Neutralizing Type I Interferon Autoantibodies in Japanese Patients With Severe COVID-19

Abstract

PurposeAutoantibodies (aAbs) to type I interferons (IFNs) have been found in <1% of individuals under the age of 60 in the general population, with the prevalence increasing among those over 65. Neutralizing autoantibodies (naAbs) to type I IFNs have been found in at least 15% of patients with life-threatening COVID-19 pneumonia in several cohorts of primarily European descent. We aimed to define the prevalence of aAbs to IFN-α2 in 3,456 Japanese controls aged 20–91 and of aAbs and naAbs to IFN-α2 and IFN-ω in 627 Japanese COVID-19 patients aged 0–104, among whom were 170 critical, 235 severe, 112 moderate, 105 mild, and 5 asymptomatic infections.MethodsELISA and ISRE reporter assays were used to detect aAbs and naAbs using E. coli-produced IFNs.ResultsIn an uninfected general Japanese population aged 20–91, we found aAbs in 0.087% of individuals. naAbs to type I IFNs (IFN-α2 and/or IFN-ω, 100 pg/mL) were detected in 10.6% of patients with critical infections, 2.6% of patients with severe infections, and ≤1% of patients with asymptomatic to mild infections. They were higher in COVID-19 patients over 50 (5.8%) than in younger patients (0%) and higher in men (5.5%) than in women (1.1%). A significant but not strong correlation between aAbs and naAbs to IFN-α2 existed (r=-0.307, p-value<0.0001), stressing the importance of measuring naAbs.ConclusionIn the largest study focusing on a single ethnic and geographic group, we show that Japanese individuals with pre-existing naAbs have a much higher risk of life-threatening COVID-19 pneumonia.

Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease

“…While this broadly contrasts with the findings of others who noted an association between presence of anti-IFN autoantibodies and increased COVID-19 disease severity parameters [2,3,5,7], this difference could be explained by a lack of power in our exploratory study or masking effects of the high standard of care in a high-resource setting. Nevertheless, the proportion of critically ill COVID-19 patients in our cohort with anti-IFN autoantibodies is remarkably consistent with the findings from several independent severe COVID-19 cohorts recently studied across Europe, Asia, and the Americas, despite the use of different detection assays [2][3][4][5][6][7][8][9][10][11]24,25]. Indeed, in the future, it will probably be important to have standardized quantitative assays and reporting standards for such anti-IFN autoantibodies, as varying assay sensitivities may mean that their presence is under or overestimated.…”

“…We did not identify any patients who were unambiguously positive for anti-IFNβ autoantibodies. The identification of anti-IFN autoantibodies in approximately 10% of severe COVID-19 patients is fully in line with previous reports from others [2][3][4][5][6][7][8][9][10][11].…”

“…The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has highlighted a previously unappreciated type of functional IFN deficiency mediated by autoantibodies that neutralize the action of several type I IFNs, particularly the IFNα or IFNω subtypes [2], and rarely IFNβ [3]. Across multiple independent studies, around 10% of critically ill Coronavirus Disease 2019 (COVID-19) patients, but not those with very mild infections, have serum autoantibodies that inhibit the antiviral function of IFNα and/or IFNω in vitro [2][3][4][5][6][7][8][9][10][11]. Furthermore, presence of anti-IFN autoantibodies has been associated with 20% of all COVID-19 deaths, and this has disproportionately affected older individuals [3,12].…”

From rare disorders of immunity to common determinants of infection: Following the mechanistic thread

“…In a subsequent study, the neutralization of lower, more physiological concentrations of IFN-α and/or IFN-ω (100 pg/mL, again with plasma diluted 1/10), and of IFN-β, was found to underlie 15% of critical cases, and 20% of cases in patients over the age of 80 years ( Bastard et al., 2021a ). These studies have been replicated in at least 26 other cohorts in the Americas, Europe, and Asia ( Abers et al., 2021 , Acosta-Ampudia et al., 2021 , Akbil et al., 2022 , Bastard et al, 2021 , Busnadiego et al., 2022 , Carapito et al., 2021 , Chang et al., 2021 , Chauvineau-Grenier et al., 2022 , Eto et al ., 2022 , Frasca et al., 2022 , Goncalves et al., 2021 , Koning et al., 2021 , Lamacchia et al, 2022 , Lemarquis et al, 2021 , Mathian et al, 2022 , Meisel et al, 2021 , Raadsen et al., 2022 , Savvateeva et al., 2021 , Simula et al, 2022 , Solanich et al., 2021 , Soltani-Zangbar et al, 2022 , Troya et al., 2021 , van der Wijst et al., 2021 , Vazquez et al., 2021 , Wang et al., 2021 , Ziegler et al., 2021 .…”

“…In a subsequent study, the neutralization of lower, more physiological concentrations of IFN-a and/or IFN-u (100 pg/mL, again with plasma diluted 1/10), and of IFN-b, was found to underlie 15% of critical cases, and 20% of cases in patients over the age of 80 years (Bastard et al, 2021a). These studies have been replicated in at least 26 other cohorts in the Americas, Europe, and Asia (Abers et al, 2021;Acosta-Ampudia et al, 2021;Akbil et al, 2022;Bastard et al, 2021;Busnadiego et al, 2022;Carapito et al, 2021;Chang et al, 2021;Chauvineau-Grenier et al, 2022;Eto et al, 2022;Frasca et al, 2022;Goncalves et al, 2021;Koning et al, 2021;Lamacchia et al, 2022;Lemarquis et al, 2021;Mathian et al, 2022;Meisel et al, 2021;Raadsen et al, 2022;Savvateeva et al, 2021;Simula et al, 2022;Solanich et al, 2021;Soltani-Zangbar et al, 2022;Troya et al, 2021;van der Wijst et al, 2021;Vazquez et al, 2021;Wang et al, 2021;Ziegler et al, 2021). These auto-Abs had been known for 40 years, in patients treated with recombinant IFN-a or -b (Zhang et al, 2022a), or with autoimmune conditions, such as systemic lupus erythematosus (SLE), myasthenia gravis, thymoma, autoimmune polyendocrinopathy syndrome type 1 (APS-1), immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), or RAG1/ RAG2 hypomorphic mutations (Bastard et al, 2020(Bastard et al, , 2021d.…”