Complement activation and endothelial perturbation parallel COVID-19 severity and activity

Abstract

Background Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet. Objective To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients. Methods In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma. Results The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels. Conclusions Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.

Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19

“…We considered 72 patients, who were enrolled in both the FOGS [ 11 , 17 ] and the COHERENT studies [ 25 ] at the Fondazione IRCCS Ca’ Granda Milan, between March 16th and April 29th , 2020 (at the beginning of the 1st wave in Italy), for whom both genetic data and characterization of complement activation were available. To avoid confounders, we restricted the analysis to unrelated individuals of European descent [ 11 , 17 ].…”

“…These patients were selected by the larger case-control FOGS cohort of 508 cases and 890 controls up to June 2020, whose clinical features were previously reported [ 17 ]. The severity of COVID-19 was graded on the basis of clinical, radiological and laboratory data as follows: mild when the patients were kept under observation with low intensity care, moderate when they required intermediate care with non-invasive ventilation, or severe when they were admitted to an intensive care unit for mechanical ventilation [ 23 , 25 ].…”

“…Nasopharingeal swabs were tested for the presence of SARS-CoV-2 using a One-Step Reverse Transcription Real-Time PCR kit (GeneFinder COVID-19 Plus Real Amp kit, ELITe, platform InGenius ELITech, Torino, Italy) according to manufacturer instructions, as previously described [ 25 ]. The InGenius platform displays a sensibility of 1000 cp/ml and a specificity of 100%.…”

“…Complement activation status was determined on the day of admission, as previously described [ 25 ]. Plasma levels of soluble C5b-9 (SC5b-9) were measured using a solid-phase assay (MicroVue Complement SC5b-9 Plus EIA kit, Quidel Corporation, San Diego, CA, USA); intra- and inter-assay coefficients of variation (CVs) were respectively 6.8% and 13.1%; the lower detection limit was 3.7 ng/mL.…”

“…This process may be directly triggered by the SARS-CoV-2 Spike protein [ 24 ] as well as by the antibodies against the virus themselves. We recently showed that in hospitalized patients complement activation was associated with disease severity and perturbation of the endothelium, a main target of SARS-CoV-2 infection [ 7 , 25 ]. Since it is not known whether the susceptibility to the activation of the complement pathway following SARS-CoV-2 infection contributes the inter-individual variability in COVID-19 severity, the aim of this study was to examine the possible association between complement activation and chromosome 3 gene cluster variation and/or ABO blood group in a well characterized cohort of hospitalized COVID-19 patients.…”