Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains.

Tuberculosis (TB) is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB), due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

Epidemiological, clinical and mechanistic perspectives of tuberculosis in older people.

With the ageing population globally, tuberculosis (TB) in older people becomes a major clinical and public health challenge. In many Asian countries, especially those located in the eastern and southeastern parts of the continent, geriatric TB is a significant problem. TB in the older patients is more difficult to diagnose in the early course of disease, and has poorer treatment outcomes, largely as increased failure and death. More drug-induced adverse reactions are also experienced by this population during TB therapy. Oxidative stress and mitochondrial dysfunction are now well recognized to be associated with the ageing process, and it is likely that the cellular and molecular perturbations interact inextricably with the immunological dysfunction biophysiologically inherent to ageing. These underlying mechanistic bases putatively contribute to the development of TB in the geriatric population and worsen the disease outcomes, especially when the TB is compounded by co-morbid conditions such as smoking and diabetes mellitus. Unravelling these mechanisms further would yield knowledge that might potentially help to prevent reactivated TB in older people, and also to better manage the established disease with drug regimens and other new therapeutic strategies. In addition, addressing the social elements associated with geriatric TB is also imperative in the relief of individual patient suffering and improvement of overall disease control.

Effects of diabetes mellitus on the clinical presentation and treatment response in tuberculosis.

BACKGROUND AND OBJECTIVE: With the colliding global epidemics of diabetes mellitus (DM) and tuberculosis (TB), we studied the effects of DM on the presentation of TB and its response to treatment. METHODS: Consecutive TB patients from 2006 to 2010 in a territory-wide treatment programme offering 9-month extended treatment for TB patients with DM were examined and followed up prospectively to assess their treatment response. Successful treatment completers were tracked through the TB registry and death registry for relapse, death or till 31 December 2014, whichever was the earliest. RESULTS: DM was independently associated with more chest symptoms (adjusted OR (AOR): 1.13) and systemic symptoms (AOR: 1.30) but less with other site-specific symptoms (AOR: 0.58) at TB presentation. There was more frequent pulmonary involvement (AOR: 1.69), with more extensive lung lesion (AOR: 1.25), lung cavity (AOR: 2.00) and positive sputum smear (AOR: 1.83) and culture (AOR: 1.38), but no difference in the proportion of retreatment cases or isoniazid and/or rifampicin resistance. After treatment initiation, there was higher overall incidence (AOR: 1.38) of adverse effects (mainly gastrointestinal symptoms, renal impairment and peripheral neuropathy but less fever and skin hypersensitivity reactions), more smear non-conversion (AOR: 1.59) and culture non-conversion (AOR: 1.40) at 2 months, and lower combined cure/treatment completion rate at 12 months (AOR: 0.79), but no difference in the relapse rate after having successfully completed treatment. CONCLUSION: DM adversely affected the clinical presentation and treatment response of TB, but there was no difference in the drug resistance and relapse rates.

Smoking adversely affects treatment response, outcome and relapse in tuberculosis.

The impact of smoking on tuberculosis outcome was evaluated in a territory-wide treatment programme. 16,345 consecutive patients undergoing chemotherapy for active tuberculosis in government chest clinics in Hong Kong from 2001 to 2003 were followed up prospectively for 2 years for treatment outcome and subsequently tracked through the territory-wide tuberculosis notification registry for relapse until the end of 2012. Smoking was associated with more extensive lung disease, lung cavitation and positive sputum smear and culture at the baseline. In both current smokers and ex-smokers, sputum smears and cultures were significantly more likely to remain positive after 2 months of treatment. Both categories of smokers were significantly less likely to achieve cure or treatment completion within 2 years. Overall, 16.7% of unsuccessful treatment outcomes were attributable to smoking, with the key contributor being default in current smokers and death in ex-smokers. Among successful treatment completers, there was a clear gradient (hazard ratios of 1.00, 1.33 and 1.63) of relapse risk from never-smokers to ex-smokers and current smokers, with an overall population attributable risk of 19.4% (current smokers: 12.2%; ex-smokers: 7.2%). Smoking adversely affects baseline disease severity, bacteriological response, treatment outcome and relapse in tuberculosis. Smoking cessation likely reduces relapse and secondary transmission.

Clinical research and development of tuberculosis diagnostics: moving from silos to synergy.

The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations.

Lower lung cancer mortality in obesity.

BACKGROUND: Malignancy is the leading cause of death in Hong Kong, and lung cancer tops the list of all cancer deaths. METHODS: A cohort of clients aged ≥65 years, enrolled at 18 elderly health centres in Hong Kong from 2000 to 2003, was followed up prospectively through linkage with the territory-wide death registry for causes of death until 31 December 2008, using the identity card number as unique identifier. All subjects with suspected cancer, significant weight loss of >5% within past 6 months or obstructive lung disease at the baseline were excluded. RESULTS: After a total of 423 061 person-years of follow-up, 932, 690 and 1433 deaths were caused by lung cancer, other tobacco-related malignancies and non-tobacco-related malignancies, respectively. Body mass index (BMI) was independently (and negatively) associated with death from lung cancer after adjustment for other baseline variables, whereas there was only a minor or no effect for other smoking-related malignancies and non-tobacco-related malignancies. Obesity with BMI ≥30 [adjusted hazard ratio (HR), 0.55, 95% confidence interval (CI) 0.38-0.80] was associated with reduced lung cancer mortality, which was more prominent than the opposing effect of underweight (adjusted HR, 1.38, 95% CI 1.05-1.79). Consistent effects of BMI were observed after stratification into never-smokers and ever-smokers and in sensitivity analysis after excluding deaths within the first 3 years. CONCLUSION: Obesity was associated with lower lung cancer mortality in this prospective cohort analysis. As the effect was rather specific for lung cancer, further studies are indicated to explore the underlying mechanism.

Passive smoking and tuberculosis.

BACKGROUND: Increasing evidence has incriminated active smoking as a causal factor for tuberculosis (TB). However, the effect of secondhand tobacco smoke exposure on TB has not been similarly elucidated. METHODS: A cohort of 15 486 female never-smokers aged 65 to 74 years and living with their surviving husband were enrolled at 18 Elderly Health Centers in Hong Kong from 2000 to 2003 and followed up prospectively through linkage with the territory-wide TB notification registry and death registry for TB and death until December 31, 2008, using an identity card number as a unique identifier. The relationship between passive smoking and the development of TB was assessed with adjustment for other baseline characteristics. RESULTS: Passive exposure to secondhand tobacco smoke in the household was independently associated with obstructive lung disease (odds [OR], 1.43; 95% confidence interval [CI], 1.16-1.77) and diabetes mellitus (OR, 1.13; 95% CI, 1.02-1.26) at baseline and with the development of both active TB (hazard ratio [HR], 1.49; 95% CI, 1.01-2.19) and culture-confirmed TB (HR, 1.70; 95% CI, 1.04-2.80) on prospective follow-up after potentially confounding background variables were controlled for. Passive smoking accounted for 13.7% of active TB and for 18.5% of culture-positive TB in this cohort. CONCLUSIONS: Similar to active smoking, passive exposure to secondhand tobacco smoke in the household also predisposes to the development of TB. Increased emphasis should therefore be put on tobacco control in national TB programs.

Hepatotoxicity of pyrazinamide: cohort and case-control analyses.

RATIONALE: Relatively little is known about the hepatotoxicity of pyrazinamide. OBJECTIVES: We compared continuation-phase regimens incorporating pyrazinamide, isoniazid, and/or rifampin with those containing isoniazid and rifampin to evaluate the hepatotoxicity of pyrazinamide. METHODS: Cohort and nested case-control analyses were conducted on a cohort of 3,007 patients with active tuberculosis (TB) managed at government chest clinics under a TB control program with treatment started from January 1 through June 30, 2001. Cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when serum alanine transaminase exceeded three times the upper limit of normal. Each case was matched by sex and age with three control subjects selected randomly from the rest of the cohort. Treatment regimens of cases within 4 weeks preceding hepatotoxicity were compared with those of matched control subjects in comparable periods relative to the date of commencing treatment. MEASUREMENTS AND MAIN RESULTS: Hepatotoxicity occurred in 150 (5.0%) patients at any time including 48 (1.6%) cases. From 12 or more weeks after starting treatment, the estimated risk of hepatotoxicity was 2.6% for regimens incorporating pyrazinamide, isoniazid, and/or rifampin, and 0.8% for standard regimens containing isoniazid and rifampin. Multivariable conditional logistic analysis showed a significant association between hepatotoxicity and, respectively, hepatitis B, previous hepatotoxicity, and treatment regimens. The adjusted odds ratio (95% confidence interval) of hepatotoxicity for regimens incorporating pyrazinamide, isoniazid, and/or rifampin relative to standard regimens was 2.8 (1.4-5.9). CONCLUSIONS: Adding pyrazinamide to isoniazid and rifampin increases the risk of hepatotoxicity appreciably.

Diabetic control and risk of tuberculosis: a cohort study.

Diabetes mellitus is associated with tuberculosis. A cohort of 42,116 clients aged 65 years or more, enrolled at 18 Elderly Health Service centers in Hong Kong in 2000, were followed up prospectively through the territory-wide tuberculosis registry for development of tuberculosis from 3 months after enrollment to December 31, 2005, by use of their identity card numbers as unique identifier. The effects of diabetes mellitus and diabetic control on tuberculosis risk were assessed with adjustment for sociodemographic and other background variables. Diabetes mellitus was associated with a modest increase in the risk of active, culture-confirmed, and pulmonary (with or without extrapulmonary involvement) but not extrapulmonary (with or without pulmonary involvement) tuberculosis, with adjusted hazard ratios of 1.77 (95% confidence interval: 1.41, 2.24), 1.91 (95% confidence interval: 1.45, 2.52), 1.89 (95% confidence interval: 1.48, 2.42), and 1.00 (95% confidence interval: 0.54, 1.86), respectively. Diabetic subjects with hemoglobin A1c <7% at enrollment were not at increased risk. Among diabetic subjects, higher risks of active, culture-confirmed, and pulmonary but not extrapulmonary tuberculosis were observed with baseline hemoglobin A1c > or =7% (vs. <7%), with adjusted hazard ratios of 3.11 (95% confidence interval: 1.63, 5.92), 3.08 (95% confidence interval: 1.44, 6.57), 3.63 (95% confidence interval: 1.79, 7.33), and 0.77 (95% confidence interval: 0.18, 3.35), respectively.

Lower risk of tuberculosis in obesity.

BACKGROUND: Obesity is increasingly prevalent in both developed and developing areas. Although undernutrition is well associated with tuberculosis, few studies have systematically examined the association with obesity. Method A cohort of 42 116 individuals 65 years or older enrolled at 18 health centers for elderly patients in Hong Kong, China (which has a tuberculosis incidence of approximately 90 per 100,000 population), in 2000 were followed up prospectively through the territory-wide tuberculosis registry for the development of active tuberculosis from 3 months after enrollment until December 31, 2005, using the identity card number as the unique identifier. The association with body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters), as categorized by the Asian standards, was assessed with the control of other baseline characteristics. RESULTS: Obese (BMI>or=30) and overweight (BMI, 25 to <30) individuals were at significantly lower risks of developing active tuberculosis than normal-weight individuals (BMI, 18.5 to <25), with hazard ratios (95% confidence intervals) of 0.36 (0.20-0.66) and 0.55 (0.44-0.70), respectively, after adjustment for baseline demographic, social, and clinical variables. An inverse linear association was observed predominantly for pulmonary but not extrapulmonary tuberculosis. This association persisted after controlling for potential confounders or excluding individuals with known tuberculosis risk factors. CONCLUSIONS: Obesity is associated with a lower risk of active pulmonary tuberculosis in the older population of Hong Kong. The presence of such a strong but selective association across the whole spectrum of BMI could have major biological, clinical, and/or epidemiological implications. Further studies are indicated to explore the underlying mechanisms, potential clinical utilities, and possible epidemiological consequences.

Dosing schedules of 6-month regimens and relapse for pulmonary tuberculosis.

RATIONALE: The optimal approach for reducing tuberculosis relapse is open. OBJECTIVES: We examined the possibility of reducing relapse by increasing dosing schedules. METHODS: We conducted a systematic review of published clinical trials involving adult cohorts with pulmonary tuberculosis treated using 6-mo rifamycin-containing regimens, which were grouped under seven categories ordered by dosing schedules. Assuming cavitation and positive 2-mo culture were the driving forces for relapse, a static deterministic model apportioned observed numbers with and without relapse in each cohort into eight subgroups. Combining subgroups stratified by cavitation, 2-mo culture, and regimens enabled estimation of adjusted relapse risks. chi2 Tests for trend and logistic regression analysis examined the relationship between relapse and dosing schedules. RESULTS: We identified 200 cases of bacteriologic relapse out of 5,208 patients in 32 cohorts. A logistic risk model showed a significant dose-response relationship between dosing schedules and relapse, with the following odds (95% confidence intervals) of relapse relative to daily regimens: 1.6 (0.6-4.1) for daily initial phase (IP) plus thrice-weekly continuation phase (CP), 2.8 (1.3-6.1) for daily IP plus twice-weekly CP, 2.8 (1.4-5.7) for thrice-weekly, 5.0 (2.4-10.5) for daily IP plus once-weekly rifapentine, and 7.1 (3.3-15.3) for thrice-weekly IP plus once-weekly rifapentine. In the presence of cavitation, only 6-mo daily or daily IP plus thrice-weekly CP attained best-estimated relapse risks below 5%; they reached 6% when 2-mo culture was also positive. CONCLUSIONS: Cavitary tuberculosis is best treated with 6-mo regimens comprising daily IP and thrice-weekly CP, which may be extended when 2-mo culture is positive.

Determinants of spirometric abnormalities among silicotic patients in Hong Kong.

BACKGROUND: Silicosis is the second commonest notified occupational disease in Hong Kong. AIM: To characterize the determinants of spirometric abnormalities in silicosis. METHOD: The spirometric patterns of consecutive silicotic patients on confirmation by the Pneumoconiosis Medical Board from 1991 to 2002 were correlated with demographic characteristics, occupational history, smoking history, tuberculosis (TB) history and radiographic features by univariate and multiple regression analyses. RESULTS: Of 1576 silicotic patients included, 55.6% showed normal spirometry, 28.5% normal forced vital capacity (FVC>or=80% predicted) but reduced forced expiratory ratio (FER<70%), 7.6% reduced FVC but normal FER, and 8.4% reduced both FVC and FER. Age, ever-smoking, cigarette pack-years, industry, job type, history of TB, size of lung nodules and progressive massive fibrosis (PMF) were all significantly associated with airflow limitation on univariate analysis (all P<0.05), while sex and profusion of nodules were not. Only age, cigarette pack-years, history of TB, size of lung nodules and PMF remained as significant independent predictors of airflow obstruction in multiple logistic regression analysis. After controlling for airflow obstruction, only shorter exposure duration, history of TB and profusion of nodules were significant independent predictors of reduced FVC. As well as age, history of TB, cigarette pack-years, PMF and nodule size contributed comparable effects to airflow obstruction in multiple linear regression analyses, while profusion of nodules was the strongest factor for reduced vital capacity. CONCLUSIONS: In an occupational compensation setting, disease indices and history of tuberculosis are independent predictors of both airflow obstruction and reduced vital capacity for silicotic patients.

A nested case-control study on treatment-related risk factors for early relapse of tuberculosis.

This nested case-control study aimed at evaluating treatment-related risk factors of relapse of tuberculosis under a service program of directly observed treatment. Out of 12,183 patients with pulmonary tuberculosis who completed treatment within 1 year, 113 relapsed within 30 months after commencement of therapy. The overall 30-month relapse rate was 0.9% (95% confidence interval [CI] 0.8-1.1%). On matching 113 cases with 226 control subjects in a conditional logistic model, thrice-weekly treatment increased the risk of relapse in comparison with daily treatment (odds ratio 3.92, 95% CI 1.78-8.63), whereas prolonging both intensive phase and overall treatment by 50% or more protected against relapse (odds ratio 0.24, 95% CI 0.08-0.70). When pretreatment culture was positive and cavitation was absent, the 30-month relapse rate for standard thrice-weekly regimen was 1.1% (95% CI 0.6-2.0%). The corresponding rates in the presence of cavitation were 7.8% (95% CI 4.0-14.6%) for standard thrice-weekly regimen; 3.3% (95% CI 1.9-5.5%) for standard daily regimen; 0.5% (95% CI 0.1-2.6%) for extended thrice-weekly regimen; and 0.4% (95% CI 0.1-0.9%) for extended daily regimen. Further studies are required to reduce the risk of relapse under program settings.

Smoking and tuberculosis among the elderly in Hong Kong.

A cohort of 42,655 clients that were first registered with the Elderly Health Service in 2000 were followed prospectively through the tuberculosis (TB) notification registry until the end of 2002. A total of 286 active TB cases (186 culture confirmed) were identified. The annual TB notification rates were 735, 427, and 174 per 100,000 among current smokers, ex-smokers, and never-smokers, respectively (p < 0.001). The trend in TB risk persisted after the control of background characteristics using Cox proportional hazards analysis (adjusted hazard ratios [HRs]: 2.63, 1.41, and 1, p < 0.001). In comparison with never-smokers, current smokers had an excess risk of pulmonary TB (adjusted HR, 2.87; 95% confidence interval [CI], 2.00-4.11; p < 0.001), but not extrapulmonary TB (adjusted HR, 1.04; 95% CI, 0.33-3.30; p = 0.95). Among the current smokers, those who developed TB smoked more cigarettes per day than those who did not (13.43, SD 8.76 vs. 10.96, SD 7.87, p = 0.01). A statistically significant dose-response relationship was observed with respect to active TB and culture-confirmed TB (both p < 0.05). Smoking accounted for 32.8% (95% CI, 14.9-48.0%), 8.6% (95% CI, 3.3-15.1%), and 18.7% (95% CI, 7.7-30.4%) of the TB risk among males, females, and the entire cohort, respectively. Approximately 44.9% (95% CI, 20.7-64.6%) of the sex difference was attributable to smoking.

Multiplex PCR amplimer conformation analysis for rapid detection of gyrA mutations in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates.

A new strategy known as multiplex PCR amplimer conformation was developed for detection of mutation in the gyrA gene of 138 clinical isolates of Mycobacterium tuberculosis. The method generated a single-stranded and heteroduplex DNA banding pattern of multiplex PCR amplimers of the region of interest that was extremely sensitive to specific mutations, thus enabling much more sensitive and reliable mutation analysis compared to the standard single-stranded conformation polymorphism technique. The genetic profiles of the gyrA gene of the 138 isolates as detected by MPAC were confirmed by nucleotide sequencing and were found to correlate strongly with the in vitro susceptibilities of the mutant strains to six fluoroquinolones (ofloxacin, levofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and sitafloxacin). All 32 isolates that contained gyrA mutations exhibited cross-resistance to the six fluoroquinolones (ofloxacin MIC for 90% of strains > 16 mg/liter), although moxifloxacin, gatifloxacin, and sitafloxacin (MIC for 90% of strains /==" BORDER="0"> 16 mg/liter). All gyrA mutations were clustered in codons 90, 91, and 94, and aspartic acid 94 was most frequently mutated. Twenty-three isolates without gyrA mutations were also found to exhibit reduced susceptibility to ofloxacin (MIC for 90% of strains = 4 mg/liter), but largely remained susceptible to other drugs (MIC for 90% of strains

Tuberculosis in older people: a retrospective and comparative study from Hong Kong.

OBJECTIVES: To compare tuberculosis (TB) in older and younger patients. DESIGN: A retrospective and comparative observational study. SETTING: Four chest clinics and two chest hospitals in Hong Kong. PARTICIPANTS: All notifications from the participating hospitals and clinics in 1996 were extracted from the TB notification registry. The characteristics of patients aged 65 and older were compared with a one-in-three random sampling of those aged 16 to 64. MEASUREMENTS: Demographic, clinical, radiological, and laboratory data of the two groups were compared alongside treatment and outcomes. RESULTS: Older people with TB were more likely to be male, to smoke, to have had TB previously, to have coexisting medical diseases, to be socioeconomically disadvantaged, and to weigh less than younger people with TB. Dyspnea, weight loss, and malaise were more common, whereas extrathoracic lymph node enlargement was less common. Chest radiograph showed more extensive disease and lower zone involvement. Positive tuberculin test was present in only 61.9%. Sputum bacteriology was more likely to be positive. There was a longer delay in presentation and commencement of treatment, and 77.2% required at least one admission. Adverse effects of treatment, notably hepatic dysfunction, occurred more commonly. Fluoroquinolones appeared well tolerated. Only 72.5% of the older people were cured or completed their treatment. Mortality was 16%. Age of 65 and older, comorbidity, socioeconomic disadvantage, moderate-extensive disease, positive sputum smear, and poor adherence were factors independently associated with unfavorable outcomes (P <.001 to P = .01; odds ratios = 1.61-27.02). CONCLUSION: Substantial differences were found between older and younger TB patients. Many of these were associated with unfavorable outcome. Increased awareness in disease recognition and better medical and social support are therefore needed in addressing the growing problem of TB in older people.