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

Abstract

Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

“…It is also not unreasonable to speculate that, despite an infection with a vaccine-covered viral variant and a normal antibody response to the vaccine, a small proportion of the patients with such auto-Abs might not be fully protected by the vaccine, especially if infected with a high viral inoculum. By inference from previous studies, the auto-Abs of the 8 patients neutralizing IFN-α2 also probably neutralizes the 13 types of IFN-α ( 10 , 20 , 22 , 35 , 36 ). These findings suggest that a potent post-vaccine humoral immunity can be insufficient to fight SARS-CoV-2 infection, especially in patients with auto-Abs neutralizing both IFN-α2 and IFN-ω, and even more so at high concentration.…”

“…Our results here suggest it may be beneficial to test for auto-Abs to type I IFN in vaccinated patients diagnosed with breakthrough COVID-19 pneumonia of varying severity. Testing uninfected people, including vaccinated individuals, may also be considered, especially in those over 70 years old given the high prevalence of auto-Abs to type I IFNs in this population (>4%) and their lower global type I IFN immunity ( 30 , 36 ). One of the 10 patients suffered from APS-1 and thus most likely harbored these auto-Abs since early childhood ( 20 , 21 , 37 ), while another patient had myasthenia gravis, which is also commonly associated with these auto-Abs ( 38 ).…”

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

“…In addition, XR TLR7 deficiency was identified in 7% of the 71 unrelated male children with COVID-19 pneumonia, with no significant difference between male patients born to consanguineous parents and male patients born to non-consanguineous parents (20 vs. 7.7%, Fisher’s exact test, P = 0.27), and 6.1% of 49 unrelated male children with critical COVID-19 pneumonia, vs. 1.3% of adult males with critical pneumonia ages 16–60 yr ( Asano et al, 2021 ). This higher proportion probably results from (a) the small number of patients with these inborn errors reaching adulthood undiagnosed, and (b) other risk factors, such as auto-Abs against type I IFN, which increase with age ( Manry et al, 2022 ). However, the clinical penetrance of these four recessive type I IFN deficiencies for COVID-19 pneumonia probably increases with age and probably depends on the deficiency.…”

“…The pediatric population is, therefore, generally considered “safe,” with an IFR of ∼0.001%, and a frequency of critical pneumonia thought to be on the order of 0.01%, but which remains to be estimated accurately ( Knock et al, 2021 ; Le Vu et al, 2021 ). The risks of comorbidities and auto-Abs against type I IFNs both increase with age ( Bastard et al, 2021a ; Manry et al, 2022 ), whereas the levels of tonic type I IFN immunity in the respiratory tract decrease with age ( Loske et al, 2021 ), and the production of type I IFN by pDCs is stronger in children than in adults ( Splunter et al, 2019 ). These factors may both protect children and contribute to the age-dependent increase in the risk of COVID-19 pneumonia.…”

The AI-Assisted Identification and Clinical Efficacy of Baricitinib in the Treatment of COVID-19

“…Presumably this inhibition of the initial IFN response allows the virus to replicate in the early stages of the disease. Consistent with this, patients that have defects in the IFN system (e.g., anti-IFN autoantibodies) tend to experience severe disease and delayed viral clearance [19][20][21][22]. IFN response genetic variants have also been identified which are associated with severe disease [23], including the antiviral restriction enzyme activators OAS1, 2 and 3, the antiviral receptor TLR7 [24] and the IFN receptor IFNAR2.…”