Dysregulated complement activation in COVID-19: The Role of Soluble Complement Inhibitors

In viral infections, complement activation can contribute to viral clearance, but excessive activation, as observed in severe COVID-19, may drive immunopathology. While much is known about complement-activating factors in COVID-19, insight into the role of endogenous complement inhibitors remains limited. We performed a longitudinal analysis within the BEAT-COVID cohort, comprising hospitalized patients with SARS-CoV-2 infection admitted to the intensive care unit (ICU) or ward, and age-matched healthy controls. Serum levels of the complement activation marker soluble membrane attack complex (sC5b-9) and soluble inhibitors C1-Inhibitor (C1-INH), C4b-Binding Protein (C4BP), Factor H, and Factor I were measured by ELISA. In vitro endothelial complement sensitivity was assessed by flow cytometry. Soluble inhibitors were also measured in a cohort of patients with long COVID. Patients admitted to the ICU showed elevated sC5b-9 levels compared to patients admitted to the ward and controls, correlating with disease severity, length of hospitalization, and need for mechanical ventilation, but not mortality. Unexpectedly, levels of all soluble complement inhibitors were elevated, particularly in patients admitted to the ICU. Factor H levels positively correlated with sC5b-9. Endothelial cells pre-incubated with serum from patients admitted to the ICU became more susceptible to complement attack. In patients with long COVID, Factor H and C4BP levels remained elevated compared to pre-pandemic healthy controls. Severe COVID-19 is characterized by extensive complement activation despite elevated circulating inhibitor levels, suggesting impaired local complement regulation at the cell surface, potentially amplified by overwhelming systemic activation, rather than inhibitor deficiency.