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. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) 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., Ang2) 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.

Interleukin-1- Receptor Kinase 4 Inhibition: Achieving Immunomodulatory Synergy to Mitigate the Impact of COVID-19

“…The complement pathway can typically be activated by 3 arms: classical pathway, alternative pathway, and lectin pathway. In this study, increased activation of the alterative pathway was noted and was found to be associated with worse outcomes in COVID-19 infection ( 6 ).…”

“…Complement activation has also been suggested to play an important role and be a distinct entity in severe COVID-19 infection. In Ma et al, circulating markers of complement activation were found to be higher in patients with respiratory failure in COVID-19 compared to those with non-respiratory failure with COVID-19 and influenza (6). The complement pathway can typically be activated by 3 arms: classical pathway, alternative pathway, and lectin pathway.…”

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

“…In one study, patients with severe COVID-19 were found to have increased levels of Factor B and Ba, a zymogen which downregulates complement inhibitory protein expression 46 . In another, C3 expression was found to correlate with viral load, with an increase in its expression in AT2 cells from lung biopsy and BAL scRNAseq datasets, and its processing into its active form in SARS-CoV-2 infected lung epithelial cell lines in vitro 47 . There is therefore good evidence to support exploration of complement inhibition in severe COVID-19.…”

Massive Arterial Cerebral Thrombosis in a 59-year old Female Patient With Severe COVID-19

“…Endothelial injury, microvascular inflammation and/or coagulapathy play a central role in the pathogenesis of acute respiratory distress syndrome and organ failure in patients with severe COVID-19 [6,7]. Studies have shown increased inflammatory markers such as interleukin (IL)-6 and other acute phase reactants and markers of complement activation in the circulation of individuals hospitalized with COVID-19 than in controls [8,9].…”