Escalated complement activation during hospitalization is associated with higher risk of 60‐day mortality in SARS‐CoV‐2‐infected patients

Background The complement system, an upstream recognition system of innate immunity, is activated upon SARS‐CoV‐2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID‐19, its persistence post‐recovery and dynamic changes in relation to disease severity. Methods Serial blood samples were obtained from two cohorts of hospitalized COVID‐19 patients ( n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3–5 and days 7–10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO 2 /FiO 2 ratio <26.6 kPa) and/or admission to intensive care unit, 60‐day total mortality and pulmonary pathology after 3 months. Findings During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d ( p < 0.001), compared to patients with moderate COVID‐19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60‐day mortality ( p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months ( p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls. Conclusion Hospitalized COVID‐19 patients display prominent and long‐lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in‐hospital changes of complement activation products.