Most people experience mild COVID-19, but 10-15% of patients develop severe disease requiring hospitalization and oxygen support, while 3-5% progress to a critical condition with a high risk of fatality. In addition to age-related factors and chronic diseases, the immune response plays a crucial role in COVID-19, particularly the level of type I interferons (IFN-I) – key protective cytokines in viral infections.
Patients with severe COVID-19 exhibit reduced IFN-I levels and delayed production. Specifically, 13.6% of critical COVID-19 patients were found to have autoantibodies that neutralize IFN-α and IFN-ω, impairing typical antiviral defense. Additionally, severe COVID-19 patients exhibit elevated levels of pro-inflammatory cytokines/chemokines (TNF, IL-6, IL-1b, IL-8), increased C-reactive protein (CRP), D-dimer, and ferritin, lymphopenia, and low concentrations of plasmacytoid dendritic cells, which produce IFN-I.
How IFN-α2 Levels Relate to COVID-19 Outcomes
French researchers investigated the dynamics of the IFN response to COVID-19. The study included 140 patients:
- Group 1 – patients with severe pneumonia requiring at least 3 L/min of oxygen (81 individuals);
- Group 2 – patients with critical pneumonia requiring non-invasive or mechanical ventilation in the intensive care unit (59 individuals).
The control group consisted of 20 healthy blood donors.
The study lasted 90 days, measuring patients’ circulating IFN-α2 concentrations and SARS-CoV-2 viral load.
In patients with fatal outcomes, IFN-α2 levels declined more rapidly within the first six days of hospitalization. High viral load was also associated with an increased risk of death.
At hospital admission, baseline IFN-α2 levels in both groups were elevated compared to the control group. Severe patients had higher IFN-α2 levels than critical patients. However, baseline and day-6 IFN-α2 levels were not correlated with survival.
Some patients with severe and critical COVID-19 were found to have autoantibodies (auto-Abs) neutralizing IFN-α2. Auto-Abs neutralized high IFN-α2 concentrations in 3.7% and 5.2% of severe and critical patients, respectively, and low concentrations in 5.2% and 6.2%, respectively. IFN-α2 levels remained consistently low in these patients, but this did not affect disease outcomes. Auto-Abs against IFN-α2 or IFN-ω were present in 5% and 19.4% of patients in high and low concentrations, respectively. The presence of these autoantibodies was not associated with an increased risk of death.
Compared to healthy individuals, severe and critical COVID-19 patients had lower levels of plasmacytoid dendritic cells (pDCs) responsible for IFN-I production. The reduction in pDCs did not correlate with plasma IFN-α2 levels and was not linked to mortality.
IFN-α2 levels on day 6 declined more significantly in severe patients who later died than in survivors. The change in IFN-α2 levels from day 1 to day 6 (D6/D1 ratio) predicted mortality risk, but only in patients without neutralizing autoantibodies against IFN-α2 – likely because patients with such autoantibodies already had consistently low IFN-α2 levels. The lower the D6/D1 ratio, the higher the risk of death from COVID-19.
Over time, viral load significantly decreased in both severe and critical patients. However, among severe patients who died after day 6, viral load on days 1 and 6 was higher than in survivors. On the first day (at admission), viral load correlated with serum IFN-α2 levels, but by day 6, this correlation disappeared.
Conclusion
In severe and critical COVID-19 patients, IFN-α2 levels were elevated compared to healthy individuals and correlated with viral load. However, patients who failed to maintain sufficient IFN-α2 levels faced a higher risk of fatal outcomes. High viral load on days 1 and 6 was also associated with an increased risk of death.
Neutralizing autoantibodies against IFN-α2 were found in 5% of severe and critical patients. Their presence correlated with low IFN levels but did not affect mortality.
Type I IFN deficiency may result from congenital abnormalities in TLR7 and TLR3 receptors, IRF7 protein, or neutralizing autoantibodies against IFN.
Early interferon administration may prevent severe COVID-19 progression. Recent studies have shown that pegylated interferon-λ (a type III interferon) reduces the risk of severe COVID-19, while IFN-α2b accelerates viral clearance. Type I IFN treatment, in combination with dexamethasone and tocilizumab, may be beneficial for severe patients with a rapid decline in IFN-α2.
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Reference
More rapid blood interferon α2 decline in fatal versus surviving COVID-19 patients
