Abstract
BackgroundThe SARS-CoV-2 infection triggers excessive immune response resulting in increased levels of pro-inflammatory cytokines, endothelial injury, and intravascular coagulopathy. The complement system (CS) activation participates to this hyperinflammatory response. However, it is still unclear which activation pathways (classical, alternative, or lectin pathway) pilots the effector mechanisms that contribute to critical illness. To better understand the immune correlates of disease severity, we performed an analysis of CS activation pathways and components in samples collected from COVID-19 patients hospitalized in Grenoble Alpes University Hospital between 1 and 30 April 2020 and of their relationship with the clinical outcomes.MethodsWe conducted a retrospective, single-center study cohort in 74 hospitalized patients with RT-PCR-proven COVID-19. The functional activities of classical, alternative, and mannose-binding lectin (MBL) pathways and the antigenic levels of the individual components C1q, C4, C3, C5, Factor B, and MBL were measured in patients’ samples during hospital admission. Hierarchical clustering with the Ward method was performed in order to identify clusters of patients with similar characteristics of complement markers. Age was included in the model. Then, the clusters were compared with the patient clinical features: rate of intensive care unit (ICU) admission, corticoid treatment, oxygen requirement, and mortality.ResultsFour clusters were identified according to complement parameters. Among them, two clusters revealed remarkable profiles: in one cluster (n = 15), patients exhibited activation of alternative and lectin pathways and low antigenic levels of MBL, C4, C3, Factor B, and C5 compared to all the other clusters; this cluster had the higher proportion of patients who died (27%) and required oxygen support (80%) or ICU care (53%). In contrast, the second cluster (n = 19) presented inflammatory profile with high classical pathway activity and antigenic levels of complement components; a low proportion of patients required ICU care (26%) and no patient died in this group.ConclusionThese findings argue in favor of prominent activation of the alternative and MBL complement pathways in severe COVID-19, but the spectrum of complement involvement seems to be heterogeneous requiring larger studies.
Highlights
The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection drives sustained inflammatory response considered to be a major cause of disease severity and death in patients with COVID-19 [1]
SARS-CoV-2 infection triggers an innate immune response including complement system (CS) activation which is a key weapon both implicated in disease resolution and organ damage depending on the time of infection [15]
Recent studies addressing the role of complement in the pathogenesis of COVID-19 have shown a relationship between respiratory failure, intravascular coagulopathy, and complement overactivation in COVID-19 patients [3, 16]
Summary
The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection drives sustained inflammatory response considered to be a major cause of disease severity and death in patients with COVID-19 [1]. Patients treated with complement blockers (anti-C5a mAb [eculizumab] or C3-inhibitor) exhibited a drop in inflammatory markers and significant clinical improvement [5,6,7,8,9] It is still not fully understood which of the three complement activation pathways (classical, alternative, or lectin pathway) drives the effector mechanisms that contribute to the tissue injury. To address these questions, we performed extensive analysis of CS activation pathways and components in samples collected from hospitalized COVID-19 patients and their relationship with the clinical outcomes. To better understand the immune correlates of disease severity, we performed an analysis of CS activation pathways and components in samples collected from COVID-19 patients hospitalized in Grenoble Alpes University Hospital between 1 and 30 April 2020 and of their relationship with the clinical outcomes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
