20 September 2021: Editorial
Editorial: Autoantibodies to Components of the Immune System, Including Type 1 Interferons, and the Risk of Severe COVID-19Dinah V. Parums1CDEF*
Med Sci Monit 2021; 27:e934766
ABSTRACT: During the past two years, clinical studies have attempted to identify risk factors to predict clinical outcomes following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In July 2021, a study using a high-throughput technique detected autoantibodies to chemokines, cytokines, and complement components in patients with symptomatic coronavirus disease 2019 (COVID-19). In August 2021, a study identified pre-existing autoantibodies to type 1 interferons (IFNs) in 10% of patients with severe COVID-19 but not asymptomatic individuals. Autoantibodies may be the long-awaited markers of clinical risk for severe COVID-19 in patients with SARS-CoV-2 infection. This Editorial aims to present some recent findings of autoantibodies to components of the immune system, including type 1 IFNs, and the risk of severe COVID-19.
Keywords: Editorial, Autoantibodies, Interferons, Risk, severe acute respiratory syndrome coronavirus 2, COVID-19, COVID-19, Humans, Interferon Type I, SARS-CoV-2
During the past two years, observational clinical studies and population studies have attempted to identify risk factors to predict clinical outcomes following infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1–4]. However, the risk factors for severe coronavirus disease 2019 (COVID-19) and the clinical outcomes are likely to vary between individuals [3–5]. These associations or general risk factors are not absolute, as severe disease and mortality from COVID-19 have been reported in young patients and previously healthy individuals [3,4].
In July 2021, the US National COVID Cohort Collaborative (N3C) Consortium reported the findings from a retrospective cohort study on the predictive factors associated with the development of severe COVID-19 . The N3C study cohort included 174,568 adults with confirmed SARS-CoV-2 infection diagnosed between January 1, 2020, and December 7, 2020, the largest COVID-19 cohort currently evaluated . In the study cohort, 18.6% of patients were hospitalized, and 20.2% required invasive ventilation . Patient mortality, or discharge to hospice care, was reported in 11.6% of hospitalized patients with COVID-19 .
Therefore, there is still a need to understand why age and certain underlying health conditions increase the severity of COVID-19 and patient mortality . Identifying risk factors or profiles for both susceptibility and severity of COVID-19 is of global importance for allocating healthcare resources during the COVID-19 pandemic [5,6].
In a publication in the journal Nature, in July 2021, Wang and colleagues reported using a high-throughput technique to detect autoantibodies to screen a cohort of 194 individuals with confirmed SARS-CoV-2 . In this study, 172 patients had COVID-19, and 22 healthcare staff were asymptomatic or had mild symptoms . The high-throughput screening method screened for autoantibodies to 2,770 secreted and extracellular proteins . Patients with symptomatic COVID-19 had a significant increase in autoantibody reactivity compared with non-infected individuals . The screening method detected autoantibodies to chemokines, cytokines, and complement components, which are all immune modulators .
In August 2021, an international team of immunologists identified pre-existing autoantibodies to type 1 interferons (IFNs) in 10% of patients with severe COVID-19, but not in individuals with asymptomatic infection . Immunologists at the Rockefeller University, New York City, led this international research team . The study included 3,595 patients from 38 countries with confirmed severe COVID-19 admitted to intensive care units (ICUs) . Of these critically ill patients, 13.6% had autoantibodies, and of the patients who died while in the ICU, 18% had autoantibodies . In critically ill patients under 40 years of age, autoantibodies were present in 21% . These neutralizing autoantibodies were to either IFN-α or IFN-ω, and 1.3% of patients with critical COVID-19 and 0.9% of patients who died had autoantibodies to IFN-β. . The autoantibodies to IFNs were identified as a cause rather than a consequence of the development of severe COVID-19 . In October 2020, this research group previously showed that autoantibodies were present in only 4 in 1,000 healthy people who had blood samples collected before the COVID-19 pandemic .
Several studies have reported an association between the reduced activity of IFNs and increased susceptibility to severe COVID-19 [10,11]. In October 2020, Zhang and colleagues reported that inborn errors of TLR3-dependent and IRF7-dependent type I IFN immunity were associated with severe and life-threatening COVID-19 pneumonia . In August 2021, Asano and colleagues showed that individuals with genetic mutations that alter the activity of type 1 interferons were at increased risk of developing severe COVID-19 . Type I IFNs have a key role in innate and adaptive immune cell responses during infection from organisms that include viruses . Also, type I IFNs are involved in complex immuno-regulatory networks that usually, but not always, protect the host from infection, with minimal immunological damage to the host .
Ongoing studies have identified a possible role for autoantibodies in the development of clinically severe COVID-19. It is possible that autoantibodies to components of the immune system, which are either pre-existing or develop after infection, impair immune control of SARS-CoV-2. The role of autoantibodies to components of the immune system in the pathogenesis of COVID-19 may involve inhibition of immunoreceptor signaling or directly affect immune cells. There is the possibility that newly identified autoantibodies may be the long-awaited markers for clinical risk of severe COVID-19 in patients with SARS-CoV-2 infection.
1. Grasselli G, Greco M, Zanella ACOVID-19 Lombardy ICU Network, Risk factors associated with mortality among patients with COVID-19 in Intensive Care Units in Lombardy, Italy: JAMA Intern Med, 2020; 180(10); 1345-55
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3. Sandoval M, Nguyen DT, Vahidy FS, Graviss EA, Risk factors for severity of COVID-19 in hospital patients age 18–29 years: PLoS One, 2021; 16(7); e0255544
4. Wu Z, McGoogan JM, Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention: JAMA, 2020; 323; 1239-42
5. Bennett TD, Moffitt RA, Hajagos JGNational COVID Cohort Collaborative (N3C) Consortium, Clinical characterization and prediction of clinical severity of SARS-CoV-2 infection among US adults using data from the US National COVID Cohort Collaborative: JAMA Netw Open, 2021; 4(7); e2116901
6. Miller IF, Becker AD, Grenfell BT, Metcalf CJE, Disease and healthcare burden of COVID-19 in the United States: Nat Med, 2020; 26(8); 1212-17
7. Wang EY, Mao T, Klein J, Diverse functional autoantibodies in patients with COVID-19: Nature, 2021; 595(7866); 283-88
8. Bastard P, Gervais A, Le Voyer T, Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths: Sci Immunol, 2021; 6(62); eabl4340
9. Bastard P, Rosen LB, Zhang Q, Autoantibodies against type I IFNs in patients with life-threatening COVID-19: Science, 2020; 370(6515); eabd4585
10. Zhang Q, Bastard P, Liu Z, Inborn errors of type I IFN immunity in patients with life-threatening COVID-19: Science, 2020; 370(6515); eabd4570
11. Asano T, Boisson B, Onodi F, X-linked recessive TLR7 deficiency in ~10f men under 60 years old with life-threatening COVID-19: Sci Immunol, 2021; 6(62)
12. McNab F, Mayer-Barber K, Sher A, Type I interferons in infectious disease: Nat Rev Immunol, 2015; 15(2); 87-103
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