There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

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To halt the global tuberculosis epidemic, transmission must be stopped to prevent new infections and new cases. Identification of individuals with tuberculosis and prompt initiation of effective treatment to rapidly render them non-infectious is crucial to this task. However, in settings of high tuberculosis burden, active case-finding is often not implemented, resulting in long delays in diagnosis and treatment. A range of strategies to find cases and ensure prompt and correct treatment have been shown to be effective in high tuberculosis-burden settings. The population-level effect of targeted active case-finding on reducing tuberculosis incidence has been shown by studies and projected by mathematical modelling. The inclusion of targeted active case-finding in a comprehensive epidemic-control strategy for tuberculosis should contribute substantially to a decrease in tuberculosis incidence.

Blocking both CD28 and CD154 costimulatory pathways can induce transplant tolerance in some, but not all, transplant models. Under stringent conditions, however, this protocol often completely fails to block allograft rejection. The precise nature of such CD28/CD154 blockade-resistant rejection is largely unknown. In the present study we developed a new model in which both CD28 and CD154, two conventional T cell costimulatory molecules, are genetically knocked out (i.e., CD28/CD154 double-knockout (DKO) mice) and used this model to examine the role of novel costimulatory molecule-inducible costimulator (ICOS), OX40, 4-1BB, and CD27 in mediating CD28/CD154-independent rejection. We found that CD28/CD154 DKO mice vigorously rejected fully MHC-mismatched DBA/2 skin allografts (mean survival time, 12 days; n = 6) compared with the wild-type controls (mean survival time, 8 days; n = 7). OX40 costimulation is critically important in skin allograft rejection in this model, as blocking the OX40/OX40 ligand pathway, but not the ICOS/ICOS ligand, 4-1BB/4-1BBL, or CD27/CD70 pathway, markedly prolonged skin allograft survival in CD28/CD154 DKO mice. The critical role of OX40 costimulation in CD28/CD154-independent rejection is further confirmed in wild-type C57BL/6 mice, as blocking the OX40/OX40 ligand pathway in combination with CD28/CD154 blockade induced long term skin allograft survival (>100 days; n = 5). Our study revealed a key cellular mechanism of rejection and identified OX40 as a critical alternative costimulatory molecule in CD28/CD154-independent rejection.

BackgroundAn estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children.Methods and findingsTo inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%–19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%–48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15–20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0–8.3, p = 0.041 and aOR 5.9, 95% CI 1.7–20.5, p = 0.007, respectively). ...

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The management of children with drug-resistant tuberculosis (DR-TB) is challenging, and it is likely that in many places, the roll-out of molecular diagnostic testing will lead to more children being diagnosed. There is a limited evidence base to guide optimal treatment and follow-up in the pediatric population; in existing DR-TB guidelines, the care of children is often relegated to small "special populations" sections. This article seeks to address this gap by providing clinicians with practical advice and guidance. This is achieved through review of the available literature on pediatric DR-TB, including research studies and international guidelines, combined with consensus opinion from a team of experts who have extensive experience in the care of children with DR-TB in a wide variety of contexts and with varying resources. The review covers treatment initiation, regimen design and treatment duration, management of comorbid conditions, treatment monitoring, adverse events, adherence promotion, and infection control, all within a multidisciplinary environment.

Costimulatory signals and growth factor signals play a key role in commanding T cell activation and T cell effector function. However, how costimulatory signals and growth factor signals interact and integrate into the activation program of CD4+ and CD8+ T cells during the allograft response remains poorly defined. In the present study we found that either CD4- or CD8-deficient mice can vigorously reject the skin allografts. Blocking rapamycin-sensitive growth factor signals produced long term skin allograft survival in CD4-deficient mice (mean survival time, &gt;120 days), but not in CD8-deficient mice (mean survival time, 20 days). Analysis of CFSE-labeled cells proliferating in the allogeneic hosts revealed that clonal expansion of CD4+ T cells in vivo was more resistant to growth factor blockade than that of CD8+ T cells. However, blockade or genetic absence of CD28/CD154 costimulatory molecules rendered CD4+ T cell-mediated rejection sensitive to rapamycin, and long term skin allograft survival can be readily induced by rapamycin in the absence of CD28/CD154 signals (&gt;100 days). Furthermore, blocking OX40 costimulation induced long term skin allograft survival in CD4-deficient mice and CD8-deficient mice when both CD28 and CD154 were transiently blocked. We conclude that CD4+ and CD8+ T cells exhibit distinct sensitivity to growth factor blockade in transplant rejection, and CD28/CD154-independent rejection is sensitive to rapamycin and appears to be supported by OX40 costimulation.