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

Abstract

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.

Hospital trajectories and early predictors of clinical outcomes differ between SARS-CoV-2 and influenza pneumonia

“…An important question raised by our study is “what are the distinct pathophysiological phenomena of SARS-CoV-2 infection which underpin these observed differences between viral pneumonias?” While our study's retrospective design limits interpretation of our findings to hypothesis generation, several interesting patterns have nevertheless emerged. Age being the most important predictor of SARS-CoV-2 pneumonia outcome - in the presence of fewer comorbidities than influenza - suggests that age-dependent, rather than acquired, immunosenescence may be more important in SARS-CoV-2-driven disease, 40 , 41 , 42 , 43 a finding with particular relevance given analogous responses to SARS-CoV-2 spike protein vaccines. 44 The degree to which these hypothesized pathogen-specific differences are due to variable virus-host cell receptor binding affinity, immune evasion, host response variance, or some combination thereof requires further investigation.…”