High pneumococcal DNA loads are associated with mortality in malawian children with invasive pneumococcal disease

The pneumococcus is a major cause of meningitis and severe pneumonia in the developing world. The burden of invasive pneumococcal disease (IPD) has increased in areas with a high prevalence of HIV infection.1 In The Gambia (with a low HIV prevalence rate), the incidence of IPD has been estimated to be 240/100,000/yr in children less than 5 years and 554/100,000/yr in children less than 1 year of age.2 By contrast, in South Africa (with a high HIV prevalence rate) the incidence of IPD in children under 2 years was found to be 73/100,000/yr in HIV-uninfected children and 3036/100,000/yr in HIV-infected children.3 The increased susceptibility of HIV-infected children to IPD is predominantly because of their increased susceptibility to disease caused by pediatric serotypes (serotypes 6, 9, 14, 19, 23). Tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, IL-8, macrophage inflammatory protein-1α, monocyte chemoattractant protein-1 and nitric oxide have been shown to be elevated in murine models of pneumococcal pneumonia.4–6 IL-10 appears to down-regulate pathophysiologic changes in pneumococcal meningitis and this may be mediated by interfering with the production of reactive nitrogen intermediates.7 It is now recognized that the net biologic response of pro- and antiinflammatory cytokines may affect the outcome of certain inflammatory diseases.8 An improved understanding of the critical mediators in the host response to IPD is an important step in developing new therapeutic strategies. In children with bacteremia owing to Haemophilus influenzae or Streptococcus pneumoniae, high bacterial counts (greater than 100 organisms per milliliter of blood), at presentation, based on quantitative blood culture methods, were shown to be highly predictive of the development of serious invasive disease, such as epiglottitis or meningitis.9 This was confirmed in another study which demonstrated that the magnitude of bacteremia correlated with the severity of infection.10 Patients with H. influenzae meningitis with greater than or equal to 107 colony forming units of H. influenzae type b per milliliter of CSF had a significantly greater frequency of neurologic sequelae.11 In children the magnitude of bacteremia is usually higher than that in adults, the level of bacteremia being inversely correlated with the patients age.12 We used a modification of a multiplex real-time PCR assay13 to detect and quantify pneumococcal DNA in blood, CSF and lung aspirate samples, and to determine the relationship between bacterial loads, cytokine concentrations, disease presentation and outcome.