Secondary dengue virus infection is associated with endothelial activation and hypotension in an outpatient cohort from the Philippines

Secondary dengue infection causes severe clinical manifestations through antibody-dependent enhancement (ADE) of viral pathogenesis. This cross-sectional study compared hypotension, endothelial activation, systemic inflammation, and thrombocytopenia in children and young adults aged 1-26 years with primary and secondary dengue at an outpatient clinic in the Philippines. Secondary infection was defined by anti-DENV IgG antibodies at presentation. Among 244 patients (median age 9 years, 40% female), 93 (38%) were IgG positive. Secondary infection was associated with a 2.2-fold increased odds (95% CI, 1.1–4.1) of hypotension compared to primary infection. Endothelial activation, quantified from an index of six endothelial markers (Ang1, Ang2, sTie2, sFlt1, sICAM1, sEndoglin), was significantly higher in secondary infection (p<0.001). Systemic inflammation, quantified from an index of four plasma markers (TNF, CXCL8/IL8, CXCL10/IP10, PCT), correlated with endothelial activation (τ=0.39, P<0.001). Patients with secondary infection exhibited significantly lower platelet counts (170 ×10⁹/L vs 230 ×10⁹/L, p<0.0001). IL10 levels were elevated in secondary versus primary infection (76 pg/mL vs 33 pg/mL, p<0.001) and correlated with endothelial activation (τ=0.34, p<0.0001) and systemic inflammation (τ=0.32, p<0.0001). IL10 levels showed an inverse correlation (τ=-0.29, p<0.0001) with platelet counts. Our findings support and extend the ADE model of secondary dengue pathogenesis.