A cost-effectiveness study by Frank Cobelens and colleagues reveals that Xpert MTB/RIF is a cost-effective method of tuberculosis diagnosis that is suitable for use in low- and middle-income settings.
Rationale: The Xpert MTB/RIF is an automated molecular test for Mycobacterium tuberculosis that estimates bacterial burden by measuring the threshold-cycle (Ct) of its M. tuberculosis-specific real-time polymerase chain reaction. Bacterial burden is an important biomarker for disease severity, infection control risk, and response to therapy. Objectives: Evaluate bacterial load quantitation by Xpert MTB/RIF compared with conventional quantitative methods. Methods: Xpert MTB/RIF results were compared with smear-microscopy, semiquantiative solid culture, and time-to-detection in liquid culture for 741 patients and 2,008 samples tested in a multisite clinical trial. An internal control real-time polymerase chain reaction was evaluated for its ability to identify inaccurate quantitative Xpert MTB/RIF results. Measurements and Main Results: Assays with an internal control Ct greater than 34 were likely to be inaccurately quantitated; this represented 15% of M. tuberculosis-positive tests. Excluding these, decreasing M. tuberculosis Ct was associated with increasing smear microscopy grade for smears of concentrated sputum pellets (r s ¼ 20.77) and directly from sputum (r s ¼ 20.71). A Ct cutoff of approximately 27.7 best predicted smear-positive status. The association between M. tuberculosis Ct and time-to-detection in liquid culture (r s ¼ 0.68) and semiquantitative colony counts (r s ¼ 20.56) was weaker than smear. Tests of paired same-patient sputum showed that highviscosity sputum samples contained 332 more M. tuberculosis than nonviscous samples. Comparisons between the grade of the acid-fast bacilli smear and Xpert MTB/RIF quantitative data across study sites enabled us to identify a site outlier in microscopy. Conclusions: Xpert MTB/RIF quantitation offers a new, standardized approach to measuring bacterial burden in the sputum of patients with tuberculosis.Keywords: tuberculosis; molecular diagnostics; diagnostic techniques and procedures; diagnosis; clinical trial Measurements of bacterial load have long played an important role in tuberculosis diagnostics. Semiquantitative or quantitative measures of the number of Mycobacterium tuberculosis bacilli present within a clinical sample have been clinically useful for determining disease severity, assessing transmission risk, or monitoring therapy (1-3). Quantitative readouts have also aided in the investigation of potentially false-positive results (4-6).The Xpert MTB/RIF (Cepheid, Sunnyvale, CA) assay simultaneously detects the presence of M. tuberculosis and its susceptibility to the important first-line drug rifampin in less than 2 hours (7). The assay is contained in a small plastic cartridge, and it is run on the GeneXpert platform (Cepheid), a diagnostic The Xpert MTB/RIF assay is a rapid diagnostic test for tuberculosis and rifampin resistance. A number of studies have examined the sensitivity and specificity of the assay in various clinical settings and with various sample types. The test can also provide an estimate of the bacterial load present in the s...
BackgroundPulmonary tuberculosis (TB) persists an important contributor to the burden of diseases in developing countries. TB control success is based on the patient’s compliance to the treatment. Depressive disorders have been negatively associated with compliance of therapeutic schemes for chronic diseases. This study aimed to estimate the significance and magnitude of major depressive episode as a hazard factor for negative outcomes (NO), including abandon or death in patients receiving TB treatment.Methodology/Principal FindingsA longitudinal study was conducted to evaluate the association of major depressive episode (MDE), as measured by a 5-item version of the Center for Epidemiological Studies Depression Scale (CES-D) with NO to TB treatment. Patients with confirmed TB were enrolled before the start of TB treatment. Baseline measurements included socio-demographic variables as well as the CES-D, which was also applied every month until the end of the treatment. Death and treatment default were assessed monthly. Survivor function (SF) for NO according to MDE status (CES-D≥6) at baseline (MDEb) was estimated. Cox’s Regression was performed for bivariate analyses as well as for the multivariate model. A total of 325 patients accepted to participate in the study, of which 34 where excluded for diagnosis of MDR-TB. NO was observed in 24 patients (8.2%); 109 (37%) presented MDEb. Statistically significant difference was found on the SF of patients with and without MDEb (0.85 vs. 0.96, p-value = 0.002). The hazard ratio for NO, controlled for age, sex, marital status and instruction level was 3.54 (95%CI 1.43–8.75; p-value = 0.006).ConclusionThe presence of MDE at baseline is associated to NO of TB treatment. Targeting detection and treatment of MDE may improve TB treatment outcomes.
Background: Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in tuberculosis patients from high-burden countries, according to concordance or discordance of results from drug susceptibility testing (DST) done locally and in a reference laboratory. Methods: We collected Mycobacterium tuberculosis isolates from adult patients in Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand, stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing (DST) was done locally and at the Swiss tuberculosis reference laboratory. We examined mortality during treatment according to DST results and treatment adequacy in logistic regression models adjusting for sex, age, sputum microscopy and HIV status. Findings: 634 tuberculosis patients were included; median age was 33.2 years, 239 (37.7%) were female, 272 (42.9%) HIV-positive and 69 (10.9%) patients died. Based on the reference laboratory DST, 394 (62.2%) strains were pan-susceptible, 45 (7.1%) mono-resistant, 163 (25.7%) multidrug-resistant (MDR-TB), and 30 (4.7%) had pre-extensive or extensive drug resistance (pre-XDR/XDR-TB). Results of reference and local laboratories were discordant in 121 (19.1%) cases. Overall, sensitivity and specificity to detect any resistance were 90.8% and 84.3%, respectively. Mortality ranged from 6.0% (20/336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57.1% (8/14) in patients with resistant strains who were under treated. In logistic regression, compared to concordant DST results, the adjusted odds ratio of death was 7.33 (95% CI 2.70–19.95) for patients with discordant results potentially leading to under treatment. Interpretation: Inaccurate DST by comparison to a reference standard led to under treatment of drug resistant tuberculosis and increased mortality. Rapid molecular DST of first- and second-line drugs at diagnosis is required to improve outcomes in patients with MDR-TB and pre-XDR/XDR-TB.
Currently available nucleic acid amplification platforms for tuberculosis (TB) detection are not designed to be simple or inexpensive enough to implement in decentralized settings in countries with a high burden of disease. The loop-mediated isothermal amplification platform (LAMP) may change this. We conducted a study in adults with symptoms suggestive of TB in India, Uganda, and Peru to establish the feasibility of using TB-LAMP (Eiken Chemical Co.) in microscopy laboratories compared with using smear microscopy against a reference standard of solid and liquid cultures. Operational characteristics were evaluated as well. A total of 1,777 participants met the eligibility criteria and were included for analysis. A pproximately 9 million people developed tuberculosis (TB), and 1.5 million people died from the disease in 2013 (1). Substantial progress has been made in increasing treatment success, but 2.9 million of these cases were not diagnosed or diagnosis was not reported due to limited access to diagnostic tests, insufficient sensitivity, or long turnaround time. More rapid and accurate detection at lower levels of care is necessary to reach these lost and missed cases (2). Nucleic acid amplification tests (NAATs) offer speed and sensitivity for pathogen detection, but until recently, no commercial systems had been designed to be simple or inexpensive enough for decentralized settings (3).Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA), a rapid automated molecular test, has been a major step in the right direction, but initial investment in the equipment and subsequent maintenance remain quite expensive. The development of a less costly approach through the use of manual techniques may expand the application of NAATs.TB-LAMP is a manual TB detection method that is based on the novel loop-mediated isothermal amplification platform (LAMP) from Eiken Chemical Co. in Japan. LAMP has several features that make it attractive as a diagnostics platform for resource-poor settings. It takes less than 2 h (Ͻ60 min of hands-on time), it is less complex than traditional molecular methods, and it generates a fluorescent result that can be detected with the naked eye (4). In a recent study in peripheral laboratories in China using the TB-LAMP assay, the sensitivities in smear-positive, culturepositive sputum specimens and smear-negative, culture-positive sputum specimens were 92.1% (152/165; 95% confidence interval [CI], 86.9% to 95.3%) and 53.8% (113/210; 95% CI, 47.1% to 60.4%), respectively, using solid culture as a reference. The specificity in culture-negative samples was 98.3% (938/954; 95% CI, 97.3% to 99.0%) (5).In this study, we aimed to evaluate the feasibility and operational characteristics of LAMP in microscopy centers, including Citation Gray CM, Katamba A, Narang P, Giraldo J, Zamudio C, Joloba M, Narang R, Paramasivan CN, Hillemann D, Nabeta P, Amisano D, Alland D, Cobelens F, Boehme CC. 2016. Feasibility and operational performance of tuberculosis detection by loop-mediated isothermal amplification platform in ...
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