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Association of complement pathways with COVID-19 severity and outcomes
Kishor Devalaraja-Narashimha1, Peter J Ehmann1, Cong Huang2
1Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
Insights
Complement activation is key in COVID-19. High levels of certain complement biomarkers indicate increased mortality risk in hospitalized patients, suggesting their use as prognostic indicators.
Area of Science:
- Immunology
- Pathophysiology
- Biomarker Discovery
Background:
- Complement activation is implicated in the pathogenesis of COVID-19.
- Understanding complement's role is crucial for managing severe disease.
Purpose of the Study:
- To assess complement activation products and protein levels in hospitalized COVID-19 patients.
- To evaluate complement pathway markers as predictors of clinical outcomes.
Main Methods:
- Longitudinal measurements of complement biomarkers in 89 hospitalized COVID-19 patients.
- Correlation of biomarker levels with clinical and laboratory parameters in a randomized trial setting.
Main Results:
- All complement pathways were activated; alternative pathway activation was predominant early in disease.
- Complement biomarkers correlated with multi-organ dysfunction and inflammatory injury.
- Elevated sC5b-9, C3a, factor Bb, and low mannan-binding lectin levels were associated with increased mortality.
Conclusions:
- Specific complement pathway components are important prognostic biomarkers in COVID-19.
- These findings enhance understanding of COVID-19 pathophysiology.
Objectives:
Complement activation has been implicated in COVID-19 pathogenesis. This study aimed to assess the levels of complement activation products and full-length proteins in hospitalized patients with COVID-19, and evaluated whether complement pathway markers are associated with outcomes.
Methods:
Longitudinal measurements of complement biomarkers from 89 hospitalized adult patients, grouped by baseline disease severity, enrolled in an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial and treated with intravenous sarilumab (200 mg or 400 mg) or placebo (NCT04315298), were performed. These measurements were then correlated with clinical and laboratory parameters.
Results:
All complement pathways were activated in hospitalized patients with COVID-19. Alternative pathway activation was predominant earlier in the disease course. Complement biomarkers correlated with multiple variables of multi-organ dysfunction and inflammatory injury. High plasma sC5b-9, C3a, factor Bb levels, and low mannan-binding lectin levels were associated with increased mortality. Sarilumab treatment showed a modest inhibitory effect on complement activation. Moreover, sera from patients spontaneously deposited C5b-9 complex on the endothelial surface ex vivo, suggesting a microvascular thrombotic potential.
Conclusion:
These results advance our understanding of COVID-19 disease pathophysiology and demonstrate the importance of specific complement pathway components as prognostic biomarkers in COVID-19.