TY - JOUR
T1 - Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection
AU - Ma, Lina
AU - Sahu, Sanjaya K.
AU - Cano, Marlene
AU - Kuppuswamy, Vasanthan
AU - Bajwa, Jamal
AU - McPhatter, Ja'Nia
AU - Pine, Alexander
AU - Meizlish, Matthew L.
AU - Goshua, George
AU - Chang, C. Hong
AU - Zhang, Hanming
AU - Price, Christina
AU - Bahel, Parveen
AU - Rinder, Henry
AU - Lei, Tingting
AU - Day, Aaron
AU - Reynolds, Daniel
AU - Wu, Xiaobo
AU - Schriefer, Rebecca
AU - Rauseo, Adriana M.
AU - Goss, Charles W.
AU - O'Halloran, Jane A.
AU - Presti, Rachel M.
AU - Kim, Alfred H.
AU - Gelman, Andrew E.
AU - Dela Cruz, Charles S.
AU - Lee, Alfred I.
AU - Mudd, Philip A.
AU - Chun, Hyung J.
AU - Atkinson, John P.
AU - Kulkarni, Hrishikesh S.
N1 - Funding Information:
This study utilized samples obtained from the Washington University School of Medicine's COVID-19 biorepository, which is supported by: the Barnes-Jewish Hospital Foundation; the Siteman Cancer Center grant P30 CA091842 from the National Cancer Institute of the National Institutes of Health; and the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Experimental support was also partially provided by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University Immunomonitoring Laboratory, in support of the Rheumatic Diseases Core Center (NIH WLC6313040077). The study was supported by National Institutes of Health grants K08HL148510 (HSK), T32HL007317 (MC), R35GM136352 (JPA), R01EYE028602 (JPA), R01HL094601 (AEG), P01AI116501 (AEG), R01HL126094 (CSDC) and R01HL142818 (HJC). Additional support was provided by Emergency Medicine Foundation (PAM), Children's Discovery Institute (HSK), Washington University Institute of Clinical Translational Sciences, (ICTS) SPIRIT award (HSK), Rheumatic Diseases Research Resource-Based Center (P30AR073752, HSK), Alexion Pharmaceuticals (HSK), The Clark Family/Clayco Foundation International Cerebroretinal Vasculopathy (CRV) Research Award (JPA), Washington University Institute of Clinical Translational Sciences (ICTS) COVID-19 Research Program (AEG), Jacqueline G. and William E. Maritz Endowed Chair in Immunology and Oncology (AEG), Patterson Trust Award in Clinical Research (CSDC), Yale University CTSA SPIRIT award (CSDC), American Heart Association Transformative Research Project (HJC), and DeLuca Foundation (AIP).
Publisher Copyright:
Copyright © 2021, American Association for the Advancement of Science.
PY - 2021/5
Y1 - 2021/5
N2 - Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.
AB - Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.
UR - http://www.scopus.com/inward/record.url?scp=85106378796&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.abh2259
DO - 10.1126/sciimmunol.abh2259
M3 - Article
C2 - 34446527
AN - SCOPUS:85106378796
SN - 2470-9468
VL - 6
JO - Science Immunology
JF - Science Immunology
IS - 59
M1 - eabh2259
ER -