Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

Abstract

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7–9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2–5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6–35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1–9.6]) of IFN-ω and/or IFN-α2.

Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies

“…It is logical to assume that the appearance and maintenance of these neutralizing autoAbs led to this functional impairment of innate antiviral immunity, thus contributing to an increased susceptibility to severe viral infections as previously reported (reviewed in Bastard et al [2024a] ; Hale [2023] ). The consequences of harboring other neutralizing anti-IFN-I autoAbs (e.g., against IFNβ or IFNω) could not be readily discerned in our subcohort due to the relatively low numbers of positive individuals identified, although a recent report suggests that neutralization of IFNα may have greater pathogenic consequences than neutralization of IFNω ( Bastard et al, 2024b ). Nevertheless, a key finding from our work was the observation that following induction, neutralizing anti-IFN-I autoAbs can be effectively maintained in circulation lifelong (over at least 15 years in one individual), meaning that the consequences of anti-IFN-I development could result in extremely long-lasting IFN-I functional deficiency and increased susceptibility to infection.…”

“…Specifically, the prevalence of autoAbs neutralizing the IFN-I cytokines IFNα and/or IFNω increases sharply with age in apparently healthy individuals, such that a conservative estimate of prevalence in those >70 years old is about eight times higher (1.4%) than that in younger individuals (0.17%) ( Bastard et al, 2021 ). Furthermore, the presence of neutralizing anti-IFN-I autoAbs in individuals has been associated with an increased susceptibility to severe infections caused by several viral pathogens, including SARS-CoV-2 ( Akbil et al, 2022 ; Bastard et al, 2020 , 2024b ; Busnadiego et al, 2022 ; Chauvineau-Grenier et al, 2022 ; Credle et al, 2022 ; Eto et al, 2022 ; Frasca et al, 2022 ; Goncalves et al, 2021 ; Manry et al, 2022 ; Mathian et al, 2022 ; Scordio et al, 2022 ; Solanich et al, 2021 ; Troya et al, 2021 ; Wang et al, 2021 ), MERS-CoV ( Alotaibi et al, 2023 ), influenza A virus ( Zhang et al, 2022 ), West Nile virus ( Gervais et al, 2023 ; Lin et al, 2023 ), and various herpesviruses ( Bayat et al, 2015 ; Burbelo et al, 2010 ; Busnadiego et al, 2022 ; Hetemaki et al, 2021 ; Mathian et al, 2022 ; Mogensen et al, 1981 ; Pozzetto et al, 1984 ). Given that >100 million people worldwide have been estimated to harbor neutralizing anti-IFN-I autoAbs ( Bastard et al, 2024a ) and are therefore at increased risk of severe infectious disease outcomes, it is critical to understand factors associated with their development and pathogenic mechanisms to inform future mitigation strategies.…”