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.

Figure 1. Relative risks of death associated with auto-Abs neutralizing low concentrations of IFN-α2 or -ω, by age and sex.

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 years. Vertical bars represent the 95% CI.

Figure 2. Relative risks of death associated with auto-Abs neutralizing various combinations of type I IFNs, by age.

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 years of age with (A) auto-Abs neutralizing low concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω, IFN-α2, 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.

Figure 3. SARS-CoV-2 infection fatality rates by age.

IFRs are provided in the general population for both sexes (gray) and for males only (blue) using the data of O’Driscoll et al. ; IFR_AAB (green) are shown for individuals carriers of 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 IFR, to a much greater extent than maleness, and by inference than other classical common risk factors providing ORs of death similar to maleness (around 2) such as some comorbidities, or the most significant common genetic variant on chromosome 3³.

Figure 4. SARS-CoV-2 infection fatality rates for carriers of various combinations of neutralizing auto-Abs, by age.

IFR_aab values (%) 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, 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 lFN-β. Vertical bars represent the 95% CI. Horizontal black lines represent the IFR provided by O’Driscoll et al.