Evaluation of immune-endothelial activation markers for the differentiation of severe dengue

Severe dengue (SD) or dengue hemorrhagic fever is characterized by immune hyperactivation, endothelial dysfunction and vascular leakage. Early detection of the onset of SD, particularly during the febrile phase or before the onset of the critical phase is highly desirable. However, most dengue patients present late (≥ 5 days of illness) to the hospital, which coincides with the beginning of the critical phase. Biomarkers associated with these pathological processes may therefore serve as severity-associated markers. This study investigated the clinical utility of the immune-endothelial activation panel as a potential indicator for differentiating SD from dengue fever (DF). A multicenter cross-sectional study was conducted using sera of clinically- and laboratory-confirmed SD and DF patients, non-dengue febrile illness patients (NDFI) and healthy individuals. Serum levels of monocyte/macrophage activation markers CD163, CD14 and ferritin; endothelial activation and vascular permeability markers SDC-1 and VCAM-1; and cytokines CCL2, CCL3, CXCL9, CXCL10 and IL-10 were measured by ELISA or immunoplex assays. The ability to distinguish SD from DF was measured using Receiver Operating Characteristic (ROC) analysis. CD163, ferritin, SDC-1, VCAM-1 and CCL2 levels were significantly different between SD and DF, as well as between DF and NDFI. CD163, SDC-1 and VCAM-1 levels differed significantly between primary and secondary dengue. These indicators performed moderately as standalones in distinguishing SD from DF. However, a combination of SDC-1, CD163 and VCAM-1 improved diagnostic performance (AUC = 0.784, 95% Cl:0.725–0.835). Notably, combining AST, a hepatic injury marker with all four indicators (SDC-1, CD163, VCAM-1 and ferritin) significantly enhanced the diagnostic performance of this panel (AUC = 0.850, 95% Cl: 0.781–0.904). A multi-marker panel consisting of immune-endothelial activation and hepatic injury can increase the accuracy of identifying SD during the critical phase of the illness. Given the absence of a specific test for the detection of impending SD, the strength of this multi-marker panel may support timely decision-making for high-risk patient management while safely discharging others to optimise the usage of hospital resources.