Anna M. Mandalakas

Interferon-gamma release assays and childhood tuberculosis: systematic review and meta-analysis.

BACKGROUND Children infected with Mycobacterium tuberculosis have significant risk of developing tuberculosis (TB) and can therefore benefit from preventive therapy. OBJECTIVE To assess the value of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) in the diagnosis of TB infection and disease in children. METHODS Thirty-three studies were included, assessing commercial IGRAs (QuantiFERON®-TB [QFT] and T-SPOT.®TB) and TST. Reference standards for infection were incident TB or TB exposure. Test performance for disease diagnosis was evaluated in studies assessing children with confirmed and/or clinically diagnosed TB, compared to children where TB was excluded. RESULTS Two small studies measured incident TB in children tested with QFT and found weak positive predictive value. Association of test response with exposure-categorized dichotomously or as a gradient-was similar for all tests. The sensitivity and specificity of all tests were similar in diagnosing the disease. Stratified analysis suggested lower sensitivity for all tests in young or human immunodeficiency virus infected children. CONCLUSIONS Available data suggest that TST and IGRAs have similar accuracy for the detection of TB infection or the diagnosis of disease in children. Heterogeneous methodology limited the comparability of studies and the interpretation of results. A rigorous, standardized approach to evaluate TB diagnostic tests in children is needed.BACKGROUND Children infected with Mycobacterium tuberculosis have significant risk of developing tuberculosis(TB) and can therefore benefit from preventive therapy. OBJECTIVE To assess the value of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST)in the diagnosis of TB infection and disease in children. METHODS Thirty-three studies were included, assessing commercial IGRAs (QuantiFERON®-TB [QFT] andT-SPOT.®TB) and TST. Reference standards for infection were incident TB or TB exposure. Test performance for disease diagnosis was evaluated in studies assessing children with confirmed and/or clinically diagnosed TB,compared to children where TB was excluded. RESULTS Two small studies measured incident TB in children tested with QFT and found weak positive predictive value. Association of test response with exposure-categorized dichotomously or as a gradient-was similar for all tests. The sensitivity and specificity of all tests were similar in diagnosing the disease. Stratified analysis suggested lower sensitivity for all tests in young or human immuno deficiency virus infected children. CONCLUSIONS Available data suggest that TST and IGRAs have similar accuracy for the detection of TB infection or the diagnosis of disease in children. Heterogeneous methodology limited the comparability of studies and the interpretation of results. A rigorous, standardized approach to evaluate TB diagnostic tests in children is needed.

Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in children: a systematic review and meta-analysis.

BACKGROUND Microbiological confirmation of childhood tuberculosis is rare because of the difficulty of collection of specimens, low sensitivity of smear microscopy, and poor access to culture. We aimed to establish summary estimates for sensitivity and specificity of of the Xpert MTB/RIF assay compared with microscopy in the diagnosis of pulmonary tuberculosis in children. METHODS We searched for studies published up to Jan 6, 2015, that used Xpert in any setting in children with and without HIV infection. We systematically reviewed studies that compared the diagnostic accuracy of Xpert MTB/RIF (Xpert) with microscopy for detection of pulmonary tuberculosis and rifampicin resistance in children younger than 16 years against two reference standards-culture results and culture-negative children who were started on anti-tuberculosis therapy. We did meta-analyses using a bivariate random-effects model. FINDINGS We identified 15 studies including 4768 respiratory specimens in 3640 children investigated for pulmonary tuberculosis. Culture tests were positive for tuberculosis in 12% (420 of 3640) of all children assessed and Xpert was positive in 11% (406 of 3640). Compared with culture, the pooled sensitivities and specificities of Xpert for tuberculosis detection were 62% (95% credible interval 51-73) and 98% (97-99), respectively, with use of expectorated or induced sputum samples and 66% (51-81) and 98% (96-99), respectively, with use of samples from gastric lavage. Xpert sensitivity was 36-44% higher than was sensitivity for microscopy. Xpert sensitivity in culture-negative children started on antituberculosis therapy was 2% (1-3) for expectorated or induced sputum. Xperts pooled sensitivity and specificity to detect rifampicin resistance was 86% (95% credible interval 53-98) and 98% (94-100), respectively. INTERPRETATION Compared with microscopy, Xpert offers better sensitivity for the diagnosis of pulmonary tuberculosis in children and its scale-up will improve access to tuberculosis diagnostics for children. Although Xpert helps to provide rapid confirmation of disease, its sensitivity remains suboptimum compared with culture tests. A negative Xpert result does not rule out tuberculosis. Good clinical acumen is still needed to decide when to start antituberculosis therapy and continued research for better diagnostics is crucial. FUNDING WHO, Global TB Program of Texas Childrens Hospital.

Highly discordant T cell responses in individuals with recent exposure to household tuberculosis

Background: There are limited data comparing interferon-γ release assays (IGRAs) for the detection of Mycobacterium tuberculosis infection in highly endemic settings. Methods: A cross-sectional household contact study was conducted to measure the agreement of two IGRAs in relation to the tuberculin skin test (TST) to detect M tuberculosis infection and to assess the influence of M tuberculosis exposure and age. Results: In 82 individuals in household contact, 93% of children and 42% of adults had a high M tuberculosis contact score. The TST was positive in 78% of adults and 54% of children, the T-SPOT.TB was positive in 89% of children and 66% of adults and the QuantiFERON TB Gold (QTF) was positive in a similar proportion of adults and children (38.1% and 39.6%). In children there was poor agreement between the TST and T-SPOT.TB (κ = −0.15) and the T-SPOT.TB and the QTF (κ = −0.03), but good agreement between the TST and the QTF (κ = 0.78) using 10 mm cut-off. In adults there was fair to moderate agreement between the TST and T-SPOT.TB (κ = 0.38), the TST and QTF (κ = 0.34) and T-SPOT.TB and QTF (κ = −0.50). High levels of exposure to M tuberculosis were associated with at least a sevenfold odds of being T-SPOT.TB positive (95% CI 7.67 to 508.69) and a threefold odds of being QTF positive (95% CI 3.02 to 30.54). There was a significant difference in the magnitude of T-SPOT.TB early secretory antigenic target (ESAT)-6 and culture filtrate protein 10 kD (CFP-10) spot counts between adults and children. Conclusions: The T-SPOT.TB may be more sensitive than the TST or QTF for detecting recent M tuberculosis infection in children. Differences between assays and the predictive utility of these findings for subsequent disease development should be prospectively assessed.

Evaluation of tuberculosis diagnostics in children: 2. Methodological issues for conducting and reporting research evaluations of tuberculosis diagnostics for intrathoracic tuberculosis in children. Consensus from an expert panel.

Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children. In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children.

Modelling the cost-effectiveness of strategies to prevent tuberculosis in child contacts in a high-burden setting

Background WHO recommends isoniazid preventive therapy (IPT) for young children in close contact with an infectious tuberculosis (TB) case. No models have examined the cost effectiveness of this recommendation. Methods A decision analysis model was developed to estimate health and economic outcomes of five TB infection screening strategies in young household contacts. In the no-testing strategy, children received IPT based on age and reported exposure. Other strategies included testing for infection with a tuberculin skin test (TST), interferon γ release assay (IGRA) or IGRA after TST. Markov modelling included age-specific disease states and probabilities while considering risk of re-infection in a high-burden country. Results Among the 0–2-year-old cohort, the no-testing strategy was most cost effective. The discounted societal cost of care per life year saved ranged from US

Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update

237 (no-testing) to US

Utility of host markers detected in Quantiferon supernatants for the diagnosis of tuberculosis in children in a high-burden setting.

538 (IGRA only testing). Among the 3–5-year-old cohort, strategies employing an IGRA after a negative TST were most effective, but were associated with significant incremental cost (incremental cost-effectiveness ratio >US

Well-quantified tuberculosis exposure is a reliable surrogate measure of tuberculosis infection.

233 000), depending on the rate of Mycobacterium tuberculosis infection. Conclusion Screening for M tuberculosis infection and provision of IPT in young children is a highly cost-effective intervention. Screening without testing for M tuberculosis infection is the most cost-effective strategy in 0–2-year-old children and the preferred strategy in 3–5-year-old children. Lack of testing capacity should therefore not be a barrier to IPT delivery. These findings highlight the cost effectiveness of contact tracing and IPT delivery in young children exposed to TB in high-burden countries.

Detecting tuberculosis infection in HIV-infected children: a study of diagnostic accuracy, confounding and interaction.

Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspected of having intrathoracic tuberculosis. The changes proposed should enhance harmonized classification for intrathoracic tuberculosis disease in children across studies, resulting in greater comparability and the much-needed ability to pool study results.

Operational challenges in managing Isoniazid Preventive Therapy in child contacts: A high-burden setting perspective

Background The diagnosis of childhood tuberculosis (TB) disease remains a challenge especially in young and HIV-infected children. Recent studies have identified potential host markers which, when measured in Quantiferon (QFT-IT) supernatants, show promise in discriminating between Mycobacterium tuberculosis (M.tb) infection states. In this study, the utility of such markers was investigated in children screened for TB in a setting with high TB incidence. Methodology and Principal Findings 76 children (29% HIV-infected) with or without active TB provided blood specimens collected directly into QFT-IT tubes. After overnight incubation, culture supernatants were harvested, aliquoted and frozen for future immunological research purposes. Subsequently, the levels of 12 host markers previously identified as potential TB diagnostic markers were evaluated in these supernatants for their ability to discriminate between M.tb infection and disease states using the Luminex platform. Of the 76 children included, 19 (25%) had culture confirmed TB disease; 26 (46%) of the 57 without TB had positive markers of M.tb infection defined by a positive QFT-IT test. The potentially most useful analytes for diagnosing TB disease included IFN-α2, IL-1Ra, sCD40L and VEGF and the most useful markers for discriminating between QFT-IT positive children as TB or latent infection included IL-1Ra, IP-10 and VEGF. When markers were used in combinations of four, 84% of all children were accurately classified into their respective groups (TB disease or no TB), after leave-one-out cross validation. Conclusions Measurement of the levels of IFN-α2, IL-1Ra, sCD40L, IP-10 and VEGF in QFT-IT supernatants may be a useful method for diagnosing TB disease and differentiating between active TB disease and M.tb infection in children. Our observations warrant further investigation in larger well-characterized clinical cohorts.