Is scale-up worth it? Challenges in economic analysis of diagnostic tests for tuberculosis.

David Dowdy and colleagues discuss the complexities of costing new TB diagnostic tests, including GeneXpert, and argue that flexible analytic tools are needed for decision-makers to adapt large-sample cost-effectiveness data to local conditions

Quality of tuberculosis care by Indian pharmacies: Mystery clients offer new insights

For many patients in India, pharmacies are their first point of contact, where most drugs, including antibiotics, can be purchased over-the-counter (OTC). Recent standardised (simulated) patient studies, covering four Indian cities, provide new insights on how Indian pharmacies manage patients with suspected or known tuberculosis. Correct management of the simulated patients ranged from 13% to 62%, increasing with the certainty of the TB diagnosis. Antibiotics were frequently dispensed OTC to patients, with 16% to 37% receiving such drugs across the cases. On a positive note, these studies showed that no pharmacy dispensed first-line anti-TB drugs. Engagement of pharmacies is important to not only improve TB detection and care, but also limit the abuse of antibiotics

Serial Testing for Tuberculosis: Can We Make Sense of T Cell Assay Conversions and Reversions?

The authors discuss a new study, which they say is a valuable addition to the existing literature on the performance of interferon gamma release assays in serial testing for TB infection

Mathematical Modeling of Tuberculosis Bacillary Counts and Cellular Populations in the Organs of Infected Mice

Background: Mycobacterium tuberculosis is a particularly aggressive microorganism and the host's defense is based on the induction of cellular immunity, in which the creation of a granulomatous structure has an important role. Methodology: We present here a new 2D cellular automata model based on the concept of a multifunctional process that includes key factors such as the chemokine attraction of the cells; the role of innate immunity triggered by natural killers; the presence of neutrophils; apoptosis and necrosis of infected macrophages; the removal of dead cells by macrophages, which induces the production of foamy macrophages (FMs); the life cycle of the bacilli as a determinant for the evolution of infected macrophages; and the immune response. Results: The results obtained after the inclusion of two degrees of tolerance to the inflammatory response triggered by the infection shows that the model can cover a wide spectrum, ranging from highly-tolerant (i.e. mice) to poorly-tolerant hosts (i.e. mini-pigs or humans). Conclusions: This model suggest that stopping bacillary growth at the onset of the infection might be difficult and the important role played by FMs in bacillary drainage in poorly-tolerant hosts together with apoptosis and innate lymphocytes. It also shows the poor ability of the cellular immunity to control the infection, provides a clear protective character to the granuloma, due its ability to attract a sufficient number of cells, and explains why an already infected host can be constantly reinfected

Biomarkers for diagnosis of childhood tuberculosis: A systematic review.

INTRODUCTION: As studies of biomarkers of tuberculosis (TB) disease provide hope for a simple, point-of-care test, we aimed to synthesize evidence on biomarkers for diagnosis of TB in children and compare their accuracy to published target product profiles (TPP). METHODS: We conducted a systematic review of biomarkers for diagnosis of pulmonary TB in exclusively paediatric populations, defined as age less than 15 years. PubMed, EMBASE and Web of Science were searched for relevant publications from January 1, 2000 to November 27, 2017. Studies using mixed adult and paediatric populations or reporting biomarkers for extrapulmonary TB were excluded. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) framework. No meta-analysis was done because the published childhood TB biomarkers studies were mostly early stage studies and highly heterogeneous. RESULTS: The 29 studies included in this systematic review comprise 20 case-control studies, six cohort studies and three cross-sectional studies. These studies reported diverse and heterogeneous forms of biomarkers requiring different types of clinical specimen and laboratory assays. Majority of the studies (27/29 [93%]) either did not meet the criteria in at least one of the four domains of the QUADAS-2 reporting framework or the assessment was unclear. However, the diagnostic performance of biomarkers reported in 22 studies met one or both of the WHO-recommended minimal targets of 66% sensitivity and 98% specificity for a new diagnostic test for TB disease in children, and/or 90% sensitivity and 70% specificity for a triage test. CONCLUSION: We found that majority of the biomarkers for diagnosis of TB in children are promising but will need further refining and optimization to improve their performances. As new data are emerging, stronger emphasis should be placed on improving the design, quality and general reporting of future studies investigating TB biomarkers in children

Bacteriophage-Based Tests for the Detection of \u3cem\u3eMycobacterium tuberculosis\u3c/em\u3e in Clinical Specimens: A Systematic Review and Meta-analysis

Background: Sputum microscopy, the most important conventional test for tuberculosis, is specific in settings with high burden of tuberculosis and low prevalence of non tuberculous mycobacteria. However, the test lacks sensitivity. Although bacteriophage-based tests for tuberculosis have shown promising results, their overall accuracy has not been systematically evaluated. Methods: We did a systematic review and meta-analysis of published studies to evaluate the accuracy of phage-based tests for the direct detection of M. tuberculosis in clinical specimens. To identify studies, we searched Medline, EMBASE, Web of science and BIOSIS, and contacted authors, experts and test manufacturers. Thirteen studies, all based on phage amplification method, met our inclusion criteria. Overall accuracy was evaluated using forest plots, summary receiver operating (SROC) curves, and subgroup analyses. Results: The data suggest that phage-based assays have high specificity (range 0.83 to 1.00), but modest and variable sensitivity (range 0.21 to 0.88). The sensitivity ranged between 0.29 and 0.87 among smear-positive, and 0.13 to 0.78 among smear-negative specimens. The specificity ranged between 0.60 and 0.88 among smear-positive and 0.89 to 0.99 among smear-negative specimens. SROC analyses suggest that overall accuracy of phage-based assays is slightly higher than smear microscopy in direct head-to-head comparisons. Conclusion: Phage-based assays have high specificity but lower and variable sensitivity. Their performance characteristics are similar to sputum microscopy. Phage assays cannot replace conventional diagnostic tests such as microscopy and culture at this time. Further research is required to identify methods that can enhance the sensitivity of phage-based assays without compromising the high specificity