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1.  Gamma Interferon Release Assays for Detection of Mycobacterium tuberculosis Infection 
Clinical Microbiology Reviews  2014;27(1):3-20.
SUMMARY
Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.
doi:10.1128/CMR.00034-13
PMCID: PMC3910908  PMID: 24396134
2.  Modeling the Impact of Alternative Strategies for Rapid Molecular Diagnosis of Tuberculosis in Southeast Asia 
American Journal of Epidemiology  2013;178(12):1740-1749.
Novel diagnostic tests hold promise for improving tuberculosis (TB) control, but their epidemiologic impact remains uncertain. Using data from the World Health Organization (2011–2012), we developed a transmission model to evaluate the deployment of 3 hypothetical TB diagnostic tests in Southeast Asia under idealized scenarios of implementation. We defined diagnostics by their sensitivity for smear-negative TB and proportion of patients testing positive who initiate therapy (“point-of-care amenability”), with tests of increasing point-of-care amenability having lower sensitivity. Implemented in the public sector (35% of care-seeking attempts), each novel test reduced TB incidence by 7%–9% (95% uncertainty range: 4%–13%) and mortality by 20%–22% (95% uncertainty range: 14%–27%) after 10 years. If also deployed in the private sector (65% of attempts), these tests reduced incidence by 13%–16%, whereas a perfect test (100% sensitivity and treatment initiation) reduced incidence by 20%. Annually detecting 20% of prevalent TB cases through targeted screening (70% smear-negative sensitivity, 85% treatment initiation) also reduced incidence by 19%. Sensitivity and point-of-care amenability are equally important considerations when developing novel diagnostic tests for TB. Novel diagnostics can substantially reduce TB incidence and mortality in Southeast Asia but are unlikely to transform TB control unless they are deployed actively and in the private sector.
doi:10.1093/aje/kwt210
PMCID: PMC3858106  PMID: 24100953
diagnostic techniques and procedures; epidemiologic methods; Southeast Asia; theoretical models; tuberculosis
3.  Challenges with QuantiFERON-TB Gold Assay for Large-Scale, Routine Screening of U.S. Healthcare Workers 
Rationale: North American occupational health programs that switched from the tuberculin skin test (TST) to IFN-γ release assays for latent tuberculosis screening are reporting challenges with interpretation of serial testing results in healthcare workers (HCWs). However, limited data exist on the reproducibility of serial IFN-γ release assay results in low-risk HCWs.
Objectives: To evaluate the short-term reproducibility of QuantiFERON-TB Gold In-Tube (QFT) in a large cohort of HCWs and to define a QFT cutoff yielding a conversion rate equivalent to historical TST rates.
Methods: We retrospectively evaluated the QFT results from HCWs with two or more QFT tests performed between June 2008 and July 2010 at an academic institution. Outcome measures were proportions of reproducibility, quantitative results, and conversion rates with alternate QFT cutoffs.
Measurements and Main Results: A total of 9,153 HCWs with two or more QFT tests were included in the analysis. Of 8,227 individuals with a negative result, 4.4% (n = 361) converted their QFT result over 2 years. A total of 261 (72.3%) of the HCWs with conversions underwent repeat short-term testing after the first positive result with 64.8% reverting (n = 169). An IFN-γ cutoff of 5.3 IU/ml or higher (manufacturer’s cutoff is ≥0.35 IU/ml) yielded a conversion rate of 0.4%, equal to our institution’s historical TST conversion rate.
Conclusions: The manufacturer’s definition of QFT conversion results in an inflated conversion rate that is incompatible with our low-risk setting. A significantly higher QFT cutoff value is needed to match the historical TST conversion rate. Nonreproducible conversions in most converters suggested false-positive results.
doi:10.1164/rccm.201305-0831OC
PMCID: PMC3826285  PMID: 23978270
interferon-γ release assay; QuantiFERON; healthcare workers; reproducibility of results
4.  Delays in diagnosis and treatment of pulmonary tuberculosis in India: a systematic review 
SUMMARY
Objective
To systematically review Indian literature on delays in TB diagnosis and treatment.
Methods
We searched multiple sources for studies on delays in pulmonary TB and chest symptomatic patients. Studies were included if numeric data on any delay were reported. Patient delay was defined as the time interval between onset of symptoms and the patient’s first contact with a healthcare provider. Diagnostic delay was defined as the time interval between the first consultation with a healthcare provider and diagnosis. Treatment delay was defined as the time interval between diagnosis and initiation of anti-TB treatment. Total delay was defined as time interval from the onset of symptoms until treatment initiation.
Results
Among 541 potential citations identified, 23 studies met our inclusion criteria. Included studies used a variety of definitions for onset of symptoms and delays. Median (IQR) estimates of patient, diagnostic and treatment delay were 18.4 (14.3-27.0), 31.0 (24.5-35.4) and 2.5 days (1.9-3.6), respectively, for TB and chest symptomatic patients combined. The median total delay was 55.3 days (46.5-61.5). About 48% of all patients first consulted private providers and 2.7 healthcare providers, on average, were consulted before diagnosis. Number and type of provider first consulted were the most important risk factors for delay.
Conclusions
These findings underscore the need to develop novel strategies for reducing patient and diagnostic delays and engaging first-contact healthcare providers.
doi:10.5588/ijtld.13.0585
PMCID: PMC4070850  PMID: 24670558
Tuberculosis; Delayed Diagnosis; Delivery of Health Care; Care Seeking Behaviour; India
5.  The Importance of Implementation Strategy in Scaling Up Xpert MTB/RIF for Diagnosis of Tuberculosis in the Indian Health-Care System: A Transmission Model 
PLoS Medicine  2014;11(7):e1001674.
Using a modelling approach, David Dowdy and colleagues investigate how different implementation strategies for Xpert MTB/RIF within the complex, fragmented healthcare system of India may affect tuberculosis control.
Please see later in the article for the Editors' Summary
Background
India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited.
Methods and Findings
We developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: −1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: −5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four-module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research.
Conclusions
The impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Tuberculosis—a contagious bacterial disease that usually infects the lungs—is a global public health problem. Each year, about 8.7 million people develop active tuberculosis and about 1.4 million people die from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with active disease cough or sneeze. The characteristic symptoms of tuberculosis are a persistent cough, fever, weight loss, and night sweats. Diagnostic tests for tuberculosis include sputum smear microscopy (microscopic analysis of mucus coughed up from the lungs), the growth of M. tuberculosis from sputum samples, and new molecular tests (for example, the automated Xpert MTB/RIF test) that rapidly and accurately detect M. tuberculosis in patient samples and determine its resistance to certain antibiotics. Tuberculosis can be cured by taking several antibiotics daily for at least six months, although the recent emergence of multidrug-resistant (MDR) tuberculosis is making the disease increasingly hard to treat.
Why Was This Study Done?
About 25% of all tuberculosis cases occur in India. Most people in India with underlying tuberculosis initially seek care for cough from the private health-care sector, which comprises informal providers with no formal medical training and providers with some training in mainstream or alternative medicine. Private providers rarely investigate for tuberculosis, and patients often move between providers, with long diagnostic delays. The public sector ultimately diagnoses and treats more than half of tuberculosis cases. However, the public sector relies on sputum smear microscopy, which misses half of cases, and the full diagnostic process from symptom onset to treatment initiation can take several months, during which time individuals remain infectious. Could the rollout of molecular diagnostic tests improve tuberculosis control in India? The Indian Revised National Tuberculosis Control Programme (RNTCP) is currently introducing the Xpert MTB/RIF test (Xpert) as a rapid method for drug susceptibility testing in the public sector in people at high risk of MDR tuberculosis, but is this the most effective rollout strategy? Here, the researchers use a mathematical transmission model to investigate the likely effects of the rollout of Xpert in India using different implementation strategies.
What Did the Researchers Do and Find?
The researchers explored the impact of several rollout strategies on the incidence of tuberculosis (the number of new cases of tuberculosis in the population per year) by developing a mathematical model of tuberculosis transmission, care-seeking behavior, and diagnostic/treatment practices in India. Compared to a baseline scenario of no improved diagnostic testing, provision of Xpert to 40% of public-sector patients at high risk of MDR tuberculosis (scenario 1, the current national strategy) reduced the incidence of tuberculosis by 0.2% and the incidence of MDR tuberculosis by 2.4%. Implementation of this strategy required 2,500 additional courses of MDR tuberculosis treatment and the continuous use of 60 Xpert machines, about half the machines procured in India during 2013. A scenario that added access to Xpert for 20% of all individuals with tuberculosis symptoms seeking diagnosis in the public sector and 20% of individuals seeking care from qualified private practitioners to scenario 1 reduced the incidence of tuberculosis by 14.1% compared to the baseline scenario but required more than 2,200 Xpert machines and reliable treatment referral. Notably, a scenario that encouraged informal providers to refer suspected tuberculosis cases to the public sector for smear-based diagnosis (no Xpert rollout) had a greater impact on the incidence of tuberculosis than Xpert scale-up within the public sector.
What Do These Findings Mean?
These findings are subject to considerable uncertainty because of the assumptions made in the transmission model about private-sector treatment patterns, patient care-seeking behavior, and infectiousness, and the quality of the data fed into the model. Nevertheless, these findings suggest that the rollout of Xpert (or other new diagnostic methods with similar characteristics) could substantially reduce the burden of tuberculosis due to poor diagnosis in India. Importantly, these findings highlight how the impact of Xpert rollout relies not only on the accuracy of the test but also on the behavior of patients and providers, the level of access to new tools, and the availability of treatment following diagnosis. Thus, to ensure that new diagnostic methods have the maximum impact on tuberculosis in India, it is necessary to engage the whole private health-care sector and to provide adequate referral systems, improved treatment quality, and increased resources across all health-care sectors.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001674.
The World Health Organization (WHO) provides information (in several languages) on all aspects of tuberculosis, including general information on tuberculosis diagnostics and specific information on the roll out of the Xpert MTB/RIF test; further information about WHO's endorsement of Xpert MTB/RIF is included in a Strategic and Technical Advisory Group for Tuberculosis report; the Global Tuberculosis Report 2013 provides information about tuberculosis around the world, including in India
The Stop TB Partnership is working towards tuberculosis elimination and provides patient stories about tuberculosis (in English and Spanish); the Tuberculosis Vaccine Initiative (a not-for-profit organization) also provides personal stories about tuberculosis
The US Centers for Disease Control and Prevention has information about tuberculosis and its diagnosis (in English and Spanish)
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis
TBC India provides information about tuberculosis control in India, including information on the RNTCP
The Initiative for Promoting Affordable and Quality TB Tests promotes WHO-endorsed TB tests in India
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001674
PMCID: PMC4098913  PMID: 25025235
6.  A Bayesian framework for estimating the incremental value of a diagnostic test in the absence of a gold standard 
Background
The absence of a gold standard, i.e., a diagnostic reference standard having perfect sensitivity and specificity, is a common problem in clinical practice and in diagnostic research studies. There is a need for methods to estimate the incremental value of a new, imperfect test in this context.
Methods
We use a Bayesian approach to estimate the probability of the unknown disease status via a latent class model and extend two commonly-used measures of incremental value based on predictive values [difference in the area under the ROC curve (AUC) and integrated discrimination improvement (IDI)] to the context where no gold standard exists. The methods are illustrated using simulated data and applied to the problem of estimating the incremental value of a novel interferon-gamma release assay (IGRA) over the tuberculin skin test (TST) for latent tuberculosis (TB) screening. We also show how to estimate the incremental value of IGRAs when decisions are based on observed test results rather than predictive values.
Results
We showed that the incremental value is greatest when both sensitivity and specificity of the new test are better and that conditional dependence between the tests reduces the incremental value. The incremental value of the IGRA depends on the sensitivity and specificity of the TST, as well as the prevalence of latent TB, and may thus vary in different populations.
Conclusions
Even in the absence of a gold standard, incremental value statistics may be estimated and can aid decisions about the practical value of a new diagnostic test.
doi:10.1186/1471-2288-14-67
PMCID: PMC4077291  PMID: 24886359
Area under the curve; Bayesian estimation; Incremental value; Informative priors; Integrated discrimination improvement; Imperfect diagnostic tests; Latent class models; Tuberculosis
7.  Aligning New Tuberculosis Drug Regimens and Drug Susceptibility Testing: A Needs Assessment and Roadmap for Action 
The Lancet infectious diseases  2013;13(5):449-458.
New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease.
doi:10.1016/S1473-3099(13)70025-2
PMCID: PMC4012744  PMID: 23531393
Tuberculosis; drug susceptibility testing; diagnostics; drug regimens; modeling; surveillance; implementation; operational
8.  Impact of Blood Volume, Tube Shaking, and Incubation Time on Reproducibility of QuantiFERON-TB Gold In-Tube Assay 
Journal of Clinical Microbiology  2013;51(11):3521-3526.
Gamma interferon (IFN-γ) release assays (IGRAs) are functional assays used serially to measure the efficacy of novel tuberculosis (TB) vaccines and to screen health care workers for latent tuberculosis infection (LTBI). However, studies have shown nonreproducible IGRA results. In this study, we investigated the effects of blood volume (0.8, 1.0, and 1.2 ml), tube shaking (gentle versus vigorous), and incubation duration (16, 20, and 24 h) on the reproducibility of QuantiFERON-TB Gold In-Tube (QFT-GIT) results for 50 subjects (33 uninfected and 17 infected). The median IFN-γ TB response (TB antigen [Ag] minus nil value) was significantly higher with 0.8 ml blood (1.04 IU/ml) than with 1.0 ml (0.85 IU/ml; P = 0.002) or 1.2 ml (0.49 IU/ml; P < 0.001) for subjects with LTBI. Compared with 0.8 ml (11.8%), there were larger proportions of false-negative results with 1.0 ml (29.4%; P = 0.2) and 1.2 ml (41.2%; P = 0.05) of blood for infected subjects. Blood volume did not significantly change the proportions of positive results in uninfected controls. Compared with gentle shaking, vigorous shaking increased the median IFN-γ response in nil (0.04 versus 0.06 IU/ml; P < 0.001) and TB Ag (0.12 versus 0.24 IU/ml; P = 0.004) tubes and increased TB responses (TB Agvigorous minus nilgentle) (0.02 versus 0.08 IU/ml; P = 0.004). The duration of incubation did not have a significant impact on the proportion of positive results in uninfected or infected subjects. This study identified blood volume and tube shaking as novel preanalytical sources of variability which require further standardization in order to improve the quality and reproducibility of QFT-GIT results.
doi:10.1128/JCM.01627-13
PMCID: PMC3889728  PMID: 23966505
9.  Do We Need to Detect Isoniazid Resistance in Addition to Rifampicin Resistance in Diagnostic Tests for Tuberculosis? 
PLoS ONE  2014;9(1):e84197.
Background
Multidrug-resistant tuberculosis (MDR-TB) is resistant to both rifampicin (RIF) and isoniazid (INH). Whereas many TB diagnostics detect RIF-resistance, few detect INH-monoresistance, which is common and may increase risk of acquired MDR-TB. Whether inclusion of INH-resistance in a first-line rapid test for TB would have an important impact on MDR-TB rates remains uncertain.
Methods
We developed a transmission model to evaluate three tests in a population similar to that of India: a rapid molecular test for TB, the same test plus RIF-resistance detection (“TB+RIF”), and detection of RIF and INH-resistance (“TB+RIF/INH”). Our primary outcome was the prevalence of INH-resistant and MDR-TB at ten years.
Results
Compared to the TB test alone and assuming treatment of all diagnosed MDR cases, the TB+RIF test reduced the prevalence of MDR-TB among all TB cases from 5.5% to 3.8% (30.6% reduction, 95% uncertainty range, UR: 17–54%). Despite using liberal assumptions about the impact of INH-monoresistance on treatment outcomes and MDR-TB acquisition, expansion from TB+RIF to TB+RIF/INH lowered this prevalence only from 3.8% to 3.6% further (4% reduction, 95% UR: 3–7%) and INH-monoresistant TB from 15.8% to 15.1% (4% reduction, 95% UR: (-8)-19%).
Conclusion
When added to a rapid test for TB plus RIF-resistance, detection of INH-resistance has minimal impact on transmission of TB, MDR-TB, and INH-monoresistant TB.
doi:10.1371/journal.pone.0084197
PMCID: PMC3880287  PMID: 24404155
10.  Challenges in the Development of an Immunochromatographic Interferon-Gamma Test for Diagnosis of Pleural Tuberculosis 
PLoS ONE  2013;8(12):e85447.
Existing diagnostic tests for pleural tuberculosis (TB) have inadequate accuracy and/or turnaround time. Interferon-gamma (IFNg) has been identified in many studies as a biomarker for pleural TB. Our objective was to develop a lateral flow, immunochromatographic test (ICT) based on this biomarker and to evaluate the test in a clinical cohort. Because IFNg is commonly present in non-TB pleural effusions in low amounts, a diagnostic IFNg-threshold was first defined with an enzyme-linked immunosorbent assay (ELISA) for IFNg in samples from 38 patients with a confirmed clinical diagnosis (cut-off of 300pg/ml; 94% sensitivity and 93% specificity). The ICT was then designed; however, its achievable limit of detection (5000pg/ml) was over 10-fold higher than that of the ELISA. After several iterations in development, the prototype ICT assay for IFNg had a sensitivity of 69% (95% confidence interval (CI): 50-83) and a specificity of 94% (95% CI: 81-99%) compared to ELISA on frozen samples. Evaluation of the prototype in a prospective clinical cohort (72 patients) on fresh pleural fluid samples, in comparison to a composite reference standard (including histopathological and microbiologic test results), showed that the prototype had 65% sensitivity (95% CI: 44-83) and 89% specificity (95% CI: 74-97). Discordant results were observed in 15% of samples if testing was repeated after one freezing and thawing step. Inter-rater variability was limited (3%; 1out of 32). In conclusion, despite an iterative development and optimization process, the performance of the IFNg ICT remained lower than what could be expected from the published literature on IFNg as a biomarker in pleural fluid. Further improvements in the limit of detection of an ICT for IFNg, and possibly combination of IFNg with other biomarkers such as adenosine deaminase, are necessary for such a test to be of value in the evaluation of pleural tuberculosis.
doi:10.1371/journal.pone.0085447
PMCID: PMC3871622  PMID: 24376880
11.  Incremental value of T-SPOT.TB for diagnosis of active pulmonary tuberculosis in children in a high-burden setting: a multivariable analysis 
Thorax  2013;68(9):860-866.
Introduction
Interferon γ release assays (IGRAs) are increasingly used for tuberculosis (TB) infection, but their incremental value beyond patient demographics, clinical signs and conventional tests for active disease has not been evaluated in children.
Methods
The incremental value of T-SPOT.TB was assessed in 491 smear-negative children from two hospitals in Cape Town, South Africa. Bayesian model averaging was used to select the optimal set of patient demographics and clinical signs for predicting culture-confirmed TB. The added value of T-SPOT.TB over and above patient characteristics and conventional tests was measured using statistics such as the difference in the area under the receiver operating characteristic curve (AUC), the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI).
Results
Cough longer than 2 weeks, fever longer than 2 weeks, night sweats, malaise, history of household contact and HIV status were the most important predictors of culture-confirmed TB. Binary T-SPOT.TB results did not have incremental value when added to the baseline model with clinical predictors, chest radiography and the tuberculin skin test. The AUC difference was 3% (95% CI 0% to 7%). Using risk cut-offs of <10%, 10–30% and >30%, the NRI was 7% (95% CI −8% to 31%) but the CI included the null value. The IDI was 3% (95% CI 0% to 11%), meaning that the average predicted probability across all possible cut-offs improved marginally by 3%.
Conclusions
In a high-burden setting, the T-SPOT.TB did not have added value beyond clinical data and conventional tests for diagnosis of TB disease in smear-negative children.
doi:10.1136/thoraxjnl-2012-203086
PMCID: PMC3862980  PMID: 23674550
Clinical Epidemiology; Tuberculosis
12.  Nutritional Status of Adult Patients with Pulmonary Tuberculosis in Rural Central India and Its Association with Mortality 
PLoS ONE  2013;8(10):e77979.
Under-nutrition is a known risk factor for TB and can adversely affect treatment outcomes. However, data from India are sparse, despite the high burden of TB as well as malnutrition in India. We assessed the nutritional status at the time of diagnosis and completion of therapy, and its association with deaths during TB treatment, in a consecutive cohort of 1695 adult patients with pulmonary tuberculosis in rural India during 2004 - 2009.Multivariable logistic regression was used to obtain adjusted estimates of the association of nutritional status with deaths during treatment. At the time of diagnosis, median BMI and body weights were 16.0 kg/m2and 42.1 kg in men, and 15.0 kg/m2and 34.1 kg in women, indicating that 80% of women and 67% of men had moderate to severe under-nutrition (BMI<17.0 kg/m2). Fifty two percent of the patients (57% of men and 48% of women) had stunting indicating chronic under-nutrition. Half of women and one third of men remained moderately to severely underweight at the end of treatment. 60 deaths occurred in 1179 patients (5%) in whom treatment was initiated. Severe under-nutrition at diagnosis was associated with a 2 fold higher risk of death. Overall, a majority of patients had evidence of chronic severe under-nutrition at diagnosis, which persisted even after successful treatment in a significant proportion of them. These findings suggest the need for nutritional support during treatment of pulmonary TB in this rural population.
doi:10.1371/journal.pone.0077979
PMCID: PMC3812022  PMID: 24205052
13.  Gamma Interferon Release Assay for Monitoring of Treatment Response for Active Tuberculosis: an Explosion in the Spaghetti Factory 
Journal of Clinical Microbiology  2013;51(2):607-610.
Few studies have correlated the results of interferon (gamma interferon) release assays (IGRAs) with known markers of tuberculosis (TB) treatment response. We report the results of serial QuantiFERON-TB gold in-tube assay (QFT) testing on 149 patients with active tuberculosis and correlate the results with smear and culture conversion. We show that QFT results do not offer much value for treatment monitoring of TB disease.
doi:10.1128/JCM.02278-12
PMCID: PMC3553895  PMID: 23175268
14.  Bayesian Meta-Analysis of the Accuracy of a Test for Tuberculous Pleuritis in the Absence of a Gold Standard Reference 
Biometrics  2012;68(4):1285-1293.
Summary
Absence of a perfect reference test is an acknowledged source of bias in diagnostic studies. In the case of tuberculous pleuritis, standard reference tests such as smear microscopy, culture and biopsy have poor sensitivity. Yet meta-analyses of new tests for this disease have always assumed the reference standard is perfect, leading to biased estimates of the new test’s accuracy. We describe a method for joint meta-analysis of sensitivity and specificity of the diagnostic test under evaluation, while considering the imperfect nature of the reference standard. We use a Bayesian hierarchical model that takes into account within- and between-study variability. We show how to obtain pooled estimates of sensitivity and specificity, and how to plot a hierarchical summary receiver operating characteristic curve. We describe extensions of the model to situations where multiple reference tests are used, and where index and reference tests are conditionally dependent. The performance of the model is evaluated using simulations and illustrated using data from a meta-analysis of nucleic acid amplification tests (NAATs) for tuberculous pleuritis. The estimate of NAAT specificity was higher and the sensitivity lower compared to a model that assumed that the reference test was perfect.
doi:10.1111/j.1541-0420.2012.01773.x
PMCID: PMC3728030  PMID: 22568612 CAMSID: cams3174
Bayesian; Bivariate model; Diagnostic test accuracy; Latent class model; Meta-analysis
16.  Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis 
The Lancet infectious diseases  2011;12(1):45-55.
Summary
Background
We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than that of the tuberculin skin test (TST).
Methods
Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals.
Findings
15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2–6), even in IGRA-positive individuals, was 4–48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42–3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 [95% CI 1·29–3·46] for IGRA vs 1·60 [0·94–2·72] for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals.
Interpretation
Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients’ preferences rather than on predictive ability alone.
Funding
Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.
doi:10.1016/S1473-3099(11)70210-9
PMCID: PMC3568693  PMID: 21846592
17.  Repeat IGRA Testing in Canadian Health Workers: Conversions or Unexplained Variability? 
PLoS ONE  2013;8(1):e54748.
Background
Although North American hospitals are switching from tuberculin testing (TST) to interferon-gamma release assays (IGRAs), data are limited on the association between occupational exposure and serial QuantiFERON-TB Gold In-Tube (QFT) results in healthcare workers (HCWs).
Methods
In a cohort of Canadian HCWs, TST and QFT were performed at study enrolment (TST1 and QFT1) and 1 year later (TST2 and QFT2). Conversion and reversion rates were estimated, and correlation with TB exposure was assessed.
Results
Among 258 HCWs, median age was 36.8 years, 188/258 (73%) were female and 183/258 (71%) were Canadian-born. In 245 subjects with a negative QFT1 we found a QFT conversion rate of 5.3% (13/245, 95% CI 2.9–8.9%). Using more stringent definitions, QFT conversion rates ranged from 2.0 to 5.3%. No TST conversions were found among the 241 HCWs with negative TST1, and no measure of recent TB exposure was associated with QFT conversions. In the 13 HCWs with a positive QFT1, 62% reverted.
Conclusion
Using the conventional QFT conversion definition, we found a higher than expected rate of conversion. Recent occupational exposures were not associated with QFT conversions, and no TST conversions occurred in this cohort, suggesting the ‘conversions’ may not reflect new TB infection.
doi:10.1371/journal.pone.0054748
PMCID: PMC3561382  PMID: 23382955
18.  Development of a Simple Reliable Radiographic Scoring System to Aid the Diagnosis of Pulmonary Tuberculosis 
PLoS ONE  2013;8(1):e54235.
Rationale
Chest radiography is sometimes the only method available for investigating patients with possible pulmonary tuberculosis (PTB) with negative sputum smears. However, interpretation of chest radiographs in this context lacks specificity for PTB, is subjective and is neither standardized nor reproducible. Efforts to improve the interpretation of chest radiography are warranted.
Objectives
To develop a scoring system to aid the diagnosis of PTB, using features recorded with the Chest Radiograph Reading and Recording System (CRRS).
Methods
Chest radiographs of outpatients with possible PTB, recruited over 3 years at clinics in South Africa were read by two independent readers using the CRRS method. Multivariate analysis was used to identify features significantly associated with culture-positive PTB. These were weighted and used to generate a score.
Results
473 patients were included in the analysis. Large upper lobe opacities, cavities, unilateral pleural effusion and adenopathy were significantly associated with PTB, had high inter-reader reliability, and received 2, 2, 1 and 2 points, respectively in the final score. Using a cut-off of 2, scores below this threshold had a high negative predictive value (91.5%, 95%CI 87.1,94.7), but low positive predictive value (49.4%, 95%CI 42.9,55.9). Among the 382 TB suspects with negative sputum smears, 229 patients had scores <2; the score correctly ruled out active PTB in 214 of these patients (NPV 93.4%; 95%CI 89.4,96.3). The score had a suboptimal negative predictive value in HIV-infected patients (NPV 86.4, 95% CI 75,94).
Conclusions
The proposed scoring system is simple, and reliably ruled out active PTB in smear-negative HIV-uninfected patients, thus potentially reducing the need for further tests in high burden settings. Validation studies are now required.
doi:10.1371/journal.pone.0054235
PMCID: PMC3548832  PMID: 23349835
19.  Promise versus Reality: Optimism Bias in Package Inserts for Tuberculosis Diagnostics 
Journal of Clinical Microbiology  2012;50(7):2455-2461.
Laboratorians and clinicians often rely on package inserts of diagnostic tests to assess their accuracy. We compared test accuracy for tuberculosis diagnostics reported in 19 package inserts against estimates in published meta-analyses and found that package inserts generally report overoptimistic accuracy estimates. However, package inserts of most tests approved by the U.S. Food and Drug Administration (FDA) or endorsed by the World Health Organization provide more realistic estimates that agree with meta-analyses.
doi:10.1128/JCM.00842-12
PMCID: PMC3405594  PMID: 22573592
20.  Promoting Affordable and Quality Tuberculosis Testing in India 
doi:10.4103/0974-2727.115895
PMCID: PMC3758696  PMID: 24014959
21.  Interferon-γ Release Assays for Active Pulmonary Tuberculosis Diagnosis in Adults in Low- and Middle-Income Countries: Systematic Review and Meta-analysis 
The Journal of Infectious Diseases  2011;204(Suppl 4):S1120-S1129.
Background. The diagnostic value of interferon-γ release assays (IGRAs) for active tuberculosis in low- and middle-income countries is unclear.
Methods. We searched multiple databases for studies published through May 2010 that evaluated the diagnostic performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB (T-SPOT) among adults with suspected active pulmonary tuberculosis or patients with confirmed cases in low- and middle-income countries. We summarized test performance characteristics with use of forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, and bivariate random effects models.
Results. Our search identified 789 citations, of which 27 observational studies (17 QFT-GIT and 10 T-SPOT) evaluating 590 human immunodeficiency virus (HIV)–uninfected and 844 HIV-infected individuals met inclusion criteria. Among HIV-infected patients, HSROC/bivariate pooled sensitivity estimates (highest quality data) were 76% (95% confidence interval [CI], 45%–92%) for T-SPOT and 60% (95% CI, 34%–82%) for QFT-GIT. HSROC/bivariate pooled specificity estimates were low for both IGRA platforms among all participants (T-SPOT, 61% [95% CI, 40%–79%]; QFT-GIT, 52% [95% CI, 41%–62%]) and among HIV-infected persons (T-SPOT, 52% [95% CI, 40%–63%]; QFT-GIT, 50% [95% CI, 35%–65%]). There was no consistent evidence that either IGRA was more sensitive than the tuberculin skin test for active tuberculosis diagnosis.
Conclusions. In low- and middle-income countries, neither the tuberculin skin test nor IGRAs have value for active tuberculosis diagnosis in adults, especially in the context of HIV coinfection.
doi:10.1093/infdis/jir410
PMCID: PMC3192542  PMID: 21996694
22.  Point-of-Care Urine Tests for Smoking Status and Isoniazid Treatment Monitoring in Adult Patients 
PLoS ONE  2012;7(9):e45913.
Background
Poor adherence to isoniazid (INH) preventive therapy (IPT) is an impediment to effective control of latent tuberculosis (TB) infection. TB patients who smoke are at higher risk of latent TB infection, active disease, and TB mortality, and may have lower adherence to their TB medications. The objective of our study was to validate IsoScreen and SmokeScreen (GFC Diagnostics, UK), two point-of-care tests for monitoring INH intake and determining smoking status. The tests could be used together in the same individual to help identify patients with a high-risk profile and provide a tailored treatment plan that includes medication management, adherence interventions, and smoking cessation programs.
Methodology/Principal Findings
200 adult outpatients attending the TB and/or the smoking cessation clinic were recruited at the Montreal Chest Institute. Sensitivity and specificity were measured for each test against the corresponding composite reference standard. Test reliability was measured using kappa statistic for intra-rater and inter-rater agreement. Univariate and multivariate logistic regression models were used to explore possible covariates that might be related to false-positive and false-negative test results. IsoScreen had a sensitivity of 93.2% (95% confidence interval [CI] 80.3, 98.2) and specificity of 98.7% (94.8, 99.8). IsoScreen had intra-rater agreement (kappa) of 0.75 (0.48, 0.94) and inter-rater agreement of 0.61 (0.27, 0.90). SmokeScreen had a sensitivity of 69.2% (56.4, 79.8), specificity of 81.6% (73.0, 88.0), intra-rater agreement of 0.77 (0.56, 0.94), and inter-rater agreement of 0.66 (0.42, 0.88). False-positive SmokeScreen tests were strongly associated with INH treatment.
Conclusions
IsoScreen had high validity and reliability, whereas SmokeScreen had modest validity and reliability. SmokeScreen tests did not perform well in a population receiving INH due to the association between INH treatment and false-positive SmokeScreen test results. Development of the next generation SmokeScreen assay should account for this potential interference.
doi:10.1371/journal.pone.0045913
PMCID: PMC3461034  PMID: 23029310
23.  Correction: Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients 
Ahuja, Shama D. | Ashkin, David | Avendano, Monika | Banerjee, Rita | Bauer, Melissa | Bayona, Jamie N. | Becerra, Mercedes C. | Benedetti, Andrea | Burgos, Marcos | Centis, Rosella | Chan, Eward D. | Chiang, Chen-Yuan | Cox, Helen | D'Ambrosio, Lia | DeRiemer, Kathy | Dung, Nguyen Huy | Enarson, Donald | Falzon, Dennis | Flanagan, Katherine | Flood, Jennifer | Garcia-Garcia, Maria L. | Gandhi, Neel | Granich, Reuben M. | Hollm-Delgado, Maria G. | Holtz, Timothy H. | Iseman, Michael D. | Jarlsberg, Leah G. | Keshavjee, Salmaan | Kim, Hye-Ryoun | Koh, Won-Jung | Lancaster, Joey | Lange, Christophe | de Lange, Wiel C. M. | Leimane, Vaira | Leung, Chi Chiu | Li, Jiehui | Menzies, Dick | Migliori, Giovanni B. | Mishustin, Sergey P. | Mitnick, Carole D. | Narita, Masa | O'Riordan, Philly | Pai, Madhukar | Palmero, Domingo | Park, Seung-kyu | Pasvol, Geoffrey | Peña, Jose | Pérez-Guzmán, Carlos | Quelapio, Maria I. D. | Ponce-de-Leon, Alfredo | Riekstina, Vija | Robert, Jerome | Royce, Sarah | Schaaf, H. Simon | Seung, Kwonjune J. | Shah, Lena | Shim, Tae Sun | Shin, Sonya S. | Shiraishi, Yuji | Sifuentes-Osornio, José | Sotgiu, Giovanni | Strand, Matthew J. | Tabarsi, Payam | Tupasi, Thelma E. | van Altena, Robert | Van der Walt, Martie | Van der Werf, Tjip S. | Vargas, Mario H. | Viiklepp, Pirett | Westenhouse, Janice | Yew, Wing Wai | Yim, Jae-Joon
PLoS Medicine  2012;9(9):10.1371/annotation/230240bc-bcf3-46b2-9b21-2e6e584f7333.
doi:10.1371/annotation/230240bc-bcf3-46b2-9b21-2e6e584f7333
PMCID: PMC4188481
24.  Point-of-Care Testing for Infectious Diseases: Diversity, Complexity, and Barriers in Low- And Middle-Income Countries 
PLoS Medicine  2012;9(9):e1001306.
Madhukar Pai and colleagues discuss a framework for envisioning how point-of-care testing can be applied to infectious diseases in low- and middle-income countries.
doi:10.1371/journal.pmed.1001306
PMCID: PMC3433407  PMID: 22973183
25.  Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients 
Ahuja, Shama D. | Ashkin, David | Avendano, Monika | Banerjee, Rita | Bauer, Melissa | Bayona, Jamie N. | Becerra, Mercedes C. | Benedetti, Andrea | Burgos, Marcos | Centis, Rosella | Chan, Eward D. | Chiang, Chen-Yuan | Cox, Helen | D'Ambrosio, Lia | DeRiemer, Kathy | Dung, Nguyen Huy | Enarson, Donald | Falzon, Dennis | Flanagan, Katherine | Flood, Jennifer | Garcia-Garcia, Maria L. | Gandhi, Neel | Granich, Reuben M. | Hollm-Delgado, Maria G. | Holtz, Timothy H. | Iseman, Michael D. | Jarlsberg, Leah G. | Keshavjee, Salmaan | Kim, Hye-Ryoun | Koh, Won-Jung | Lancaster, Joey | Lange, Christophe | de Lange, Wiel C. M. | Leimane, Vaira | Leung, Chi Chiu | Li, Jiehui | Menzies, Dick | Migliori, Giovanni B. | Mishustin, Sergey P. | Mitnick, Carole D. | Narita, Masa | O'Riordan, Philly | Pai, Madhukar | Palmero, Domingo | Park, Seung-kyu | Pasvol, Geoffrey | Peña, Jose | Pérez-Guzmán, Carlos | Quelapio, Maria I. D. | Ponce-de-Leon, Alfredo | Riekstina, Vija | Robert, Jerome | Royce, Sarah | Schaaf, H. Simon | Seung, Kwonjune J. | Shah, Lena | Shim, Tae Sun | Shin, Sonya S. | Shiraishi, Yuji | Sifuentes-Osornio, José | Sotgiu, Giovanni | Strand, Matthew J. | Tabarsi, Payam | Tupasi, Thelma E. | van Altena, Robert | Van der Walt, Martie | Van der Werf, Tjip S. | Vargas, Mario H. | Viiklepp, Pirett | Westenhouse, Janice | Yew, Wing Wai | Yim, Jae-Joon
PLoS Medicine  2012;9(8):e1001300.
Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.
Background
Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.
Methods and Findings
Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1–6.0]), ofloxacin (aOR: 2.5 [1.6–3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3–2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7–4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7–4.3]), ofloxacin (aOR: 2.3 [1.3–3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4–2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4–6.0]).
Conclusions
In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
In 2010, 8.8 million people developed tuberculosis—a contagious bacterial infection—and 1.4 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs (pulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months. The standard treatment for tuberculosis comprises an initial intensive phase lasting 2 months during which four antibiotics are taken daily followed by a 4-month continuation phase during which two antibiotics are taken. However, global efforts to control tuberculosis are now being thwarted by the emergence of M. tuberculosis strains that are resistant to several antibiotics, including isoniazid and rifampicin, the two most powerful, first-line (standard) anti-tuberculosis drugs.
Why Was This Study Done?
Although multi-drug resistant tuberculosis (MDR-TB) can be cured using second-line anti-tuberculosis drugs, these are more expensive and more toxic than first-line drugs and optimal treatment regimens for MDR-TB have not been determined. Notably, there have been no randomized controlled trials of treatments for MDR-TB. Such trials, which compare outcomes (cure, treatment failure, relapse, and death) among patients who have been randomly assigned to receive different treatments, are the best way to compare different anti-tuberculosis drug regimens. It is possible, however, to get useful information about the association of various treatments for MDR-TB with outcomes from observational studies using a statistical approach called “individual patient data meta-analysis.” In observational studies, because patients are not randomly assigned to different treatments, differences in outcomes between treatment groups may not be caused by the different drugs they receive but may be due to other differences between the groups. An individual patient data meta-analysis uses statistical methods to combine original patient data from several different studies. Here, the researchers use this approach to investigate the association of specific drugs, numbers of drugs and treatment duration with the clinical outcomes of patients with pulmonary MDR-TB.
What Did the Researchers Do and Find?
The researchers used three recent systematic reviews (studies that use predefined criteria to identify all the research on a given topic) to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. They obtained individual patient data from the authors of these studies and estimated adjusted odds (chances) of treatment success from the treatment and outcome data of 9,153 patients with MDR-TB provided by 32 centers. The use of later generation quinolones, ofloxacin, and ethionamide/prothionamide as part of multi-drug regimens were all associated with treatment success compared to failure, relapse or death, as were the use of four or more likely effective drugs (based on drug susceptibility testing of mycobacteria isolated from study participants) during the initial intensive treatment phase and the use of three or more likely effective drugs during the continuation phase. The researchers also report that among patients who did not die or stop treatment, the chances of treatment success increased with the duration of the initial treatment phase up to 7.1–8.5 months and with the total duration of treatment up to 18.6–21.5 months.
What Do These Findings Mean?
These findings suggest that the use of specific drugs, the use of a greater number of effective drugs, and longer treatments may be associated with treatment success and the survival of patients with MDR-TR. However, these findings need to be interpreted with caution because of limitations in this study that may have affected the accuracy of its findings. For example, the researchers did not include all the studies they found through the systematic reviews in their meta-analysis (some authors did not respond to requests for individual patient data, for example), which may have introduced bias. Moreover, because the patients included in the meta-analysis were treated at 32 centers, there were many differences in their management, some of which may have affected the accuracy of the findings. Because of these and other limitations, the researchers note that, although their findings highlight several important questions about the treatment of MDR-TB, randomized controlled trials are urgently needed to determine the optimal treatment for MDR-TB.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001300.
The World Health Organization provides information on all aspects of tuberculosis, including MDR-TB; its guidelines for the programmatic management of drug-resistant tuberculosis are available
The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the treatment of tuberculosis and on MDR-TB
The US National Institute of Allergy and Infectious Diseases also has information on all aspects of tuberculosis, including a drug-resistant tuberculosis visual tour
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
TB & ME, a collaborative blogging project run by patients being treated for multidrug-resistant tuberculosis and Medecins sans Frontieres, provides information about MDR-TB and patient stories about treatment for MDR-TB
The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, also provides personal stories about treatment for tuberculosis
doi:10.1371/journal.pmed.1001300
PMCID: PMC3429397  PMID: 22952439

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