Persistently elevated complement alternative pathway biomarkers in COVID-19 correlate with hypoxemia and predict in-hospital mortality

Abstract

Mechanisms underlying the SARS-CoV-2-triggered hyperacute thrombo-inflammatory response that causes multi-organ damage in coronavirus disease 2019 (COVID-19) are poorly understood. Several lines of evidence implicate overactivation of complement. To delineate the involvement of complement in COVID-19, we prospectively studied 25 ICU-hospitalized patients for up to 21 days. Complement biomarkers in patient sera and healthy controls were quantified by enzyme-linked immunosorbent assays. Correlations with respiratory function and mortality were analyzed. Activation of complement via the classical/lectin pathways was variably increased. Strikingly, all patients had increased activation of the alternative pathway (AP) with elevated levels of activation fragments, Ba and Bb. This was associated with a reduction of the AP negative regulator, factor (F) H. Correspondingly, terminal pathway biomarkers of complement activation, C5a and sC5b-9, were significantly elevated in all COVID-19 patient sera. C5a and AP constituents Ba and Bb, were significantly associated with hypoxemia. Ba and FD at the time of ICU admission were strong independent predictors of mortality in the following 30 days. Levels of all complement activation markers were sustained throughout the patients’ ICU stays, contrasting with the varying serum levels of IL-6, C-reactive protein, and ferritin. Severely ill COVID-19 patients have increased and persistent activation of complement, mediated strongly via the AP. Complement activation biomarkers may be valuable measures of severity of lung disease and the risk of mortality. Large-scale studies will reveal the relevance of these findings to thrombo-inflammation in acute and post-acute COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s00430-021-00725-2.

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

“…C3 and C4 were most often measured and were generally either decreased in severe patients or non-survivors [ [100] , [101] , [102] , [103] , [104] , [105] ], or did not differ compared with non-severe patients or survivors [ [106] , [107] , [108] , [109] , [110] , [111] , [112] , [113] , [114] , [115] , [116] , [117] , [118] ]. Anaphylatoxins C3a and notably C5a were elevated and correlated with disease severity, ICU admission and mortality [ 12 , 14 , 65 , 68 , 85 , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , [127] , [128] ]. Soluble C5b-9 levels were also increased and correlated with C5a, markers of inflammation and coagulation [ 12 , 33 , 36 , 68 , 70 , 71 , 78 , 120 , 125 , [129] , [130] , [131] , [132] , [133] , [134] ].…”

“…This was in line with a meta-analysis that showed lower concentrations of both C3 and C4 in patients with high disease severity or non-survivors, compared with patients with low severity or survivors, indicating complement activation and product consumption [ 151 ]. Anaphylatoxins C3a and especially C5a were elevated and correlated with disease severity, ICU admission and mortality [ 12 , 14 , 65 , 68 , 85 , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , [127] , [128] ]. Soluble levels of C5b-9 were also increased and correlated with C5a, markers of inflammation and coagulation [ 12 , 33 , 36 , 68 , 70 , 71 , 78 , 120 , 125 , [129] , [130] , [131] , [132] , 134 ].…”

Targeting thromboinflammation in COVID-19 – A narrative review of the potential of C1 inhibitor to prevent disease progression

“…On the other hand, analyses of patient samples from our and other centers did not confirm an active role of the lectin pathway in disease progression to severe COVID-19 and pointed mainly towards an overactivated alternative pathway, at least in critically ill COVID-19 patients ( Charitos et al, 2021 , Sinkovits et al, 2021 ). In line, the S protein of SARS-CoV-2 was shown to directly activate the alternative pathway ( Yu et al, 2020 ), and recent data from Canadian ICU patients suggested markers of the alternative pathway to correlate with hypoxemia and predict in-hospital mortality, and a history of macular degeneration (often associated with complement-activating genetic polymorphisms in alternative pathway genes) was identified as risk factors for SARS-Cov-2-associated mortality ( Leatherdale et al, 2022 , Ramlall et al, 2020 ). The S protein of SARS-CoV-2 was also shown to directly activate the alternative pathway ( Yu et al, 2020 ), and circulating immune complexes may activate the classical pathway ( Castanha et al, 2022 ) in line with results from autopsy studies ( Macor et al, 2021 ).…”

Complement contributions to COVID-19

“…Postmortem studies of tissues from patients who succumbed to COVID-19 consistently revealed a thrombotic microangiopathy-like picture -- similar to aHUS -- with multiorgan microvascular endothelial damage and thrombosis and increased deposits of multiple complement fragments [17]. Sera/plasma from hospitalized COVID-19 patients revealed persistently elevated levels of complement activation fragments, and C1q, levels of which correlated with adverse outcomes [18–23]. Overall, there is immediate and seemingly simultaneous dysregulated hyperactivation of all three complement pathways that drives a rapidly progressive, organ-damaging vascular endotheliopathy.…”

“…activation fragments, and C1q, levels of which correlated with adverse outcomes [18][19][20][21][22][23]. Overall, there is immediate and seemingly simultaneous dysregulated hyperactivation of all three complement pathways that drives a rapidly progressive, organ-damaging vascular endotheliopathy.…”