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

被引:284
作者
Holter, Jan C. [1 ,2 ]
Pischke, Soeren E. [2 ,3 ,4 ]
de Boer, Eline [2 ,4 ]
Lind, Andreas [1 ]
Jenum, Synne [5 ]
Holten, Aleksander R. [2 ,6 ]
Tonby, Kristian [2 ,5 ]
Barratt-Due, Andreas [2 ,4 ]
Sokolova, Marina [2 ,4 ]
Schjalm, Camilla [2 ,4 ]
Chaban, Viktoriia [2 ,4 ]
Kolderup, Anette [2 ,7 ]
Trand, Trung [4 ]
Gjolberg, Torleif Tollefsrud [2 ,4 ,7 ,8 ]
Skeie, Linda G. [5 ]
Hesstvedt, Liv [5 ]
Ormasen, Vidar [2 ,5 ]
Fevang, Borre [9 ,10 ]
Austad, Cathrine [11 ]
Muller, Karl Erik [11 ,12 ]
Fladeby, Cathrine [1 ]
Holberg-Petersen, Mona [1 ]
Halvorsen, Bente [2 ,9 ]
Muller, Fredrik [1 ,2 ]
Aukrust, Pal [2 ,9 ,10 ,13 ]
Dudman, Susanne [1 ,2 ]
Ueland, Thor [9 ,13 ]
Andersen, Jan Terje [4 ]
Lund-Johansen, Fridtjof [4 ,14 ]
Heggelund, Lars [11 ]
Dyrhol-Riise, Anne M. [2 ,5 ]
Mollnes, Tom E. [2 ,4 ,13 ,15 ,16 ]
机构
[1] Oslo Univ Hosp, Dept Microbiol, N-0424 Oslo, Norway
[2] Univ Oslo, Inst Clin Med, N-0315 Oslo, Norway
[3] Oslo Univ Hosp, Div Emergencies & Crit Care, N-0424 Oslo, Norway
[4] Oslo Univ Hosp, Dept Immunol, N-0424 Oslo, Norway
[5] Oslo Univ Hosp, Dept Infect Dis, N-0424 Oslo, Norway
[6] Oslo Univ Hosp, Dept Acute Med, N-0424 Oslo, Norway
[7] Univ Oslo, Dept Pharmacol, N-0315 Oslo, Norway
[8] Oslo Univ Hosp, Dept Ophthalmol, N-0424 Oslo, Norway
[9] Oslo Univ Hosp, Res Inst Internal Med, N-0424 Oslo, Norway
[10] Oslo Univ Hosp, Sect Clin Immunol & Infect Dis, N-0424 Oslo, Norway
[11] Vestre Viken Hosp Trust, Dept Internal Med, N-3004 Drammen, Norway
[12] Univ Bergen, Dept Clin Sci, Fac Med, N-5007 Bergen, Norway
[13] Univ Tromso, KG Jebsen Thrombosis Res & Expertise Ctr, Fac Hlth Sci, N-9037 Tromso, Norway
[14] Univ Oslo, ImmunoLingo Convergence Ctr, N-0315 Oslo, Norway
[15] Nordland Hosp Bodo, Res Lab, N-8092 Bodo, Norway
[16] Norwegian Univ Sci & Technol, Ctr Mol Inflammat Res, N-7491 Trondheim, Norway
关键词
complement system; COVID-19; SARS-CoV-2; sC5b-9; respiratory failure; MANNOSE-BINDING LECTIN; COAGULATION; INFECTION;
D O I
10.1073/pnas.2010540117
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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/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.
引用
收藏
页码:25018 / 25025
页数:8
相关论文
共 46 条
[1]  
Amanat F, 2020, NAT MED, V26, P1033
[2]  
[Anonymous], 2020, EUR REV MED PHARMACO, V219
[3]   Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets [J].
Barratt-Due, Andreas ;
Pischke, Soren Erik ;
Nilsson, Per H. ;
Espevik, Terje ;
Mollnes, Tom Eirik .
JOURNAL OF LEUKOCYTE BIOLOGY, 2017, 101 (01) :193-204
[4]   Complement activation is a crucial pathogenic factor in catastrophic antiphospholipid syndrome [J].
Barratt-Due, Andreas ;
Floisand, Yngvar ;
Orrem, Hilde L. ;
Kvam, Ann K. ;
Holme, Pal A. ;
Bergseth, Grethe ;
Tjonnfjore, Geir E. ;
Mollnes, Tom E. .
RHEUMATOLOGY, 2016, 55 (07) :1337-1340
[5]   An international serum standard for application in assays to detect human complement activation products [J].
Bergseth, Grethe ;
Ludviksen, Judith K. ;
Kirschfink, Michael ;
Giclas, Patricia C. ;
Nilsson, Bo ;
Mollnes, Tom E. .
MOLECULAR IMMUNOLOGY, 2013, 56 (03) :232-239
[6]   Nonlinear Imputation of Pao2/Fio2 From Spo2/Fio2 Among Mechanically Ventilated Patients in the ICU: A Prospective, Observational Study [J].
Brown, Samuel M. ;
Duggal, Abhijit ;
Hou, Peter C. ;
Tidswell, Mark ;
Khan, Akram ;
Exline, Matthew ;
Park, Pauline K. ;
Schoenfeld, David A. ;
Liu, Ming ;
Grissom, Colin K. ;
Moss, Marc ;
Rice, Todd W. ;
Hough, Catherine L. ;
Rivers, Emanuel ;
Thompson, B. Taylor ;
Brower, Roy G. .
CRITICAL CARE MEDICINE, 2017, 45 (08) :1317-1324
[7]   Will Complement Inhibition Be the New Target in Treating COVID-19-Related Systemic Thrombosis? [J].
Campbell, Courtney M. ;
Kahwash, Rami .
CIRCULATION, 2020, 141 (22) :1739-1741
[8]   Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis [J].
Carvelli, Julien ;
Demaria, Olivier ;
Vely, Frederic ;
Batista, Luciana ;
Benmansour, Nassima Chouaki ;
Fares, Joanna ;
Carpentier, Sabrina ;
Thibult, Marie-Laure ;
Morel, Ariane ;
Remark, Romain ;
Andre, Pascale ;
Represa, Agnes ;
Piperoglou, Christelle ;
Cordier, Pierre Yves ;
Le Dault, Erwan ;
Guervilly, Christophe ;
Simeone, Pierre ;
Gainnier, Marc ;
Morel, Yannis ;
Ebbo, Mikael ;
Schleinitz, Nicolas ;
Vivier, Eric .
NATURE, 2020, 588 (7836) :146-+
[9]   Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR (Publication with Expression of Concern) [J].
Corman, Victor M. ;
Landt, Olfert ;
Kaiser, Marco ;
Molenkamp, Richard ;
Meijer, Adam ;
Chu, Daniel K. W. ;
Bleicker, Tobias ;
Bruenink, Sebastian ;
Schneider, Julia ;
Schmidt, Marie Luisa ;
Mulders, Daphne G. J. C. ;
Haagmans, Bart L. ;
van der Veer, Bas ;
van den Brink, Sharon ;
Wijsman, Lisa ;
Goderski, Gabriel ;
Romette, Jean-Louis ;
Ellis, Joanna ;
Zambon, Maria ;
Peiris, Malik ;
Goossens, Herman ;
Reusken, Chantal ;
Koopmans, Marion P. G. ;
Drosten, Christian .
EUROSURVEILLANCE, 2020, 25 (03) :23-30
[10]   Complement activation in patients with COVID-19: A novel therapeutic target [J].
Cugno, Massimo ;
Meroni, Pier Luigi ;
Gualtierotti, Roberta ;
Griffini, Samantha ;
Grovetti, Elena ;
Torri, Adriana ;
Panigada, Mauro ;
Aliberti, Stefano ;
Blasi, Francesco ;
Tedesco, Francesco ;
Peyvandi, Flora .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2020, 146 (01) :215-+