title: Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study*.
abstract: OBJECTIVE
  To investigate the relationship among the angiopoietin-Tie-2 system, retinopathy, and mortality in children with cerebral malaria.
  
  
  METHODS
  A case-control study of retinopathy-positive vs. retinopathy-negative children with clinically defined cerebral malaria.
  
  
  METHODS
  Queen Elizabeth Central Hospital in Blantyre, Malawi.
  
  
  METHODS
  One hundred fifty-five children presenting with severe malaria and meeting a strict definition of clinical cerebral malaria (Blantyre Coma Score ≤ 2, Plasmodium falciparum parasitemia, no other identifiable cause for coma) were included in the study.
  
  
  METHODS
  None.
  
  
  RESULTS
  Clinical and laboratory parameters were recorded at admission and funduscopic examinations were performed. Admission levels of angiopoietin-1, angiopoietin-2, and a soluble version of their cognate receptor were measured by enzyme-linked immunosorbent assay. We show that angiopoietin-1 levels are decreased and angiopoietin-2 and soluble Tie-2 levels are increased in children with cerebral malaria who had retinopathy compared with those who did not. Angiopoietin-2 and soluble Tie-2 were independent predictors of retinopathy (adjusted odds ratio [95% CI], angiopoietin-2, 4.3 [1.3-14.6], p = .019; soluble Tie-2, 9.7 [2.1-45.8], p = .004). Angiopoietin-2 and soluble Tie-2 were positively correlated with the number of hemorrhages, the severity or retinal whitening, and the extent of capillary whitening observed on funduscopic examination (p < .05 after adjustment for multiple comparisons). Angiopoietin-2 and soluble Tie-2 levels were elevated in children with cerebral malaria who subsequently died and angiopoetin-2 was an independent predictor of death (adjusted odds ratio: 3.9 [1.2-12.7], p = .024). When combined with clinical parameters, angiopoetin-2 improved prediction of mortality using logistic regression models and classification trees.
  
  
  CONCLUSIONS
  These results provide insights into mechanisms of endothelial activation in cerebral malaria and indicate that the angiopoietin-Tie-2 axis is associated with retinopathy and mortality in pediatric cerebral malaria.
authors.affiliation: Sandra A Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Canada.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Conroy
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Glover
authors.forename: Michael
authors.initials: M
authors.lastname: Hawkes
authors.forename: Laura K
authors.initials: LK
authors.lastname: Erdman
authors.forename: Karl B
authors.initials: KB
authors.lastname: Seydel
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000097:blood* / Q000150:complications / Q000401:mortality*; D008295:Malawi; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012164:Retinal Diseases / Q000097:blood* / Q000401:mortality* / Q000469:parasitology; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D042702:Angiopoietin-2; D015415:Biomarkers