Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

Abstract

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.

Thromboinflammation Supports Complement Activation in Cancer Patients With COVID-19

“…Moreover, complement activation increased significantly in the setting of COVID-19 and thromboinflammation. These findings are in agreement with a recent report by Ma et al, studying non-cancer patients with respiratory failure (29), which suggests that complement activation is a general marker of critical illness, but increases the setting of COVID-19 associated respiratory failure.…”

Complement Alternative and Mannose-Binding Lectin Pathway Activation Is Associated With COVID-19 Mortality

“…Using an original, unsupervised statistical approach by hierarchical clustering on complement and clinical parameters, this study reveals for the first time the association between AP and LP activation, and the mortality in COVID-19 patients (cluster 4). Our data are in line with Ma et al showing increased AP components in COVID-19 patients with worse prognosis (27) and with Sinkovits et al relating significant association between AP activity and COVID-19 severity (22). Furthermore, our results provide additional evidence for an association between MBL pathway activation and mortality, supported by the data of Eriksson et al (4).…”

When Immunity Kills: The Lessons of SARS-CoV-2 Outbreak

“…In patients with SARS-CoV-2-associated ARDS and purpuric skin rash, deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose-binding lectin (MBL)-associated serine protease (MASP)2 were found in both pulmonary and dermal microvessels, suggesting systemic activation of the alternative and lectin-based complement pathways (56). Higher complement activation products in blood, including soluble C5b-9, correlated with and predicted increased disease severity (57). Activation of the complement may be the consequence of the binding of the coronavirus nucleocapsid protein to the mannose-binding lectin (MBL)associated protease-2 (MASP-2), a serine protease of the lectin pathway of complement activation (58,59).…”