Complement Alternative and Mannose-Binding Lectin Pathway Activation Is Associated With COVID-19 Mortality.

Area of Science:

• Immunology
• Infectious Diseases
• Complement System Biology

Background:

• SARS-CoV-2 infection induces an excessive immune response, characterized by elevated pro-inflammatory cytokines, endothelial damage, and coagulopathy.
• The complement system (CS) plays a role in the hyperinflammatory response to SARS-CoV-2, but the specific activation pathways driving critical illness remain unclear.
• Investigating CS activation pathways is essential for understanding the immune correlates of COVID-19 disease severity.

Purpose of the Study:

• To analyze complement system activation pathways and components in hospitalized COVID-19 patients.
• To determine the relationship between complement activation patterns and clinical outcomes in COVID-19 patients.
• To identify specific complement pathways associated with severe COVID-19 illness.

Main Methods:

• Retrospective cohort study of 74 hospitalized COVID-19 patients.
• Measurement of functional activities of classical, alternative, and mannose-binding lectin (MBL) pathways.
• Quantification of antigenic levels of complement components (C1q, C4, C3, C5, Factor B, MBL).
• Hierarchical clustering to identify patient groups based on complement markers, analyzed alongside clinical features (ICU admission, oxygen requirement, mortality).

Main Results:

• Four distinct patient clusters based on complement parameters were identified.
• One cluster (n=15) showed alternative and lectin pathway activation with low complement component levels, correlating with higher mortality (27%), oxygen support (80%), and ICU admission (53%).
• Another cluster (n=19) exhibited high classical pathway activity and complement component levels, associated with lower ICU admission rates (26%) and no mortality.

Conclusions:

• Findings suggest prominent activation of alternative and MBL complement pathways in severe COVID-19.
• The study indicates heterogeneity in complement system involvement across COVID-19 patients.
• Larger studies are needed to further elucidate the spectrum of complement involvement in COVID-19 pathogenesis and severity.