Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

• Published in: Clinical & translational immunology 2022, Vol.11 (4), p.e1365-n/a
• Main Authors: Gray, Paul E, Bartlett, Adam W, Tangye, Stuart G
• Format: Article
• Language: English
• Subjects: Autoantibodies; Coronaviruses; COVID-19; Immune response; Immunodeficiency; inborn errors of immunity; Innate immunity; Interferon; interferon autoantibodies; Mortality; Primary immunodeficiencies; primary immunodeficiency; Prophylaxis; Review; Reviews; Risk factors; Severe acute respiratory syndrome coronavirus 2; TLR3 protein; TLR7 protein; Toll-like receptors; Vaccination; Viral infections
• ISSN: 2050-0068; 2050-0068
• DOI: 10.1002/cti2.1365

Since the emergence of the COVID‐19 pandemic in early 2020, a key challenge has been to define risk factors, other than age and pre‐existing comorbidities, that predispose some people to severe disease, while many other SARS‐CoV‐2‐infected individuals experience mild, if any, consequences. One explanation for intra‐individual differences in susceptibility to severe COVID‐19 may be that a growing percentage of otherwise healthy people have a pre‐existing asymptomatic primary immunodeficiency (PID) that is unmasked by SARS‐CoV‐2 infection. Germline genetic defects have been identified in individuals with life‐threatening COVID‐19 that compromise local type I interferon (IFN)‐mediated innate immune responses to SARS‐CoV‐2. Remarkably, these variants – which impact responses initiated through TLR3 and TLR7, as well as the response to type I IFN cytokines – may account for between 3% and 5% of severe COVID‐19 in people under 70 years of age. Similarly, autoantibodies against type I IFN cytokines (IFN‐α, IFN‐ω) have been detected in patients' serum prior to infection with SARS‐CoV‐2 and were found to cause c. 20% of severe COVID‐19 in the above 70s and 20% of total COVID‐19 deaths. These autoantibodies, which are more common in the elderly, neutralise type I IFNs, thereby impeding innate antiviral immunity and phenocopying an inborn error of immunity. The discovery of PIDs underlying a significant percentage of severe COVID‐19 may go some way to explain disease susceptibility, may allow for the application of targeted therapies such as plasma exchange, IFN‐α or IFN‐β, and may facilitate better management of social distancing, vaccination and early post‐exposure prophylaxis. Inborn errors of immunity of the TLR/interferon pathway and their autoantibody‐mediated phenocopies are emerging as major causes of up to 20% of severe COVID‐19 and 20% of deaths from the virus. This is a timely review that introduces the concept of inborn errors of immunity to a more broad audience of immunologists, and highlights the evidence for the role of previously unidentified of genetic and autoantibody defects of type I interferons in the viral pandemic.