tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Soeren E Pischke[SUP] 3 4 5 [/SUP], Eline de Boer[SUP] 2 5 [/SUP], Andreas Lind[SUP] 1 [/SUP], Synne Jenum[SUP] 6 [/SUP], Aleksander R Holten[SUP] 2 7 [/SUP], Kristian Tonby[SUP] 2 6 [/SUP], Andreas Barratt-Due[SUP] 2 4 5 [/SUP], Marina Sokolova[SUP] 2 5 [/SUP], Camilla Schjalm[SUP] 2 5 [/SUP], Viktoriia Chaban[SUP] 2 5 [/SUP], Anette Kolderup[SUP] 2 8 [/SUP], Trung Tran[SUP] 5 [/SUP], Torleif Tollefsrud Gj?lberg[SUP] 2 5 8 9 [/SUP], Linda G Skeie[SUP] 6 [/SUP], Liv Hesstvedt[SUP] 6 [/SUP], Vidar Orm?sen[SUP] 2 6 [/SUP], B?rre Fevang[SUP] 10 11 [/SUP], Cathrine Austad[SUP] 12 [/SUP], Karl Erik M?ller[SUP] 12 13 [/SUP], Cathrine Fladeby[SUP] 1 [/SUP], Mona Holberg-Petersen[SUP] 1 [/SUP], Bente Halvorsen[SUP] 2 10 [/SUP], Fredrik M?ller[SUP] 1 2 [/SUP], P?l Aukrust[SUP] 2 10 11 14 [/SUP], Susanne Dudman[SUP] 1 2 [/SUP], Thor Ueland[SUP] 2 10 14 [/SUP], Jan Terje Andersen[SUP] 2 5 [/SUP], Fridtjof Lund-Johansen[SUP] 5 15 [/SUP], Lars Heggelund[SUP] 12 13 [/SUP], Anne M Dyrhol-Riise[SUP] 2 6 [/SUP], Tom E Mollnes[SUP] 2 5 14 16 17 [/SUP]
Affiliations
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 PO[SUB]2[/SUB]/FiO[SUB]2[/SUB] 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.
. 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[SUP] 1 2 [/SUP], Soeren E Pischke[SUP] 3 4 5 [/SUP], Eline de Boer[SUP] 2 5 [/SUP], Andreas Lind[SUP] 1 [/SUP], Synne Jenum[SUP] 6 [/SUP], Aleksander R Holten[SUP] 2 7 [/SUP], Kristian Tonby[SUP] 2 6 [/SUP], Andreas Barratt-Due[SUP] 2 4 5 [/SUP], Marina Sokolova[SUP] 2 5 [/SUP], Camilla Schjalm[SUP] 2 5 [/SUP], Viktoriia Chaban[SUP] 2 5 [/SUP], Anette Kolderup[SUP] 2 8 [/SUP], Trung Tran[SUP] 5 [/SUP], Torleif Tollefsrud Gj?lberg[SUP] 2 5 8 9 [/SUP], Linda G Skeie[SUP] 6 [/SUP], Liv Hesstvedt[SUP] 6 [/SUP], Vidar Orm?sen[SUP] 2 6 [/SUP], B?rre Fevang[SUP] 10 11 [/SUP], Cathrine Austad[SUP] 12 [/SUP], Karl Erik M?ller[SUP] 12 13 [/SUP], Cathrine Fladeby[SUP] 1 [/SUP], Mona Holberg-Petersen[SUP] 1 [/SUP], Bente Halvorsen[SUP] 2 10 [/SUP], Fredrik M?ller[SUP] 1 2 [/SUP], P?l Aukrust[SUP] 2 10 11 14 [/SUP], Susanne Dudman[SUP] 1 2 [/SUP], Thor Ueland[SUP] 2 10 14 [/SUP], Jan Terje Andersen[SUP] 2 5 [/SUP], Fridtjof Lund-Johansen[SUP] 5 15 [/SUP], Lars Heggelund[SUP] 12 13 [/SUP], Anne M Dyrhol-Riise[SUP] 2 6 [/SUP], Tom E Mollnes[SUP] 2 5 14 16 17 [/SUP]
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 PO[SUB]2[/SUB]/FiO[SUB]2[/SUB] 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.