Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients

Abstract

Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO₂/FiO₂ ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.

Keywords: COVID-19; SARS-CoV-2; complement system; respiratory failure; sC5b-9.

Fig. 1.

Enrollment and follow-up of patients with COVID-19. Flowchart of inclusion of patients with positive COVID-19 status into the cohort study. Blood sampling to biobank, along with progression of blood data available at each successive time point. Logistic difficulties means that, although patient was available and had consented, no blood was collected at this time point.

Fig. 2.

Complement activation products (A−E) and MBL (F) levels in COVID-19 patients with and without respiratory failure at admission and days 3 to 5, and days 7 to 10 of hospitalization. COVID-19 patients were divided according to presence of respiratory failure at day of sampling (defined as PO₂/FiO₂ ratio ≤40 kPa). At admission, patients with respiratory failure had significantly higher levels of sC5b-9 (A) and C4d (E) compared to patients without respiratory failure. The majority of patients had all assessed complement activation products well above the upper reference limits, represented by the dotted lines, at every time point and for every activation product. Results are presented as box plots (line, median; box, interquartile range) with whiskers (10th to 90th percentile). For MBL, the values above the upper dotted line (>500 ng/mL) represent normal values, those between the dotted lines represent low values (100 ng/mL to 500 ng/mL), and those below the lower dotted line represent MBL defects (<100 ng/mL). Mann−Whitney U test. URL, upper reference limit; CAU, complement arbitrary units.