Proc Natl Acad Sci U S A
. 2020 Sep 17;202010540.
doi: 10.1073/pnas.2010540117. Online ahead of print.
Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients
Jan C Holter 1 2 , Soeren E Pischke 3 4 5 , Eline de Boer 2 5 , Andreas Lind 1 , Synne Jenum 6 , Aleksander R Holten 2 7 , Kristian Tonby 2 6 , Andreas Barratt-Due 2 4 5 , Marina Sokolova 2 5 , Camilla Schjalm 2 5 , Viktoriia Chaban 2 5 , Anette Kolderup 2 8 , Trung Tran 5 , Torleif Tollefsrud Gj?lberg 2 5 8 9 , Linda G Skeie 6 , Liv Hesstvedt 6 , Vidar Orm?sen 2 6 , B?rre Fevang 10 11 , Cathrine Austad 12 , Karl Erik M?ller 12 13 , Cathrine Fladeby 1 , Mona Holberg-Petersen 1 , Bente Halvorsen 2 10 , Fredrik M?ller 1 2 , P?l Aukrust 2 10 11 14 , Susanne Dudman 1 2 , Thor Ueland 2 10 14 , Jan Terje Andersen 2 5 , Fridtjof Lund-Johansen 5 15 , Lars Heggelund 12 13 , Anne M Dyrhol-Riise 2 6 , Tom E Mollnes 2 5 14 16 17
Affiliations
- PMID: 32943538
- DOI: 10.1073/pnas.2010540117
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.