Immune function in young children with previous pulmonary or miliary/meningeal tuberculosis and impact of BCG vaccination

Timothy R. Sterling, Terezinha Martire, Alexandre Silva De Almeida, Li Ding, David E. Greenberg, Lorena Alves Moreira, Houda Elloumi, Angelica P V Torres, Clemax Couto Sant'Anna, Eliane Calazans, Geraldo Paraguassu, Tebeb Gebretsadik, Ayumi Shintani, Kathleen Miller, Afranio Kritski, Jose Roberto Lapa Silva, Steven M. Holland

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

OBJECTIVE. Children <5 years old are at increased risk of miliary/meningeal tuberculosis, but the immunologic factors that place them at risk are unknown. BCG vaccine protects against miliary/meningeal tuberculosis, but the mechanism of protection is unknown. We assessed for abnormalities in immune response associated with miliary/meningeal or pulmonary tuberculosis in young children. PATIENTS AND METHODS. We conducted a case-control study among HIV-seronegative Brazilian children who were <5 years old. Case subjects had previous culture-confirmed or clinical miliary/meningeal tuberculosis. There were 2 sets of control subjects: those with culture-confirmed pulmonary tuberculosis and purified protein derivative-positive household contacts. All of the children had completed treatment. Peripheral blood mononuclear cells were stimulated (phytohemagglutinin, phytohemagglutinin + interleukin 12, lipopolysaccharide, lipopolysaccharide + interferon-γ, and purified protein derivative), and cytokine responses (interleukin 1β, interleukin-4, interleukin-6, interleukin-8, interleukin 10, interleukin 12, interferon-γ, tumor necrosis factor-α, and monocyte chemoattractant protein 1) were quantified by bead-based assay. Median cytokine responses were compared by the Kruskal-Wallis test. Multivariate analysis of variance accounted for multiple comparisons. RESULTS. There were 18 case subjects with miliary/meningeal tuberculosis, 28 pulmonary control subjects, and 29 purified protein derivative-positive control subjects. The median age was 4.2 years. There was no difference in case and control subjects by age, gender, race, BMI, or median CD4 count. Twelve (67%) of 18 case subjects, 26 (93%) of 28 pulmonary control subjects, and 28 (97%) of 29 purified protein derivative-positive subjects had received BCG vaccine. No cytokine defects were identified in case subjects with miliary/meningeal tuberculosis compared with either set of control subjects. Pulmonary control subjects had uniformly higher monocyte chemoattractant protein 1 levels than case subjects with miliary/meningeal tuberculosis and purified protein derivative-positive control subjects, both at rest and with lipopolysaccharide, lipopolysaccharide + interferon-γ, and purified protein derivative stimulation. Pulmonary control subjects did not have a higher frequency of allele G in the -2518 monocyte chemoattractant protein 1 promoter polymorphism. Case subjects with miliary/meningeal tuberculosis who had received BCG vaccine (n = 12) had lower stimulated interleukin 8 production than children who did not receive BCG vaccine (n = 6). CONCLUSIONS. Children with previous miliary/meningeal tuberculosis did not have a major defect in the cytokine pathways studied. Increased monocyte chemoattractant protein 1 levels were associated with pulmonary disease, occurred despite BCG vaccination, and were not associated with a polymorphism in the monocyte chemoattractant protein 1 promoter.

Original languageEnglish (US)
Pages (from-to)e912-e921
JournalPediatrics
Volume120
Issue number4
DOIs
StatePublished - Oct 1 2007

Keywords

  • BCG vaccine
  • M tuberculosis
  • MCP-1
  • Miliary tuberculosis
  • Tuberculosis
  • Tuberculosis meningitis

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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    Sterling, T. R., Martire, T., De Almeida, A. S., Ding, L., Greenberg, D. E., Moreira, L. A., Elloumi, H., Torres, A. P. V., Sant'Anna, C. C., Calazans, E., Paraguassu, G., Gebretsadik, T., Shintani, A., Miller, K., Kritski, A., Silva, J. R. L., & Holland, S. M. (2007). Immune function in young children with previous pulmonary or miliary/meningeal tuberculosis and impact of BCG vaccination. Pediatrics, 120(4), e912-e921. https://doi.org/10.1542/peds.2006-3150