Antibodies against type I interferon: detection and association with severe clinical outcome in COVID‐19 patients

Abstract

Objectives Impairment of type I interferon (IFN‐I) immunity has been reported in critically ill COVID‐19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto‐Abs) against IFN‐I. We set out to improve the detection and the quantification of IFN‐I auto‐Abs in a cohort of critically ill COVID‐19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease. Methods The concentration of anti ‐ IFN‐α 2 Abs was determined in the serum of 84 critically ill COVID‐19 patients who were admitted to ICU in Hospices Civils de Lyon , France, using a commercially available kit (Thermo Fisher, Catalog #BMS217). Results A total of 21 of 84 (25%) critically ill COVID‐19 patients had circulating anti‐IFN‐α 2 Abs above cut‐off (> 34 ng mL −1 ). Among them, 15 of 21 had Abs with neutralising activity against IFN‐α 2 , that is 15 of 84 (18%) critically ill patients. In addition, we noticed an impairment of the IFN‐I response in the majority of patients with neutralising anti‐IFN‐α 2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralising anti‐IFN‐α 2 auto‐Abs. We detected anti‐IFN‐α 2 auto‐Abs in COVID‐19 patients' sera throughout their ICU stay. Finally, we also found auto‐Abs against multiple subtypes of IFN‐I including IFN‐ω. Conclusions We reported that 18% of critically ill COVID‐19 patients were positive for IFN‐I auto‐Abs, whereas all mild COVID‐19 patients were negative, confirming that the presence of these antibodies is associated with a higher risk of developing a critical COVID‐19 form.

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

“…In our study, 6 patients had high titer of anti IFN- auto-Abs in ELISA and presented all a neutralizing activity in vitro against IFN-. Goncalves et al [9] showed similar results and determined a cut-off of 1000 ng/ml correlated with neutralization assays. In their study, ability of auto-Abs to neutralize only high concentrations of IFN- (10 ng/ml) was investigated.…”

“…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.…”

“…Nevertheless, according to manufacturer's results, in a panel of 57 serum samples from randomly selected apparently healthy donors and patients suffering from various diseases, anti-IFN α levels ranged between 0 and 120.5 ng/ml (mean :17.4 ng/ml; SD : 26.7 ng/ml). Moreover, this commercial ELISA was recently evaluated [9]; a cut off of 34 ng/ml was established and results >100 ng/ml were considered as high. Three patients had anti IFN- auto-Abs levels <100 ng/ml, which were considered as low, and also presented no neutralizing activity in vitro against IFN-.…”

“…It was indeed notably constituted in order to assess associations between treatments and outcomes like need of ventilation mechanic and mortality [16]. Overall, severity of patients studied here was potentially lower than that of patients hospitalized in Intensive Care Units [5,6,[9][10][11]14].…”

“…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].…”