Host biomarkers are associated with progression to dengue haemorrhagic fever: a nested case-control study

Abstract Objectives Dengue represents the most important arboviral infection worldwide. Onset of circulatory collapse can be unpredictable. Biomarkers that can identify individuals at risk of plasma leakage may facilitate better triage and clinical management. Design Using a nested case-control design, we randomly selected subjects from a prospective cohort study of dengue in Colombia (n=1582). Using serum collected within 96hours of fever onset, we tested 19 biomarkers by ELISA in cases (developed dengue hemorrhagic fever or dengue shock syndrome (DHF/DSS); n=46), and controls (uncomplicated dengue fever (DF); n=65) and healthy controls (HC); n=15. Results Ang-1 levels were lower and angptl3, sKDR, sEng, sICAM-1, CRP, CXCL10/IP-10, IL-18 binding protein, CHI3L1, C5a and Factor D levels were increased in dengue compared to HC. sICAM-1, sEng and CXCL10/IP-10 were further elevated in subjects who subsequently developed DHF/DSS (p=0.008, p=0.028 and p=0.025, respectively). In a logistic regression model, age (odds ratio (OR) (95% CI): 0.95 (0.92-0.98), p=0.001), hyperesthesia/hyperalgesia (OR; 3.8 (1.4-10.4), p=0.008) and elevated sICAM-1 (>298ng/mL: OR; 6.3 (1.5-25.7), p=0.011) at presentation were independently associated with progression to DHF/DSS. Conclusions These results suggest that inflammation and endothelial activation are important pathways in the pathogenesis of dengue and sICAM-1 levels may identify individuals at risk of plasma leakage.