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

Holter, Jan C.; Pischke, Soeren E.; de Boer, Eline; Lind, Andreas; Jenum, Synne; Holten, Aleksander R.; Tonby, Kristian; Barratt-Due, Andreas; Sokolova, Marina; Schjalm, Camilla; Chaban, Viktoriia; Kolderup, Anette; Tran, Trung; Tollefsrud Gjølberg, Torleif; Skeie, Linda G.; Hesstvedt, Liv; Ormåsen, Vidar; Fevang, Børre; Austad, Cathrine; Müller, Karl Erik; Fladeby, Cathrine; Holberg-Petersen, Mona; Halvorsen, Bente; Müller, Fredrik; Aukrust, Pål; Dudman, Susanne; Ueland, Thor; Andersen, Jan Terje; Lund-Johansen, Fridtjof; Heggelund, Lars; Dyrhol-Riise, Anne M.; Mollnes, Tom E.

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 PO(2)/FiO(2) 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.