Neutralizing Autoantibodies to Type I IFNs in >10% of Patients with Severe COVID-19 Pneumonia Hospitalized in Madrid, Spain

Abstract

Background In a recent study, autoantibodies neutralizing type I interferons (IFNs) were present in at least 10% of cases of critical COVID-19 pneumonia. These autoantibodies neutralized most type I IFNs but rarely IFN-beta. Objectives We aimed to define the prevalence of autoantibodies neutralizing type I IFN in a cohort of patients with severe COVID-19 pneumonia treated with IFN-beta-1b during hospitalization and to analyze their impact on various clinical variables and outcomes. Methods We analyzed stored serum/plasma samples and clinical data of COVID-19 patients treated subcutaneously with IFNbeta-1b from March to May 2020, at the Infanta Leonor University Hospital in Madrid, Spain. Results The cohort comprised 47 COVID-19 patients with severe pneumonia, 16 of whom (34%) had a critical progression requiring ICU admission. The median age was 71 years, with 28 men (58.6%). Type I IFN-alpha-and omega-neutralizing autoantibodies were found in 5 of 47 patients with severe pneumonia or critical disease (10.6%), while they were not found in any of the 118 asymptomatic controls (p = 0.0016). The autoantibodies did not neutralize IFN-beta. No demographic, comorbidity, or clinical differences were seen between individuals with or without autoantibodies. We found a significant correlation between the presence of neutralizing autoantibodies and higher C-reactive protein levels (p = 5.10e −03 ) and lower lymphocyte counts (p = 1.80e −02 ). No significant association with response to IFN-beta-1b therapy (p = 0.34) was found. Survival analysis suggested that neutralizing autoantibodies may increase the risk of death (4/5, 80% vs 12/42, 28.5%). Conclusion Autoantibodies neutralizing type I IFN underlie severe/critical COVID-19 stages in at least 10% of cases, correlate with increased C-RP and lower lymphocyte counts, and confer a trend towards increased risk of death. Subcutaneous IFN-beta treatment of hospitalized patients did not seem to improve clinical outcome. Studies of earlier, ambulatory IFN-beta treatment are warranted.Keywords COVID-19 . subcutaneous interferon-beta 1b . type I IFN neutralizing autoantibodies . severity biomarkers Jesús Troya and Aurora Pujol contributed equally to this work.

Autoantibodies neutralizing type I interferons in 20% of COVID-19 deaths in a French hospital

“…The full engagement status was significantly less frequent in patient with auto-Abs than in patients without auto-Abs. but like other studies [7,9], there was no difference for comorbidities. Unlike study of Troya et al [7], where a significant correlation between presence of auto-Abs neutralizing type I IFNs, raised levels of C-Protein Reactive and low lymphocytes counts was observed, in our study, no difference was seen for these biological characteristics.…”

“…but like other studies [7,9], there was no difference for comorbidities. Unlike study of Troya et al [7], where a significant correlation between presence of auto-Abs neutralizing type I IFNs, raised levels of C-Protein Reactive and low lymphocytes counts was observed, in our study, no difference was seen for these biological characteristics. It is nevertheless important to note that we compare biological characteristics obtained at hospital admission, and not maximum levels of C-Protein Reactive and minimum levels of lymphocytes count.…”

“…They were not detected in patients with asymptomatic or mild SARS-CoV-2 infection. They were also shown to block the anti viral activity of correspondent type I IFNs against SARS-CoV-2 in vitro and in vivo [5].These findings were replicated in other cohorts in Amsterdam, Madrid, San Francisco, Lyon and New Haven [6][7][8][9][10][11][12][13] Recently, auto-Abs neutralizing lower, more physiological concentrations of type I IFNs were detected in 15 to 20% of patients with critical COVID-19, notably in more than 20% of critical patients over 80 years of age. When also considering auto-Abs to IFN-beta, they were present in about 20% of deceased patients across all ages [14].…”

Differential interferon-α subtype immune signatures suppress SARS-CoV-2 infection

“…Furthermore, pegylated IFNα2a therapy in patients with inborn errors of type I IFN immunity prevented severe COVID-19 disease 46 . In addition to the impaired type I IFN response triggered by SARS-CoV-2, recent studies have demonstrated the development of autoantibodies that can neutralize type I IFNs 44,47 . To evade the antiviral effects of type I IFNs, viruses have evolved various strategies to suppress IFN induction.…”

Inducible CRISPR activation screen for interferon-stimulated genes identifies OAS1 as a SARS-CoV-2 restriction factor

“…Dysregulation of the IFN response in SARS-CoV-2 infection can be driven by both direct viral antagonism of innate immune mechanisms, as well as by host characteristics such as age, genetics and other comorbidities 20 . Additionally, several studies have identified autoantibodies against IFN as a significant negative survival factor for severe COVID-19, further emphasizing the prominent role of IFN in SARS-CoV-2 pathogenesis and clearance [21][22][23][24] . Importantly, IFNmediated effects may also be detrimental to COVID-19 outcomes.…”