Andrea L Conroy1, Margarita Gélvez2, Michael Hawkes3, Nimerta Rajwans4, Vanessa Tran5, W Conrad Liles6, Luis Angel Villar-Centeno7, Kevin C Kain8. 1. Sandra A. Rotman Laboratories, Sandra Rotman Centre, University Health Network-Toronto General Hospital, University of Toronto, Toronto, ON, M5G 1L7, Canada. Electronic address: andrea.conroy@utoronto.ca. 2. Centro de Investigaciones Epidemiológicas, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia. Electronic address: margarita.gelvez@hotmail.com. 3. Department of Pediatrics, University of Alberta, Edmonton, AB, T6G 2E1, Canada. Electronic address: mthawkes@ualberta.ca. 4. Sandra A. Rotman Laboratories, Sandra Rotman Centre, University Health Network-Toronto General Hospital, University of Toronto, Toronto, ON, M5G 1L7, Canada. Electronic address: nrajwans@uhnresearch.ca. 5. Sandra A. Rotman Laboratories, Sandra Rotman Centre, University Health Network-Toronto General Hospital, University of Toronto, Toronto, ON, M5G 1L7, Canada. Electronic address: vanessa.tran@utoronto.ca. 6. University of Washington, Department of Medicine, Seattle, WA, 98195, USA. Electronic address: WCLiles@medicine.washington.edu. 7. Centro de Investigaciones Epidemiológicas, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia. Electronic address: luisangelvillarc@gmail.com. 8. Sandra A. Rotman Laboratories, Sandra Rotman Centre, University Health Network-Toronto General Hospital, University of Toronto, Toronto, ON, M5G 1L7, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, ON, M5G 2C4, Canada. Electronic address: kevin.kain@uhn.ca.
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 96 hours 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.
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 96 hours 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.
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