David J. Horne

Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis

WHO has previously recommended sputum-smear examination at the end of the second month of treatment in patients with recently diagnosed pulmonary tuberculosis, and, if positive, extension of the intensive therapy phase. We did a systematic review and meta-analysis to assess the accuracy of a positive sputum smear or culture during treatment for predicting failure or relapse in pulmonary tuberculosis. We searched PubMed, Embase, and the Cochrane Library for studies published in English through December, 2009. We included randomised controlled trials, cohort, and case-control studies of previously untreated pulmonary tuberculosis patients who had received a standardised regimen with rifampicin in the initial phase. Accuracy results were summarised in forest plots and pooled by use of a hierarchical regression approach. 15 papers (28 studies) met the inclusion criteria. The pooled sensitivities for both 2-month smear (24% [95% CI 12-42%], six studies) and culture (40% [95% CI 25-56%], four studies) to predict relapse were low. Corresponding specificities (85% [95% CI 72-90%] and 85% [95% CI 77-91%]) were higher, but modest. For failure, 2-month smear (seven studies) had low sensitivity (57% [95% CI 41-73%]) and higher, although modest, specificity (81% [95% CI 72-87%]). Both sputum-smear microscopy and mycobacterial culture during tuberculosis treatment have low sensitivity and modest specificity for predicting failure and relapse. Although we pooled a diverse group of patients, the individual studies had similar performance characteristics. Better predictive markers are needed.

Factors associated with mortality in patients with tuberculosis

BackgroundKnown risk factors for death following a diagnosis of tuberculosis may not be applicable to current U.S. cases. We evaluated the factors associated with all-cause mortality in patients with tuberculosis in Washington State.MethodsUsing data from the Tuberculosis Information Management System of Washington State, we conducted a cohort study of all residents diagnosed with tuberculosis from 1993 through 2005. Death from any cause was ascertained through the Washington State Death Certificate Data Files. Proportional hazards models were used to estimate the independent effect on all-cause mortality of demographic, clinical, and behavioral characteristics.ResultsDuring a median follow-up of 6 years in 3451 patients treated for tuberculosis, there were 417 deaths. Mortality was independently associated with increasing age, male gender, HIV-coinfection, and U.S. birth. Within 1 year of tuberculosis diagnosis, treatment by a private provider and the use of directly observed therapy were also independently associated with increased mortality. In addition, an interaction term of private provider times directly observed therapy was also significantly associated with mortality.ConclusionsWe identified factors independently associated with increased all-cause mortality following a diagnosis of tuberculosis. The associations between mortality and provider type should be evaluated with more thorough adjustment for severity of illness, but suggest important directions for future research.

Diagnostic Accuracy and Reproducibility of WHO-Endorsed Phenotypic Drug Susceptibility Testing Methods for First-Line and Second-Line Antituberculosis Drugs

ABSTRACT In an effort to update and clarify policies on tuberculosis drug susceptibility testing (DST), the World Health Organization (WHO) commissioned a systematic review evaluating WHO-endorsed diagnostic tests. We report the results of this systematic review and meta-analysis of the diagnostic accuracy and reproducibility of phenotypic DST for first-line and second-line antituberculosis drugs. This review provides support for recommended critical concentrations for isoniazid and rifampin in commercial broth-based systems. Further studies are needed to evaluate critical concentrations for ethambutol and streptomycin that accurately detect susceptibility to these drugs. Evidence is limited on the performance of DST for pyrazinamide and second-line drugs.

Challenging Issues in Tuberculosis in Solid Organ Transplantation

Solid organ transplant (SOT) recipients are at risk for opportunistic infections including tuberculosis. Although guidelines on the management of latent tuberculosis and active tuberculosis are available, there remain a number of clinical areas with limited guidance. We discuss challenges in the diagnosis, management, and treatment of latent and active tuberculosis in SOT candidates and recipients who reside in low-tuberculosis-prevalence areas. We discuss the diagnosis of latent tuberculosis in SOT candidates/recipients using tuberculin skin tests and interferon-γ release assays and risk stratification of SOT candidates/recipients that would identify individuals at high risk for latent tuberculosis despite negative test results. Through a careful review of posttransplant tuberculosis cases, we identify a history of treated tuberculosis in SOT recipients as a risk factor for development of posttransplant active tuberculosis. Finally, we include comparisons of recommendations by several large transplant organizations and identify areas for future research.

Common Polymorphisms in the PKP3-SIGIRR-TMEM16J Gene Region Are Associated With Susceptibility to Tuberculosis

BACKGROUND Tuberculosis has been associated with genetic variation in host immunity. We hypothesized that single-nucleotide polymorphisms (SNPs) in SIGIRR, a negative regulator of Toll-like receptor/IL-1R signaling, are associated with susceptibility to tuberculosis. METHODS We used a case-population study design in Vietnam with cases that had either tuberculous meningitis or pulmonary tuberculosis. We genotyped 6 SNPs in the SIGIRR gene region (including the adjacent genes PKP3 and TMEM16J) in a discovery cohort of 352 patients with tuberculosis and 382 controls. Significant associations were genotyped in a validation cohort (339 patients with tuberculosis, 376 controls). RESULTS Three SNPs (rs10902158, rs7105848, rs7111432) were associated with tuberculosis in discovery and validation cohorts. The polymorphisms were associated with both tuberculous meningitis and pulmonary tuberculosis and were strongest with a recessive genetic model (odds ratios, 1.5-1.6; P = .0006-.001). Coinheritance of these polymorphisms with previously identified risk alleles in Toll-like receptor 2 and TIRAP was associated with an additive risk of tuberculosis susceptibility. CONCLUSIONS These results demonstrate a strong association of SNPs in the PKP3-SIGIRR-TMEM16J gene region and tuberculosis in discovery and validation cohorts. To our knowledge, these are the first associations of polymorphisms in this region with any disease.

Association between Smoking and Latent Tuberculosis in the U.S. Population: An Analysis of the National Health and Nutrition Examination Survey

Background Evidence of an association between cigarette smoking and latent tuberculosis infection (LTBI) is based on studies in special populations and/or from high prevalence settings. We sought to evaluate the association between LTBI and smoking in a low prevalence TB setting using population-based data from the National Health and Nutrition Examination Survey (NHANES). Methods In 1999–2000, NHANES assessed LTBI (defined as a tuberculin skin test measurement ≥10 mm) in participants, and those ≥20 years of age were queried regarding their tobacco use and serum cotinine was measured. We evaluated the association of LTBI with self-reported smoking history and smoking intensity in multivariable logistic regression models that adjusted for known confounders (gender, age, birthplace, race/ethnicity, poverty, education, history of BCG vaccination, and history of household exposure to tuberculosis disease). Results Estimated LTBI prevalence was 5.3% among those ≥20 years of age. The LTBI prevalence among never smokers, current smokers, and former smokers was 4.1%, 6.6%, and 6.2%, respectively. In a multivariable model, current smoking was associated with LTBI (OR 1.8; 95% CI, 1.1–2.9). The association between smoking and LTBI was strongest for Mexican-American and black individuals. In multivariate analysis stratified by race/ethnicity, cigarette packs per day among Mexican-American smokers and cotinine levels among black smokers, were significantly associated with LTBI. Conclusions In the large, representative, population-based NHANES sample, smoking was independently associated with significantly increased risks of LTBI. In certain populations, a greater risk of LTBI corresponded with increased smoking exposure.

Systematic Review of the Performance of Rapid Rifampicin Resistance Testing for Drug-Resistant Tuberculosis

Introduction Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. Methods We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. Results We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. Limitations In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. Discussion Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

Experience with rifabutin replacing rifampin in the treatment of tuberculosis

SETTING The use of a rifamycin in anti-tuberculosis treatment regimens is crucial for shortening treatment and achieving favorable outcomes. Rifampin (RMP) is the recommended rifamycin, although adverse effects (AEs) may require its discontinuation. The use of rifabutin (RFB), a rifamycin with activity against Mycobacterium tuberculosis, in patients with an RMP-related AE has not been well studied. OBJECTIVE To review our experience with RFB in tuberculosis (TB) treatment. METHODS We included TB patients who received RFB in their treatment regimens from 2003 to 2009. We evaluated the indications for RFB and, if applicable, the likelihood that RMP caused an AE. We identified RMPrelated AEs associated with RFB intolerance. RESULTS One hundred subjects were included. The indications for RFB use were RMP-related AE (57%), con- current antiretroviral therapy (21%), potential/actual interaction with other medications (14%), and as part of an alternative regimen in liver disease (8%). Nineteen patients experienced an AE while taking RFB. Among patients with a prior RMP-related AE, 80% of whom were successfully treated with RFB, only a dermatologic AE was associated with subsequent RFB intolerance. CONCLUSIONS Our study suggests that RFB is well tolerated by patients who develop RMP-related AEs. There may be an increased risk for RFB-related AE in patients who experienced RMP-related dermatologic events.

The Prevalence of Latent Tuberculosis Infection in the United States

RATIONALE Individuals with latent tuberculosis infection (LTBI) represent a reservoir of infection, many of whom will progress to tuberculosis (TB) disease. A central pillar of TB control in the United States is reducing this reservoir through targeted testing and treatment. OBJECTIVES To estimate the prevalence of LTBI in the United States using the tuberculin skin test (TST) and an IFN-γ release assay. METHODS We used nationally representative data from the 2011-2012 National Health and Nutrition Examination Survey (n = 6,083 aged ≥6 yr). LTBI was measured by both the TST and QuantiFERON-TB Gold In-Tube test (QFT-GIT). Weighted population, prevalence, and multiple logistic regression were used. MEASUREMENTS AND MAIN RESULTS The estimated prevalence of LTBI in 2011-2012 was 4.4% as measured by the TST and 4.8% by QFT-GIT, corresponding to 12,398,000 and 13,628,000 individuals, respectively. Prevalence declined slightly since 2000 among the U.S. born but remained constant among the foreign born. Earlier birth cohorts consistently had higher prevalence than more recent ones. Higher risk groups included the foreign born, close contact with a case of TB disease, and certain racial/ethnic groups. CONCLUSIONS After years of decline, the prevalence of LTBI remained relatively constant between 2000 and 2011. A large reservoir of 12.4 million still exists, with foreign-born persons representing an increasingly larger proportion of this reservoir (73%). Estimates and risk factors for LTBI were generally similar between the TST and QFT-GIT. The updated estimates of LTBI and associated risk groups can help improve targeted testing and treatment in the United States.

How Soon Should Patients with Smear-Positive Tuberculosis Be Released from Inpatient Isolation?

OBJECTIVE In patients with smear-positive pulmonary tuberculosis who are hospitalized or reside in congregate settings, guidelines recommend airborne infection isolation until sputum smear results are negative. Studies have identified factors associated with delayed sputum smear and culture conversion in patients with tuberculosis. Because these studies did not use methods of survival analysis, estimates of time to sputum smear conversion that are based on initial patient characteristics are not available. The ability to predict time to sputum smear conversion could be useful for programmatic planning and patient counseling. METHODS We performed a cohort study using survival analysis to identify factors associated with time to sputum smear and culture conversion. We defined the time to sputum smear conversion as the time elapsed from the start of treatment to the first date of sustained conversion. RESULTS Ninety-eight patients had sputum smear samples positive for acid-fast bacilli. Lower initial smear grade (on 1+ to 4+ scale) and absence of cavitation on chest radiograph were associated with earlier sputum smear conversion in bivariate analysis. In multiple regression analysis, initial smear grade (hazard ratio, 0.45; 95% confidence interval, 0.35-0.57) and drug resistance (hazard ratio, 2.30; 95% confidence interval, 1.08-4.89) remained statistically significant; a model comprising only initial smear grade performed almost as well. Predictors of sputum culture conversion were similar. CONCLUSIONS Initial smear grade was the strongest predictor of time to sputum smear and culture conversion in patients with pulmonary tuberculosis and may be a useful predictor for programmatic planning and patient counseling.