Aberrant systemic acute-phase complement responses in conjunction with soluble CR1 attribute to varying grades of dengue disease severity

BACKGROUND: Dengue virus (DENV) infection poses a serious health burden across the tropical and sub-tropical regions. The role of complement factors and acute-phase reactants in clinical dengue remains ambiguous.

METHODS: The cross-sectional study enrolled 156 participants, with 114 confirmed clinical dengue cases and 42 healthy controls. Serological profiling (NS1, anti-DENV IgM, and anti-DENV IgG), estimation of serum acute-phase reactants, clinico-laboratory parameters, and viral load were performed to classify dengue patients under dengue with warning signs (DWS+, n = 35), dengue without warning signs (DWS-, n = 74), and severe dengue (n = 5) (based on varying grades of severity) in accordance with the 2009 WHO guidelines. Measurement of complement factors, i.e., C1 inhibitor (C1Inh) (n = 145), C1q (n = 152), C2 (n = 146), C3a (n = 153), C3b (n = 152), mannose-binding lectin (MBL) (n = 151), C5a (n = 150), and soluble complement receptor 1 (sCR1, also designated as sCD35) (n = 139), was performed using commercial ELISA, and their concentrations were correlated with acute-phase reactants, clinical laboratory parameters, grades of dengue severity, and platelet levels.

RESULTS: Our analysis showed a significant alteration in early classical complement proteins, C1Inh, C1q, and C2. The levels of downstream factors and sCR1 remained largely unchanged across both the grades of dengue severity and primary/secondary dengue cohorts. Univariate analysis revealed NS1 positivity, IgG positivity, age, urea, and sCR1 as factors associated with disease severity. Our multivariate analysis showed sCR1 as the only independent predictor that correlated negatively with dengue severity. Every unit increase of sCR1 was associated with 22% reduced odds of dengue severity. Platelet counts showed a negative association with red cell distribution width (RDW) and basophils and a strong positive correlation with serum uric acid levels.

CONCLUSIONS: Our findings show that aberrant complement activation and levels of sCR1 could attribute to varying grades of dengue severity. Given its inverse association, the levels of sCR1 could likely render early prediction of dengue disease severity. The role of sCR1 in complement-mediated pathogenesis in dengue remains a gray area of investigation.