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

Abstract

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.

Keywords: COVID-19; autoantibodies; infection fatality rate; relative risk; type I IFNs.

Fig. 1.

RRDs for individuals with auto-Abs neutralizing low concentrations of IFN-α2 or IFN-ω relative to individuals without such auto-Abs, by age and sex. RRDs are displayed on a logarithmic scale (A) for six age classes and (B) for male and female subjects under and over the age of 70 y. Vertical bars represent the 95% CI.

Fig. 2.

RRDs for individuals with auto-Abs neutralizing different combinations of type I IFNs relative to individuals without such auto-Abs, by age. RRDs are displayed on a logarithmic scale for individuals under and over 70 y of age with (A) auto-Abs neutralizing low concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω, IFN-α2, and IFN-ω and (B) auto-Abs neutralizing high concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω, IFN-α2, IFN-ω, and IFN-β, relative to individuals without such combinations of auto-Abs. Vertical bars represent the 95% CI.

Fig. 3.

SARS-CoV-2 IFRs by age. IFRs are provided for the general population for both sexes (gray) and for males only (blue), from the data of O’Driscoll et al. (6); IFR_AAB (green) are shown for individuals carrying auto-Abs neutralizing low concentrations of IFN-α2 or IFN-ω. Auto-Abs against type I IFNs are associated with high RRDs and strongly increase the IFR, to a much greater extent than being male, and, by inference, than other common classical risk factors providing ORs of death similar to that for being male (around two), such as certain comorbid conditions, or the most significant common genetic variant on chromosome 3 (5).

Fig. 4.

SARS-CoV-2 IFRs for carriers of various combinations of neutralizing auto-Abs, by age. IFR_AAB values (percent) are displayed, on a logarithmic scale, by age, for individuals with (A) auto-Abs neutralizing low concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω, IFN-α2, and IFN-ω and (B) auto-Abs neutralizing high concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω, IFN-α2, IFN-ω, and IFN-β. Vertical bars represent the 95% CI. Horizontal black lines represent the IFR provided by O’Driscoll et al. (6).