title: Immune function in young children with previous pulmonary or miliary/meningeal tuberculosis and impact of BCG vaccination.
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.
  
  
  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-gamma, and purified protein derivative), and cytokine responses (interleukin 1beta, interleukin-4, interleukin-6, interleukin-8, interleukin 10, interleukin 12, interferon-gamma, tumor necrosis factor-alpha, 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-gamma, 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.
authors.affiliation: Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TN 37232-2605, USA. timothy.sterling@vanderbilt.edu
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Sterling
authors.forename: Terezinha
authors.initials: T
authors.lastname: Martire
authors.forename: Alexandre Silva
authors.initials: AS
authors.lastname: de Almeida
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: David E
authors.initials: DE
authors.lastname: Greenberg
authors.forename: Lorena Alves
authors.initials: LA
authors.lastname: Moreira
authors.forename: Houda
authors.initials: H
authors.lastname: Elloumi
authors.forename: Angelica P V
authors.initials: AP
authors.lastname: Torres
authors.forename: Clemax Couto
authors.initials: CC
authors.lastname: Sant'Anna
authors.forename: Eliane
authors.initials: E
authors.lastname: Calazans
authors.forename: Geraldo
authors.initials: G
authors.lastname: Paraguassu
authors.forename: Tebeb
authors.initials: T
authors.lastname: Gebretsadik
authors.forename: Ayumi
authors.initials: A
authors.lastname: Shintani
authors.forename: Kathleen
authors.initials: K
authors.lastname: Miller
authors.forename: Afranio
authors.initials: A
authors.lastname: Kritski
authors.forename: Jose Roberto
authors.initials: JR
authors.lastname: Lapa e Silva
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D001500:BCG Vaccine; D001938:Brazil; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016209:Interleukin-8 / Q000097:blood; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation; D008297:Male; D010835:Phytohemagglutinins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D014373:Tuberculin / Q000494:pharmacology; D014390:Tuberculosis, Meningeal / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D001500:BCG Vaccine; D018932:Chemokine CCL2; D016209:Interleukin-8; D008070:Lipopolysaccharides; D010835:Phytohemagglutinins; D014373:Tuberculin; D007371:Interferon-gamma