Published online October 1, 2007
PEDIATRICS Vol. 120 No. 4 October 2007, pp. e912-e921 (doi:10.1542/peds.2006-3150)
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ARTICLE

Immune Function in Young Children With Previous Pulmonary or Miliary/Meningeal Tuberculosis and Impact of BCG Vaccination

Timothy R. Sterling, MDa, Terezinha Martire, MDb,c, Alexandre Silva de Almeida, PhDb, Li Ding, MDd, David E. Greenberg, MDd, Lorena Alves Moreira, MSb, Houda Elloumi, PhDd, Angelica P.V. Torres, RN, BSNb, Clemax Couto Sant'Anna, MD, PhDe, Eliane Calazans, MDf, Geraldo Paraguassu, MDg,h, Tebeb Gebretsadik, MPHi, Ayumi Shintani, PhD, MPHi, Kathleen Miller, RN, BSNa, Afranio Kritski, MD, PhDb, Jose Roberto Lapa e Silva, MD, PhDb and Steven M. Holland, MDd

a Division of Infectious Diseases, Department of Medicine
i Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
b Academic Tuberculosis Program, Clementino Fraga Filho University Hospital
e Martagão Gesteira Pediatric Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
c Division of Pediatric Pneumology, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
d Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, Maryland
f Department of Pediatrics, Hospital San Sebastian, Rio de Janeiro, Brazil
g Department of Pediatric Neurosurgery, Hospital Sao Goncalo, Sao Goncalo, Brazil
h Department of Pediatric Neurosurgery, Hospital Municipal Jesus, Rio de Janeiro, Brazil

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-{gamma}, and purified protein derivative), and cytokine responses (interleukin 1β, 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.

Key Words: M tuberculosis • tuberculosis • tuberculosis meningitis • miliary tuberculosis • BCG vaccine • MCP-1

Abbreviations: IL—interleukin • MCP—monocyte chemoattractant protein • PPD—purified protein derivative • PBMC—peripheral blood mononuclear cell • IFN—interferon • TNF—tumor necrosis factor • MANOVA—multivariate analysis of variance • IQR—interquartile range

Accepted Mar 3, 2007.