Study: The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies. Image Credit: NIAID

COVID-19 Mortality Strongly Predicted by Type I Interferon Autoimmunity and Older Age

In a recent study published in the journal PNAS, researchers estimated the death rate from severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) infection and the relative risk of death (RRD) in subjects of all ages. Study participants either harbored autoantibodies (auto-Abs) that neutralized low concentrations (100 pg/mL) or high concentrations (10 ng/mL) of type I interferons (IFNs) such as FN-α, IFN-β and IFN-ω or non-carriers.

Studies have reported that pre-existing type I neutralizing self-abs IFNs are strong predictors of potentially fatal coronavirus disease 2019 (COVID-19) pneumonia. Moreover, the prevalence of self-abs and the risks of mortality from COVID-19 are higher in men and increase with age. Therefore, it is critical to quantify the impact of these self-Abs on COVID-19-associated deaths by sex and age.

​​​​​​​Study: The risk of death from COVID-19 is much higher and depends on age with anti-IFN type I autoantibodies. ​​​​​​Image credit: NIAID

About the study

In the present study, researchers estimated the IFR and RRD of COVID-19 in deceased COVID-19 patients and the general public who were either carriers of type I IFN-neutralizing auto-Abs or not. carriers.

The study included 1,261 unvaccinated deceased COVID-19 patients and 34,159 subjects from the general public who were sampled prior to the COVID-19 pandemic. The study population was between 20 and 99 years old. Patients who died from COVID-19 died from COVID-19 pneumonia.

For auto-Abs that neutralized low levels of IFN-ω and/or IFN-α2, 1,121 deceased COVID-19 patients and 10,778 general public subjects were analyzed. Auto-Abs that neutralized high concentrations of IFN-ω and/or IFN-α2 were evaluated among 1,094 deceased COVID-19 patients and 34,159 individuals from the general public. Auto-Abs that neutralized elevated IFN-β concentrations in 636 deceased COVID-19 patients and 9,126 subjects from the general public were also evaluated.

The DRR of subjects carriers of neutralizing IFN type I auto-Abs compared to non-carriers was estimated using Firth’s logistic regression model. The odds ratios (OR) obtained using logistic regression were related to the relative risks (RR). In addition to global IFRs, IFRAAB were calculated based on Bayes’ theorem. The population attributable fraction (PAF) was also assessed to assess the proportion of COVID-19 mortality attributable to self-Abs.

Results

The RRD associated with any auto-Abs combination was more significant in subjects less than 70 years of age. For self-Abs neutralizing either IFN-ω or IFN-α2, the RRDs were 17 and 5.8, respectively, for subjects under and over 70 years of age. On the other hand, for auto-Abs that neutralize IFN-ω and IFN-α2, the corresponding RRDs were 188.3 and 7.2, respectively.

RRD for individuals with neutralizing self-Abs different combinations of type I IFN compared to individuals without such self-Abs, by age.  RRDs are displayed on a logarithmic scale for people under and over 70 with (A) self-Abs neutralizing low levels of IFN-α2 and IFN-ω, IFN-α2 or d 'IFN-ω, IFN-α2 and IFN-ω and (B) self-Abs neutralizing high concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω , IFN-α2, IFN-ω and IFN-β, compared to individuals without these combinations of self-Abs.  The vertical bars represent the 95% CI.RRD for individuals with neutralizing self-Abs different combinations of type I IFNs compared to individuals without these self-Abs, by age. RRDs are displayed on a logarithmic scale for people under and over 70 with (A) self-Abs neutralizing low levels of IFN-α2 and IFN-ω, IFN-α2 or d ‘IFN-ω, IFN-α2 and IFN-ω and (B) self-Abs neutralizing high concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω , IFN-α2, IFN-ω and IFN-β, compared to individuals without these combinations of self-Abs. The vertical bars represent the 95% CI.

On the other hand, the IFRs were higher with age and varied from 0.17% to 26.7% in subjects aged less than 40 years and over 80 years, for self-Ab neutralizing IFN- ω or IFN-α2. IFRs ranged from 0.84% ​​to 40.5% for auto-Abs, which neutralized IFN-ω and IFN-α2.

For all Auto-Abs combinations, the IFRAAB was much higher than overall IFR in carriers of auto-Abs, counteracting low concentrations of IFN-ω or IFN-α2. IFRAAB values ​​exceeded 1% in subjects over 40 years of age and 10% in those over 60 years of age. The highest IFRAAB of 40.5% was observed in carriers of self-neutralizing antibodies IFN-ω and IFN-α2 aged over 80 years.

Note that the IFRAAB values ​​were higher in men than in women by 2.7 and 5 times, especially in subjects with auto-Abs that neutralized low and high concentrations of IFN-ω and IFN -α2, respectively. PAFs for self-Abs neutralizing low and high concentrations of type I IFN were found to closely match the prevalence of self-Abs in patients who died of COVID-19.

IFR SARS-CoV-2 by age.  IFRs are provided for the general population for both sexes (grey) and for males only (blue), based on data from O'Driscoll et al.  ;  IFRAAB (green) are indicated for people with self-Abs that neutralize low levels 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 being male, and, by inference, other risk factors common classics providing RCs of death similar to that of being male (about two), such as certain comorbid conditions, or the most prominent common genetic variant on chromosome 3.IFR SARS-CoV-2 by age. IFRs are provided for the general population for both sexes (grey) and for males only (blue), based on data from O’Driscoll et al. ; IFRAAB (green) are indicated for individuals carrying self-Abs that neutralize low levels 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 being male, and, by inference, other risk factors common classics providing RCs of death similar to that of being male (about two), such as certain comorbid conditions, or the most prominent common genetic variant on chromosome 3.

Type I IFN-neutralizing self-Abs increased IFRs and were associated with elevated RRDs, especially those that neutralized both IFN-ω and IFN-α2. Notably, IFRs increased significantly with age and male gender, while RRDs decreased with age and did not vary significantly with gender.

conclusion

Overall, the study results showed that male gender, increasing age, and the presence of auto-Abs against type I IFNs strongly increased the IFR of SARS-CoV-2 in deceased COVID-19 patients and the general public.

IFN type I immunity is required for protective immunity against SARS-CoV-2 infections. Auto-abs versus type I IFNs are strong and commonly used predictors of life-threatening COVID-19. Therefore, the type I IFN-neutralizing auto-ab test should be considered to assess the risk of mortality from COVID-19 in patients with COVID-19 and the general public.

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