title: Host biomarkers are associated with progression to dengue haemorrhagic fever: a nested case-control study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Conroy
authors.affiliation: Centro de Investigaciones Epidemiológicas, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia. Electronic address: margarita.gelvez@hotmail.com.
authors.forename: Margarita
authors.initials: M
authors.lastname: Gélvez
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, AB, T6G 2E1, Canada. Electronic address: mthawkes@ualberta.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Hawkes
authors.affiliation: 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.
authors.forename: Nimerta
authors.initials: N
authors.lastname: Rajwans
authors.affiliation: 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.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Tran
authors.affiliation: University of Washington, Department of Medicine, Seattle, WA, 98195, USA. Electronic address: WCLiles@medicine.washington.edu.
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.affiliation: Centro de Investigaciones Epidemiológicas, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia. Electronic address: luisangelvillarc@gmail.com.
authors.forename: Luis Angel
authors.initials: LA
authors.lastname: Villar-Centeno
authors.affiliation: 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.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005334:Fever; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011446:Prospective Studies; D019595:Severe Dengue / Q000097:blood*
chemical_list: D015415:Biomarkers
keywords: CXCL10; biomarkers; dengue; pathogenesis; sICAM-1; soluble endoglin