title: The role of angiogenic factors in predicting clinical outcome in severe bacterial infection in Malawian children.
abstract: BACKGROUND
  Severe sepsis is a disease of the microcirculation, with endothelial dysfunction playing a key role in its pathogenesis and subsequent associated mortality. Angiogenesis in damaged small vessels may ameliorate this dysfunction. The aim of the study was to determine whether the angiogenic factors (vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and angiopoietin-1 (Ang-1) and -2 (Ang-2)) are mortality indicators in Malawian children with severe bacterial infection.
  
  
  METHODS
  In 293 children with severe bacterial infection, plasma VEGF, PDGF, FGF, and Ang-1 and Ang-2 were measured on admission; in 50 of the children with meningitis, VEGF, PDGF, and FGF were also measured in the CSF. Healthy controls comprised children from some of the villages of the index cases. Univariable and multivariable logistic regression analyses were performed to develop a prognostic model.
  
  
  RESULTS
  The median age was 2.4 years, and the IQR, 0.7 to 6.0 years. There were 211 children with bacterial meningitis (72%) and 82 (28%) with pneumonia, and 154 (53%) children were HIV infected. Mean VEGF, PDGF, and FGF concentrations were higher in survivors than in nonsurvivors, but only PDGF remained significantly increased in multivariate analysis (P = 0.007). Mean Ang-1 was significantly increased, and Ang-2 was significantly decreased in survivors compared with nonsurvivors (6,000 versus 3,900 pg/ml, P = 0.03; and 7,700 versus 11,900 pg/ml, P = 0.02, respectively). With a logistic regression model and controlling for confounding factors, only female sex (OR, 3.95; 95% CI, 1.33 to 11.76) and low Ang-1 (OR, 0.23; 95% CI, 0.08 to 0.69) were significantly associated with mortality. In children with bacterial meningitis, mean CSF VEGF, PDGF, and FGF concentrations were higher than paired plasma concentrations, and mean CSF, VEGF, and FGF concentrations were higher in nonsurvivors than in survivors (P = 0.02 and 0.001, respectively).
  
  
  CONCLUSIONS
  Lower plasma VEGF, PDGF, FGF, and Ang-1 concentrations and higher Ang-2 concentrations are associated with an unfavorable outcome in children with severe bacterial infection. These angiogenic factors may be important in the endothelial dysregulation seen in severe bacterial infection, and they could be used as biomarkers for the early identification of patients at risk of a poor outcome.
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi. lmankhambo@gmail.com
authors.forename: Limangeni A
authors.initials: LA
authors.lastname: Mankhambo
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Banda
authors.forename: Graham
authors.initials: G
authors.lastname: Jeffers
authors.forename: Sarah A
authors.initials: SA
authors.lastname: White
authors.forename: Paul
authors.initials: P
authors.lastname: Balmer
authors.forename: Standwell
authors.initials: S
authors.lastname: Nkhoma
authors.forename: Happy
authors.initials: H
authors.lastname: Phiri
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Molyneux
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Hart
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Robert S
authors.initials: RS
authors.lastname: Heyderman
authors.forename: Enitan D
authors.initials: ED
authors.lastname: Carrol
mesh_terms: D042501:Angiogenic Proteins / Q000097:blood* / Q000134:cerebrospinal fluid / Q000378:metabolism; D042682:Angiopoietins / Q000097:blood* / Q000378:metabolism; D001424:Bacterial Infections / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology*; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008295:Malawi; D008297:Male; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D042501:Angiogenic Proteins; D042682:Angiopoietins; D015415:Biomarkers