOUR

T1 - The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

AU - Manry, Jérémy

AU - Bastard, Paul

AU - Gervais, Adrian

AU - Le Voyer, Tom

AU - Rosain, Jérémie

AU - Philippot, Quentin

AU - Michailidis, Eleftherios

AU - Hoffmann, Hans Heinrich

AU - Eto, Shohei

AU - Garcia-Prat, Marina

AU - Bizien, Lucy

AU - Parra-Martínez, Alba

AU - Yang, Rui

AU - Haljasmägi, Liis

AU - Migaud, Mélanie

AU - Särekannu, Karita

AU - Maslovskaja, Julia

AU - de Prost, Nicolas

AU - Tandjaoui-Lambiotte, Yacine

AU - Luyt, Charles Edouard

AU - Amador-Borrero, Blanca

AU - Gaudet, Alexandre

AU - Poissy, Julien

AU - Morel, Pascal

AU - Richard, Pascale

AU - Cognasse, Fabrice

AU - Troya, Jesús

AU - Trouillet-Assant, Sophie

AU - Belot, Alexandre

AU - Saker, Kahina

AU - Garçpn, Pierre

AU - Rivière, Jacques G.

AU - Lagier, Jean Christophe

AU - Gentile, Stéphanie

AU - Rosen, Lindsey B.

AU - Shaw, Elana

AU - Morio, Tomohiro

AU - Tanaka, Junko

AU - Dalmau, David

AU - Tharaux, Pierre Louis

AU - Sene, Damien

AU - Stepanian, Alain

AU - Mégarbane, Bruno

AU - Triantafyllia, Vasiliki

AU - Fekkar, Arnaud

AU - Heath, James R.

AU - Franco, José Luis

AU - Erikstrup, Christian

AU - Mogensen, Trine H.

AU - Casanova, Jean Laurent

AU - Amsterdam UMC Covid-19 Biobank Investigators

AU - COVID Human Genetic Effort

AU - CP-COVID-19 Group

AU - CONSTANCES cohort

AU - 3C-Dijon Study

AU - Cerba Health-Care

AU - Etablissement Français du Sang Study group

AU - HGID Lab

AU - COVID Clinicians

AU - COVID-STORM Clinicians

AU - NIAID Immune Response to COVID Group

AU - NH-COVAIR Study Group

AU - Danish CHGE

AU - Danish Blood Donor Study

AU - St. James's Hospital, SARS CoV2 Interest Group

AU - French COVID Cohort Study Group

AU - Imagine COVID Group

AU - The Milieu Intérieur Consortium

AU - CoV-Contact Cohort

N1 - Publisher Copyright: Copyright © 2022 the Author(s).

PY - 2022/5

Y1 - 2022/5

N2 - Severe 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-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼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-α2 or IFN-ω, 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-α2 or IFN-ω, 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-α2 and IFN-ω. 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.

AB - Severe 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-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼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-α2 or IFN-ω, 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-α2 or IFN-ω, 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-α2 and IFN-ω. 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.

KW - autoantibodies

KW - COVID-19

KW - infection fatality rate

KW - relative risk

KW - type I IFNs

UR - http://www.scopus.com/inward/record.url?scp=85131944795&partnerID=8YFLogxK

U2 - 10.1073/pnas.2200413119

DO - 10.1073/pnas.2200413119

M3 - Journal article

C2 - 35576468

AN - SCOPUS:85131944795

VL - 119

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 21

M1 - e2200413119

ER -