title: High pneumococcal DNA loads are associated with mortality in Malawian children with invasive pneumococcal disease.
abstract: BACKGROUND
  In bacteremia owing to Streptococcus pneumoniae, high bacterial counts at presentation have been shown to be predictive of the development of serious invasive disease. Using real-time PCR, we aimed to determine pneumococcal DNA loads in blood and CSF, and their relationship to cytokine concentrations, clinical presentation and outcome.
  
  
  METHODS
  Children with confirmed meningitis (n = 82) or pneumonia (n = 13) were prospectively recruited, and blood and CSF samples taken for pneumococcal bacterial DNA loads and cytokine determination.
  
  
  RESULTS
  At the time of admission, the median bacterial load in blood was 1.6 x 10 DNA copies/mL (range 0.00-1.54 x 10) and in CSF it was 5.77 x 10 DNA copies/mL (range 4.42 x 10 to 6.15 x 10). Median blood and CSF bacterial loads (log DNA copies/mL) were significantly higher in nonsurvivors than in survivors; blood (3.80 vs. 2.97, P = 0.003), CSF (8.17 vs. 7.50, P = 0.03). In HIV-infected children (n = 59), blood and CSF loads and plasma tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), IL-6 and IL-10 were all significantly higher in nonsurvivors than in survivors, but in HIV-uninfected children (n = 36) this difference was not significant. Blood bacterial loads and plasma cytokine concentrations were significantly associated, and were all significantly higher in children with meningitis than in those with pneumonia. In children with meningitis, median CSF cytokine concentrations were significantly higher than median plasma cytokine concentrations (P < 0.001) and CSF bacterial loads were significantly associated with CSF IL-1beta (P = 0.002) and IL-10 (P = 0.001) concentrations.
  
  
  CONCLUSIONS
  Pneumococcal DNA loads are associated with plasma cytokine concentrations, and are higher in meningitis than in pneumonia. High blood and CSF pneumococcal DNA loads are associated with a fatal outcome.
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Department of Paediatrics, College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Enitan D
authors.initials: ED
authors.lastname: Carrol
authors.forename: Malcolm
authors.initials: M
authors.lastname: Guiver
authors.forename: Standwell
authors.initials: S
authors.lastname: Nkhoma
authors.forename: Limangeni A
authors.initials: LA
authors.lastname: Mankhambo
authors.forename: John
authors.initials: J
authors.lastname: Marsh
authors.forename: Paul
authors.initials: P
authors.lastname: Balmer
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: Elizabeth M
authors.initials: EM
authors.lastname: Molyneux
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Rosalind L
authors.initials: RL
authors.lastname: Smyth
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Hart
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid; D004269:DNA, Bacterial / Q000032:analysis* / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D007223:Infant; D008295:Malawi / Q000453:epidemiology; D008297:Male; D008586:Meningitis, Pneumococcal / Q000382:microbiology / Q000401:mortality*; D022242:Pneumococcal Vaccines / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000382:microbiology / Q000401:mortality*; D011446:Prospective Studies; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000302:isolation & purification*
chemical_list: D016207:Cytokines; D004269:DNA, Bacterial; D022242:Pneumococcal Vaccines