Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID‐19

Abstract

Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID‐19. Complement activation products are detected in plasma and tissues and complement blockade considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in an COVID‐19 to date, a comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalised COVID‐19 patients collected across the hospitalisation period as part of the UK ISARIC4C study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to heathy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID‐19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID‐19 disease severity and death. The data demonstrate that early‐onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID‐19, further exacerbated in severe disease. These findings provide novel insights into COVID‐19 immunopathogenesis and inform strategies for therapeutic intervention.

Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

“…10 Progressive changes in the concentrations of some complement biomarkers have also been reported in the context of severe disease. 10,[14][15][16][17]19 In mechanistic terms, complement activation under these circumstances has been variously attributed to direct virus-mediated triggering of the classical, lectin, and/or alternative pathways, activation of the classical pathway via antiviral antibodies, and/or indirect activation via contact with infected cells and/or damaged tissue. [20][21][22][23][24] These observations have been used to rationalize interventions with complement blocking drugs to mitigate the hyperinflammatory state that characterizes severe COVID-19.…”

“…Dysregulation of the complement cascade has been implicated as a driver of inflammation in many diseases, including acute COVID-19. [9][10][11][12] Indeed, the complement system is markedly dysregulated in severe acute COVID-19, and biomarkers spanning all activation pathways predict disease outcome. 10,[13][14][15][16][17] On the basis of these observations, we hypothesized that complement dysregulation could play a key role in the pathogenesis of long COVID.…”

Pathophysiological mechanisms of thrombosis in acute and long COVID-19

“…Elevated levels of several complement factors (C3 and C5) are observed in the plasma of COVID-19 patients and these factors are correlated to disease severity ( 223 , 224 ). In a non-randomized clinical trial, eculizumab (a C5 inhibitor) significantly improved 15-day survival and oxygenation in severe COVID-19 patients ( 225 ).…”

A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

“…All three complement arms were shown to be activated in COVID-19 (17)(18)(19)(20)(21)(22)(23)(24); however, their relative contributions remain ill-defined. Whereas complement was initially described as a liver-derived cascade, studies have demonstrated unexpected celland tissue-specific production and functions for the complement system (8,(25)(26)(27)(28)(29)(30).…”