biostudies-literatureUnknownManry JIntramural NIH HHSNCATS NIH HHSNIAID NIH HHSNHGRI NIH HHSNCI NIH HHSNIH HHSSARS-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.Research squarers.3.rs-1225906https://www.ebi.ac.uk/biostudies/studies/S-EPMC8764723biostudies-literatureThe risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies.PMC8764723ZIA AI001265R01 AI091707U19 AI111825ZIA AI001270R01 AI088364R01 AI163029UL1 TR00186675N91019D00024UL1 TR001863S10 OD018521U24 HG008956UM1 HG006504Tsumura MNussenzweig MAnglicheau DLampasona VBurdet CVinh DDuvlis SSu HZins MZhang QDuffy DLifton RPiemonti LMegarbane BReyes LRichard PKurolap ACiceri FKlocperk AGervais AKoning RDelmonte OMorel PHolland SGilardin LHaljasmagi LFekkar ACasari Gde Prost NdeLamballerie XRodriguez-Gallego CEl Bakkouri JDyer ABastard PLorenzo LWauters JHeath JCognasse FShcherbina ABilguvar KTroya JCasanova JLvan de Beek DCondino-Neto ATharaux PLMane SPeterson PGentile SPan-Hammarstrom QRice CLyonnet STandjaoui-Lambiotte YRosain JErikstrup CSole-Violan JOzcelik TAlKhater SBoisson BAiuti AHammarstrom LParra-Martinez AZhang SYRiviere JGBousfiha AMeyts IKennelly SAnaya JMFellay JHagin DLe Voyer TJouanguy EColobran RShaw EVidaur LTanaka JHermine OMartinez-Picado JCoulongeat MHalwani RArrestier RMogensen THVasse MGarcia-Prat MBelot AMichailidis ESahanic SBeziat VKeles SLagier JCPujol ARamirez-Santana CHaerynck FKisand KTriantafyllia VMonneret GSarekannu KMaslovskaja JBoudhabhay IPaul SBiggs CPuel ALau YLTrouillet-Assant SMond JBoyarchuk OBarreiros LBoucherit SPrando CRigo-Bonnin RSharif-Askari FSusen SGaudet ADorgham KLuyt CEDupont AMorandeira FRoussel LGarcon PMarlet JCastagnoli RSallette JStepanian ASoler-Palacin PVidigal MRowen LSolanich XAbel LTiberghien PPhilippot QBaris-Feldman HDebette SMehlal-Sedkaoui SBondarenko AHoffmann HHEto SBouadma LStepanovskyy YAmador-Borrero BDalmau DTancevski IGorochov GYang RBurrel SBizien LAndreakos EMetz CRaoult DBiondi ALeung DMoncada-Velez MBourke NNussbaum RCobat ABonfanti PNukui YSpaan AZatz MPlanas ASnow AManry JDominguez-Garrido EKann NRosen LSene DMigaud MSaker KMorio TGregersen PPoissy JImberti LAnderson MFranco JZhang YChauvineau-Grenier AArias AVenet FNotarangelo LTangye SOkada SQuintana-Murci LfalseThe risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies.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.2022-01-01T00:00:00Z2022 Jan2024-10-15T12:56:50.042Z2022-02-11T16:22:16.955ZS-EPMC87647233504310910.21203/rs.3.rs-1225906/v1