Lower C3 and C4 Complement Serum Levels Are Associated with More Severe Forms of COVID-19 Disease

Background: In a subgroup of patients, coronavirus disease (COVID)-19 is a severe illness with high mortality due to hyperinflammation, development of acute respiratory distress syndrome, and multiorgan dysfunction syndrome. Complement system activation plays a critical role in the pathogenesis and severity of COVID-19 disease. Methods: This cross-sectional, single-center study aimed to investigate the correlation between serum C3 and C4 levels and COVID-19 severity. We included 125 patients hospitalized between December 2020 and March 2021. Patients were stratified into three groups based on the level of respiratory support needed to maintain adequate oxygenation (PaO₂ ≥ 60 mmHg): 51 patients requiring oxygen supplementation up to 15 L/min, 51 patients requiring high-flow oxygen therapy, and 23 patients requiring mechanical ventilation (MV). We analyzed the blood counts and serum levels of C3, C4, C-reactive protein (CRP), IL-6, procalcitonin, d-dimers, high-sensitive troponin I (TnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), IgA, IgG, IgM, C3, C4, rheumatoid factor, and anticitrullinated peptide antibodies. Results: Patients on MV had significantly lower levels of C3 and C4 (0.98 ± 0.24 g/L for C3 and 0.21 ± 013 g/L for C4) compared with patients with less severe disease (p < 0.001 for C3, p < 0.001 for C4). Serum C3 and C4 levels were lower in patients requiring high-flow oxygen therapy than in those requiring oxygen supplementation, however, the difference was not statistically significant. In addition, higher neutrophil counts were observed in patients on MV or high-flow oxygen therapy than in those on oxygen supplementation, and higher CRP, procalcitonin, and NT-proBNP levels were observed only in patients on MV. The levels of IL-6, d-dimers, and high-sensitive TnI were positively correlated with disease severity, whereas lymphocyte counts showed a negative correlation, and these differences were statistically significant among all three groups. Conclusion: The determination of serum levels of C3 and C4, along with other known laboratory risk factors, may contribute to the detection of patients at an increased risk for severe COVID-19.