Auto-antibodies against type I IFNs in > 10% of critically ill COVID-19 patients: a prospective multicentre study

Abstract

Background: Auto-antibodies (auto-Abs) neutralizing type I interferons (IFN) have been found in about 15% of critical cases COVID-19 pneumonia and less than 1% of mild or asymptomatic cases. Determining whether auto-Abs influence presentation and outcome of critically ill COVID-19 patients could lead to specific therapeutic interventions. Our objectives were to compare the severity at admission and the mortality of patients hospitalized for critical COVID-19 in ICU with versus without auto-Abs.

Results: We conducted a prospective multicentre cohort study including patients admitted in 11 intensive care units (ICUs) from Great Paris area hospitals with proven SARS-CoV-2 infection and acute respiratory failure. 925 critically ill COVID-19 patients were included. Auto-Abs neutralizing type I IFN-α2, β and/or ω were found in 96 patients (10.3%). Demographics and comorbidities did not differ between patients with versus without auto-Abs. At ICU admission, Auto-Abs positive patients required a higher FiO₂ (100% (70-100) vs. 90% (60-100), p = 0.01), but were not different in other characteristics. Mortality at day 28 was not different between patients with and without auto-Abs (18.7 vs. 23.7%, p = 0.279). In multivariable analysis, 28-day mortality was associated with age (adjusted odds ratio (aOR) = 1.06 [1.04-1.08], p < 0.001), SOFA score (aOR = 1.18 [1.12-1.23], p < 0.001) and immunosuppression (aOR = 1.82 [1.1-3.0], p = 0.02), but not with the presence of auto-Abs (aOR = 0.69 [0.38-1.26], p = 0.23).

Conclusions: In ICU patients, auto-Abs against type I IFNs were found in at least 10% of patients with critical COVID-19 pneumonia. They were not associated with day 28 mortality.

Keywords: Acute respiratory distress syndrome; Auto-antibodies; COVID-19; Interferon.

Fig. 1

Distribution of auto-antibodies (auto-Abs) to specific sets of type I interferons (IFNs) according to gender. a Proportion of specific sets of auto-Abs (several patients have more than one auto-Abs resulting in total number being greater than 96); b proportion of combinations of auto-Abs to specific sets of type I IFNs (total numbers add-up to 96); α2: auto-Abs anti-IFN-α2; ω: auto-Abs anti-IFN-ω; β: auto-Abs anti-IFN-β; *including 6 patients who also had anti-IFN-α2 (10 ng/mL) auto-Abs; ^#including 2 patients who also had anti-IFN-ω (10 ng/mL) auto-Abs; ^$including 6 patients who had anti-IFN-α2 (100 pg/mL) and anti-IFN-ω (100 pg/mL), 4 patients with anti-IFN-α2 (100 pg/mL + 10 ng/mL) and anti-IFN-ω (10 ng/mL), 35 patients with anti-IFN-α2 (100 pg/mL + 10 ng/mL) and anti-IFN-ω (100 pg/mL + 10 ng/mL), 6 patients with IFN-α2 (100 pg/mL + 10 ng/mL) and anti-IFN-ω (100 pg/mL) and 1 patient with IFN-α2 (10 ng/mL) + anti-IFN-ω (100 pg/mL + 10 pg/mL) auto-Abs; males are shown in blue and females in red; NS: p-value > 0.05

Fig. 2

Distribution of auto-antibodies (auto-Abs) to specific sets of type I interferons (IFNs) according to 28-day mortality. a Proportion of specific sets of auto-Abs (several patients have more than one auto-Abs resulting in total number being greater than 96; b proportion of combinations of auto-Abs to specific sets of type I IFNs (total numbers add-up to 96); α2: auto-Abs anti-IFN-α2; ω: auto-Abs anti-IFN-ω; β: auto-Abs anti-IFN-β; *including 6 patients who also had anti-IFN-α2 (10 ng/mL) auto-Abs; ^#including 2 patients who also had anti-IFN-ω (10 ng/mL) auto-Abs; ^$including 6 patients who had anti-IFN-α2 (100 pg/mL) and anti-IFN-ω (100 pg/mL), 4 patients with anti-IFN-α2 (100 pg/mL + 10 ng/mL) and anti-IFN-ω (10 ng/mL), 35 patients with anti-IFN-α2 (100 pg/mL + 10 ng/mL) and anti-IFN-ω (100 pg/mL + 10 ng/mL), 6 patients with IFN-α2 (100 pg/mL + 10 ng/mL) and anti-IFN-ω (100 pg/mL) and 1 patient with IFN-α2 (10 ng/mL) + anti-IFN-ω (100 pg/mL + 10 pg/mL) auto-Abs; c distribution of patients with simple, double or triple positive auto-Abs; P value comes from the Fisher exact test. Patients who were alive at 28-day are shown in light blue and patients who were dead at 28-day are shown in dark blue (b, c); NS: p-value > 0.05

Fig. 3

Positivity of anti-nuclear antibodies (ANA) according to gender in patients with positive anti-interferon (IFN) auto-antibodies (auto-Abs). ANA were screened in the serum of 812/925 patients of the cohort. ANA-positive patients are shown in red and ANA negative patients in pink. P value comes from the Fisher exact test