• Jan C Holter, Soeren E Pischke, Eline de Boer, Andreas Lind, Synne Jenum, Aleksander R Holten, Kristian Tonby, Andreas Barratt-Due, Marina Sokolova, Camilla Schjalm, Viktoriia Chaban, Anette Kolderup, Trung Tran, Torleif Tollefsrud Gjølberg, Linda G Skeie, Liv Hesstvedt, Vidar Ormåsen, Børre Fevang, Cathrine Austad, Karl Erik Müller, Cathrine Fladeby, Mona Holberg-Petersen, Bente Halvorsen, Fredrik Müller, Pål Aukrust, Susanne Dudman, Thor Ueland, Jan Terje Andersen, Fridtjof Lund-Johansen, Lars Heggelund, Anne M Dyrhol-Riise, and Tom E Mollnes.
• Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway.
• Proc. Natl. Acad. Sci. U.S.A. 2020 Oct 6; 117 (40): 25018-25025.

AbstractRespiratory 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.Copyright © 2020 the Author(s). Published by PNAS.

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