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Rationale: Microbiological confirmation of pulmonary tuberculosis in children is desirable. Objectives: To investigate the diagnostic accuracy and incremental yield of Xpert MTB/RIF Ultra (Ultra; Cepheid), a new rapid test, on repeated induced sputum, nasopharyngeal aspirates, and combinations of specimens. Methods: Consecutive South African children hospitalized with suspected pulmonary tuberculosis were enrolled. Measurements and Main Results: Induced sputum (IS) and nasopharyngeal aspirates (NPAs) were obtained. NPAs were frozen; IS underwent liquid culture, and an aliquot was frozen. Ultra was performed on thawed NPAs and IS specimens individually. Children were categorized as confirmed, unconfirmed , or unlikely tuberculosis according to NIH consensus case definitions. The diagnostic accuracy of Ultra was compared with liquid culture on IS. In total, 195 children (median age: 23.3 mo; 32 [16.4%] HIV-infected) had one IS and NPA, and 130 had two NPAs. There were 40 (20.5%) culture-confirmed cases. Ultra was positive on NPAs in 26 (13.3%) and on IS in 31 (15.9%). Sensitivity and specificity of Ultra on one NPA were 46% and 98%, respectively, and similar by HIV status. Sensitivity and specificity of Ultra on one IS were 74.3% and 96.9% respectively. Combining one NPA and one IS increased sensitivity to 80%. Sensitivity using Ultra on two NPAs was 54.2%, increasing to 87.5% with an IS Ultra. Conclusions: IS provides a better specimen than repeated NPA for rapid diagnosis using Ultra. However, Ultra testing of combinations of specimens provides a novel strategy that can be adapted to identify most children with confirmed pulmonary tuberculosis.

Background: Identification of the Mycobacterium tuberculosis immunoproteome and antigens associated with serologic responses in adults has renewed interest in developing a serologic test for childhood tuberculosis (TB). We investigated IgG antibody responses against M. tuberculosis antigens in children with well-characterized TB., Methods: We studied archived sera obtained from hospitalized children with suspected pulmonary TB, and classified as having confirmed TB (culture-confirmed), unlikely TB (clinical improvement without TB treatment), or unconfirmed TB (all others). A multiplexed bead-based assay for IgG antibodies against 119 M. tuberculosis antigens was developed, validated and used to test sera. The area under the curves (AUCs) of the empiric receiver-operator characteristic curves were generated as measures of predictive ability. A cross-validated generalized linear model was used to select the most predictive combinations of antigens., Results: For the confirmed TB versus unlikely TB comparison, the maximal single antigen AUC was 0.63, corresponding to sensitivity 0.60 and specificity 0.60. Older (age: 60+ months old) children's responses were better predictive of TB status than younger (age: 12-59 months old) children's, with a maximal single antigen AUC of -0.76. For the confirmed TB versus unlikely TB groups, the most predictive combinations of antigens assigned TB risk probabilities of 0.33 and 0.33, respectively, when all ages were considered, and 0.57 (interquartile range: 0.48-0.64) and 0.35 (interquartile range: 0.32-0.40) when only older children were considered., Conclusion: An antigen-based IgG test is unlikely to meet the performance characteristics required of a TB detection test applicable to all age groups.

Background: The 2012 National Institutes of Health (NIH) consensus criteria for standardized diagnostic categories of pulmonary tuberculosis in children have not been validated. We aimed to assess the NIH diagnostic criteria in children with culture-confirmed pulmonary tuberculosis and those in whom tuberculosis has been excluded., Methods: We performed a retrospective analysis of consecutive children hospitalized with suspected pulmonary tuberculosis in Cape Town, South Africa, who were enrolled in a diagnostic study. Children were categorized as definite tuberculosis (culture positive), probable tuberculosis (chest radiograph consistent), possible tuberculosis (chest radiograph inconsistent), or not tuberculosis (improved without tuberculosis treatment). We applied the NIH diagnostic categories to the cohort and evaluated their performance specifically in children with definite tuberculosis and not tuberculosis., Results: Four hundred sixty-four children (median age, 25.1 months [interquartile range, 13.5-61.5 months]) were included; 96 (20.7%) were HIV infected. Of these, 165 (35.6%) were definite tuberculosis, and 299 (64.4%) were not tuberculosis. If strict NIH symptom criteria were applied, 100 (21.6%) were unclassifiable including 21 (21.0%) with definite pulmonary tuberculosis, as they did not meet the NIH criteria due to short duration of symptoms; 71 (71%) had cough <14 days, 48 (48%) had recent weight loss, and 39 (39%) had fever <7 days. Of 364 classifiable children, there was moderate agreement (κ = 0.48) with 100% agreement for definite tuberculosis and moderate agreement for not tuberculosis (220 [60.4%] vs 89 [24.5%])., Conclusions: Entry criteria for diagnostic studies should not be restrictive. Data from this analysis have informed revision of the NIH definitions., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Setting: Tuberculosis (TB) is a common cause of mortality and morbidity in children infected with the human immunodeficiency virus (HIV). Data on isoniazid preventive therapy (IPT) efficacy in HIV-infected children receiving antiretroviral therapy (ART) are inconclusive., Objective: To assess the efficacy, tolerability and safety of isoniazid (INH) in HIV-infected children on ART., Design: A pilot randomised controlled study of INH was undertaken in HIV-infected children on ART. The primary outcome measure was TB disease or death., Results: A total of 167 children were randomised to receive INH (n = 85) or placebo (n = 82), and followed for a median of 34 months (interquartile range [IQR] 24-52). The median age was 35 months (IQR 15-65). There was one death in a child on INH and none in the placebo group. Eleven (6.6%) cases of TB occurred, 4 (5%) in the INH and 7 (9%) in the placebo group. Among the TB cases, 5 were culture confirmed-2 in the INH group and 3 in the placebo group, all susceptible to INH. Severe adverse events occurred rarely (n = 6; 2%)., Conclusion: IPT is safe and well tolerated in HIV-infected children on concomitant ART. This study supports the need for a larger study to assess efficacy in HIV-infected children living in TB-endemic areas.