title: Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case-control study.
abstract: BACKGROUND
  Severe malaria is a leading cause of childhood mortality in Africa. However, at presentation, it is difficult to predict which children with severe malaria are at greatest risk of death. Dysregulated host inflammatory responses and endothelial activation play central roles in severe malaria pathogenesis. We hypothesized that biomarkers of these processes would accurately predict outcome among children with severe malaria.
  
  
  RESULTS
  Plasma was obtained from children with uncomplicated malaria (n = 53), cerebral malaria (n = 44) and severe malarial anemia (n = 59) at time of presentation to hospital in Kampala, Uganda. Levels of angiopoietin-2, von Willebrand Factor (vWF), vWF propeptide, soluble P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), soluble endoglin, soluble FMS-like tyrosine kinase-1 (Flt-1), soluble Tie-2, C-reactive protein, procalcitonin, 10 kDa interferon gamma-induced protein (IP-10), and soluble triggering receptor expressed on myeloid cells-1 (TREM-1) were determined by ELISA. Receiver operating characteristic (ROC) curve analysis was used to assess predictive accuracy of individual biomarkers. Six biomarkers (angiopoietin-2, soluble ICAM-1, soluble Flt-1, procalcitonin, IP-10, soluble TREM-1) discriminated well between children who survived severe malaria infection and those who subsequently died (area under ROC curve>0.7). Combinational approaches were applied in an attempt to improve accuracy. A biomarker score was developed based on dichotomization and summation of the six biomarkers, resulting in 95.7% (95% CI: 78.1-99.9) sensitivity and 88.8% (79.7-94.7) specificity for predicting death. Similar predictive accuracy was achieved with models comprised of 3 biomarkers. Classification tree analysis generated a 3-marker model with 100% sensitivity and 92.5% specificity (cross-validated misclassification rate: 15.4%, standard error 4.9%).
  
  
  CONCLUSIONS
  We identified novel host biomarkers of pediatric severe and fatal malaria (soluble TREM-1 and soluble Flt-1) and generated simple biomarker combinations that accurately predicted death in an African pediatric population. While requiring validation in further studies, these results suggest the utility of combinatorial biomarker strategies as prognostic tests for severe malaria.
authors.affiliation: SA Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Erdman
authors.forename: Aggrey
authors.initials: A
authors.lastname: Dhabangi
authors.forename: Charles
authors.initials: C
authors.lastname: Musoke
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Conroy
authors.forename: Michael
authors.initials: M
authors.lastname: Hawkes
authors.forename: Sarah
authors.initials: S
authors.lastname: Higgins
authors.forename: Nimerta
authors.initials: N
authors.lastname: Rajwans
authors.forename: Kayla T
authors.initials: KT
authors.lastname: Wolofsky
authors.forename: David L
authors.initials: DL
authors.lastname: Streiner
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Christine M
authors.initials: CM
authors.lastname: Cserti-Gazdewich
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008288:Malaria / Q000145:classification / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016019:Survival Analysis; D014454:Uganda
chemical_list: D015415:Biomarkers