The past 2 years have witnessed the infection of millions of people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The course of infection is highly variable. Some young patients have died, while several centenarians, having already lived through the 1918 influenza pandemic, have survived SARS-CoV-2 infection—without experiencing severe respiratory symptoms.
These anecdotal observations belie a key risk factor that emerged early on: The risk of death doubles for every 5 years of age (1, 2). Comorbid conditions have also been shown to affect outcome, but with a lower relative risk (3). Risk factors are not causal explanations, and the question remains: Why is SARS-CoV-2 infection fatal in more than 10% of people over 80 years old but in fewer than 0.001% of individuals below 18 years old?
Since the onset of the pandemic, the COVID Human Genetic Effort (CHGE) has recruited patients infected with SARS-CoV-2 who exhibit either mild infection or severe and/or critical COVID-19 pneumonia (i.e., requiring oxygen supplementation) (4). We sequenced these patients’ exomes to test our hypothesis that some individuals with life-threatening COVID-19 have underlying inborn errors of immunity (IEI) (5).
Mutations in interferon regulatory factor 7 (IRF7) are already known to underlie severe viral infections such as fulminant influenza pneumonia (6). In patients with life-threatening COVID-19 pneumonia, including previously healthy adults, we found IEI that affect Toll-like receptor 3 (TLR3)– and IRF7-dependent type I interferon (IFN) immunity with complete or autosomal-recessive IRF7 or IFN-α/β receptor subunit 1 (IFNAR1) deficiency. A parallel unbiased genome-wide approach found loss-of-function variants of X-linked gene TLR7 in more than 1% of men with life-threatening COVID-19, leading to deficient type I IFN production (7). On this genetic basis, could other types of type I IFN pathway deficiencies account for life-threatening COVID-19 in other patients (8)?
Autoantibodies (auto-Abs) have been described for IFN-γ, interleukin-6 (IL-6), IL-17A, and IL-17F and associated with susceptibility to infection (9). We first tested for the presence of auto-Abs in a cohort of 987 individuals with critical COVID-19 compared with more than 663 asymptomatic patients (10). In patients with critical COVID-19, 10% had immunoglobulin G (IgG) auto-Abs that neutralized high amounts of IFN-ω and/or the 13 individual types of IFN-α. Further, these auto-Abs prevented IFN-α2 from blocking SARS-CoV-2 in vitro.
In autoimmune polyglandular syndrome type-1 (APS-1), affected individuals produce auto-Abs against type I IFNs from early childhood onward. Among a group of APS-1 patients, aged 8 to 48 years, infected with SARS-CoV-2, we found that most were hospitalized for COVID-19 pneumonia, with a fatal outcome for 18% (11). In a separate study of over 4000 patients with severe and/or critical COVID-19, we detected auto-Abs that neutralized more physiological concentrations of IFN-α2 and/or IFN-ω in over 15% of patients with critical COVID-19 pneumonia, including more than 20% of patients over 80 years, and ∼20% of those who died (12). Notably, another 1% of the patients only had auto-Abs against IFN-β. When we looked at a group of 34,000 uninfected individuals, we found that the prevalence of auto-Abs that neutralized high concentrations of type I IFNs increased markedly with age. Auto-Abs were present in 0.18% of those 18 to 69 years, 1.1% of those 70 to 80 years, and 3.4% of those over 80 years. The proportion of patients that produced auto-Abs neutralizing physiological concentrations (i.e., 100-fold lower) was even greater, with 1% of those under 70 years, 2.3% of those 70 to 80 years, and 6.4% of those over 80 years.
The findings outlined here provide clues to the reasons why COVID-19 is fatal for some individuals 70 years and older (8). The presence of preexisting auto-Abs against type I IFNs can account for severe disease in some older individuals, as it does in many younger patients presenting with life-threatening COVID-19. Since discovering the role of auto-Abs to type I IFNs in COVID-19 in 2020, I have focused on leading the studies of these auto-Abs in our laboratory and performing studies on COVID-19 as part of the effort led by Qian Zhang and Jean-Laurent Casanova within the CHGE (4). Our observations have several important medical implications: Patients infected with SARS-CoV-2 could be tested for auto-Abs against type I IFNs (e.g., IFN-α2, IFN-ω, IFN-β), and in individuals in at-risk groups (e.g., people 70 years and older, or patients with autoimmune conditions), these tests could be performed at any time (5, 9, 10, 12). Auto-Ab–positive patients should be vaccinated against SARS-CoV-2 as a matter of priority, but not with a live attenuated vaccine (13, 14). In cases of infection, these patients should be hospitalized and would benefit from early treatment with antiviral compounds, monoclonal antibodies (15–17), and/or IFN-β, provided they have neither pneumonia nor auto-Abs against IFN-β (18). Early administration of type I IFNs in patients infected with SARS-CoV-2 could prevent viral growth and uncontrolled infection, which can lead to a cytokine storm and life-threatening COVID-19. Other treatments designed to enhance the type I IFN pathway, or to replicate its antiviral effects, are of potential interest for the treatment of SARS-CoV-2 infection.
Beyond COVID-19, many other viral diseases increase in severity with age, suggesting a possible role of auto-Abs against type I IFNs in their severity. We have shown previously that auto-Abs that neutralize type I IFNs underlie one-third of adverse reactions to the live-attenuated yellow fever virus vaccine (11). It therefore appears likely that these auto-Abs also underlie other viral infections, especially those for which severity increases with age. Influenza affects millions of people worldwide every year, causing between 200,000 and 650,000 deaths (19). It remains unclear why deaths from influenza disproportionately affect the elderly (20), but some of these deaths could be due to auto-Abs that neutralize type I IFNs. Why does the prevalence of auto-Abs against IFNs increase with age? The answer might provide hints to targeted treatments for preventing auto-Abs from being produced in the first place, or for their targeted removal prior to infection. It might also help to explain other issues, from the redundancy of type I IFNs to the causes of various autoimmune diseases.
PHOTO: COURTESY OF QUENTIN LEMAIRE/INSTITUT IMAGINE
GRAND PRIZE WINNER
Paul Bastard
Paul Bastard, MD, PhD, is currently working as a chief resident in the Department of Pediatrics at the Necker Hospital for Sick Children (AP-HP, Paris, France) while also doing research in the Necker branch of the laboratory of Jean-Laurent Casanova, located at the Imagine Institute (University of Paris and INSERM) and the Rockefeller University (New York, USA). His research focuses on the genetic and immunological determinants of severe viral diseases, including the causes and consequences of autoantibodies against type I interferons.
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