American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.
hThe Xpert MTB/RIF (Xpert) assay is becoming a principal screening tool for diagnosing rifampin-resistant Mycobacterium tuberculosis complex (MTBC) infection. However, little is known about the performance of the Xpert assay in infections with both drug-sensitive and drug-resistant strains (mixed MTBC infections). We assessed the performance of the Xpert assay for detecting rifampin resistance using phenotypic drug sensitivity testing (
Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.
SUMMARY
BACKGROUND
Data on alcohol abuse as a risk factor for the development of multidrug-resistant tuberculosis (MDR-TB) are scarce.
OBJECTIVE
To describe the patterns of alcohol use in MDR-TB patients and to determine whether alcohol use is associated with the development of MDR-TB in Botswana.
METHODS
We compared the level of alcohol use among MDR-TB patients against three control groups: 1) non-MDR-TB patients, 2) human immunodeficiency virus (HIV) infected patients without a history of TB, and 3) the general population. Alcohol use and abuse was measured with the Alcohol Use Disorders Identification Test 10 (AUDIT) questionnaire.
RESULTS
Of a total national population of 164 MDR-TB cases, 114 (70%) were interviewed. MDR-TB cases had a lifetime prevalence of alcohol use of 35.1%, which was lower than that of all control groups (P < 0.001). MDR-TB cases had higher 1-month prevalence of alcohol dependence symptoms and a lower 1-year period prevalence of alcohol dependence symptoms (P < 0.01 and P = 0.01 respectively). Among patients with TB, alcohol abuse was found to be a risk factor for the development of MDR-TB.
CONCLUSION
MDR-TB patients in Botswana have high rates of alcohol use and abuse. Among TB patients, alcohol abuse is associated with the diagnosis of MDR-TB, and could be an important modifiable factor.
Objectives
We determined the performance of a sensor array (an electronic nose) made of 8 metalloporphyrins coated quartz microbalances sensors for the diagnosis and prognosis of pulmonary tuberculosis (TB) using exhaled breath samples.
Methods
TB cases and healthy controls were prospectively enrolled. Signals from volatile organic compounds (VOCs) in breath samples were measured at days 0, 2, 7, 14, and 30 of TB therapy and correlated with clinical and microbiological measurements.
Results
51 pulmonary TB cases and 20 healthy HIV-uninfected controls were enrolled in the study. 31 (61%) of the 51 pulmonary TB cases were coinfected with HIV. At day 0 (before TB treatment initiation) the sensitivity of our device was estimated at 94.1% (95% confidence interval [CI], 83.8-98.8%) and specificity was 90.0% (95% CI, 68.3-98.8%) for distinguishing TB cases from controls. Time-dependent changes in the breath signals were identified as time on TB treatment progressed. Time-dependent signal changes were more pronounced among HIV-uninfected patients.
Conclusion
The identification of VOCs signals in breath samples using a sensor array achieved high sensitivity and specificity for the diagnosis of TB and allowed following signal changes during TB treatment.
Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amikacin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumulative days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days · mg · h/liter, while that of 20% occurred at 120,000 days · mg · h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis.
HIV/TB patients with high levels of immune activation demonstrated impaired isoniazid clearance. Future efforts should determine the role of this relationship in clinical hepatotoxicity events.
Among patients starting first-line tuberculosis therapy in Botswana, mixed infections were associated with poor tuberculosis treatment outcomes, independent of heteroresistance.
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