Joint Associations of Multiple Lifestyle Factors With Risk of Active Tuberculosis in the Population: The Singapore Chinese Health Study.

BACKGROUND: Little is known about the joint associations of multiple lifestyle risk factors including smoking, low body mass index, physical inactivity, alcohol consumption, and low diet quality with risk of active tuberculosis. METHODS: We analyzed data from the Singapore Chinese Health Study, a prospective cohort study of 63 257 Chinese adults aged 45-74 years enrolled between 1993 and 1998. Incident cases of active tuberculosis were identified via linkage with the National TB Registry through 31 December 2016. Cox proportional hazards regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) of tuberculosis risk in relation to the combined scores of lifestyle risk factors. RESULTS: Compared with participants with none of the risk factors, the adjusted HRs (95% CI) of active tuberculosis for participants with 1, 2, 3, 4, and 5 risk factors were 1.24 (1.02-1.51), 1.84 (1.51-2.23), 2.52 (2.03-3.14), 4.07 (3.07-5.41), and 9.04 (5.44-15.02), respectively (Ptrend < .0001). The HR for those with 5 factors was ~1.5 times the product of individual risk estimates from the 5 factors on a multiplicative scale. The stepwise increase in risk of active tuberculosis with increasing number of lifestyle risk factors was significantly stronger in participants with diabetes than their counterparts without diabetes at recruitment (Pinteraction = .01). CONCLUSIONS: Multiple lifestyle risk factors were associated with risk of active tuberculosis in a synergistic manner. Our findings highlight the importance of public health programs and interventions targeting these factors simultaneously to reduce the tuberculosis burden among the general population.

Whole genome sequencing analysis of multidrug-resistant tuberculosis in Singapore, 2006-2018.

There were 290 multidrug-resistant (MDR)-TB cases diagnosed in Singapore from 2006 to 2018. Eighty-one percent were foreign-born. Spoligotyping and MIRU-VNTR methods identified 108 patients in 24 clusters. The Beijing spoligotype accounted for 22 clusters. Whole genome sequencing (WGS) analysis reduced the number of clustered patients and clusters to 43 and nine respectively. One MIRU cluster was redefined into three WGS clusters. All the clusters had foreign-born source cases. Forty percent of local-born, versus 9% of foreign-born, MDR-TB cases belonged to WGS clusters. WGS more accurately elucidated potential MDR-TB transmission which was overestimated by conventional genotyping methods in Singapore.

Latent tuberculosis infection: Opportunities and challenges.

Diagnosing and treating latent tuberculosis (TB) infection (LTBI) is recognized by the World Health Organization as an important strategy to accelerate the decline in global TB and achieve TB elimination. Even among low-TB burden countries that have achieved high rates of detection and successful treatment for active TB, a number of barriers have prevented implementing or expanding LTBI treatment programmes. Of those infected with TB, relatively few will develop active disease and the current diagnostic tests have a low predictive value. LTBI treatment using isoniazid (INH) has low completion rates due to the long duration of therapy and poor tolerability. Both patients and physicians often perceive the risk of toxicity to be greater than the risk of reactivation TB. As a result, LTBI treatment has had a limited or negligible role outside of countries with high resources and low burden of disease. New tools have emerged including the interferon-gamma release assays that more accurately diagnose LTBI, particularly in people vaccinated with Bacillus Calmette-Guerin (BCG). Shorter, better tolerated treatment using rifamycins are proving safe and effective alternatives to INH. While still imperfect, TB prevention using these new diagnostic and treatment tools appear cost effective in modelling studies in the United States and have the potential to improve TB prevention efforts globally. Continued research to understand the host-organism interactions within the spectrum of LTBI is needed to develop better tools. Until then, overcoming the barriers and optimizing our current tools is essential for progressing toward TB elimination.

Dietary Intake of Antioxidant Vitamins and Carotenoids and Risk of Developing Active Tuberculosis in a Prospective Population-Based Cohort Study.

Antioxidants may protect against oxidative stress, which is associated with tuberculosis (TB) disease. However, direct evidence for a protective association between dietary antioxidants and TB incidence in humans has been lacking. The relationship between intake of antioxidant vitamins (vitamins A, C, D, and E) and individual carotenoids (α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and lutein) and TB incidence was examined in the Singapore Chinese Health Study, a prospective cohort study of 63,257 adults aged 45-74 years enrolled during 1993-1998. Baseline intake of these antioxidants was estimated using a validated semiquantitative food frequency questionnaire including questions on use of dietary supplements. After an average of 16.9 years of follow-up, 1,186 incident active TB cases were identified among cohort participants. Compared with the lowest quartile, reduced risk of active TB was observed for the highest quartile of vitamin A intake (hazard ratio = 0.71, 95% confidence interval: 0.59, 0.85; P-trend < 0.01) and ß-carotene intake (hazard ratio = 0.76, 95% confidence interval: 0.63, 0.91; P-trend < 0.01), regardless of smoking status. Lower TB risk was seen for vitamin C intake among current smokers only. Other vitamins and carotenoids were not associated with TB risk. These results suggest that vitamin C may reduce TB risk among current smokers by ameliorating oxidative stress, while vitamin A and ß-carotene may have additional antimycobacterial properties.

Country-wide genotyping of Mycobacterium tuberculosis complex in Singapore, 2011-2017.

OBJECTIVE: To describe the molecular epidemiology of Mycobacterium tuberculosis complex (MTBC) and factors associated with its transmission in Singapore. METHODS: Spoligotyping, 24-loci mycobacterial interspersed repetitive units - variable number of tandem repeats (MIRU-VNTR) typing and demographic data from the national TB notification registry of MTBC culture-positive cases notified from January 2011 to December 2017 were analysed. RESULTS: Of the 12,046 culture-positive cases notified, complete spoligotyping and MIRU-VNTR typing results were available for 8690 (72.1%) belonging to 4950 (57.0%) local-born and 3740 (43.0%) foreign-born persons. From these, 4810 (55.3%) were identified in 883 clusters. The proportion of recent transmission was 45.2%. The East-Asian Lineage 2 accounted for 4045 (47.1%) of isolates, and disproportionately accounted for large clusters. Clustered cases were more likely to be older than 50 years, male, Malay, local-born, Singapore citizens or Permanent Residents, of lower socioeconomic status, imprisoned; to harbour East-Asian Lineage 2 strain; to have cavitary pulmonary TB, positive sputum smear or be recalcitrant treatment defaulters. They were less likely to have multidrug-resistant, or isoniazid or rifampicin mono-resistant TB. CONCLUSION: We demonstrated the diversity of MTBC strains and, notwithstanding the likely over-estimation of clustering using these genotyping methods, elucidated factors associated with TB transmission in Singapore.

Tuberculosis among foreign-born persons, Singapore, 2000-2009.

We determined the proportion of foreign-born persons with tuberculosis (TB) in Singapore. This proportion increased from 25.5% in 2004 to 37.6% in 2009. Unskilled workers from countries with high incidences of TB accounted for the highest number of and greatest increase in foreign-born TB case-patients.

Recurrent Tuberculosis Disease in Singapore.

BACKGROUND: Previously treated (ie, recurrent) tuberculosis (TB) cases account for approximately 7%-8% of incident TB globally and in Singapore. Molecular fingerprinting has enabled the differentiation of these patients into relapsed or reinfection cases. METHODS: Patient demographics, disease characteristics, and treatment information were obtained from the national TB notification registry and TB Control Unit. We performed a retrospective, case-control study to evaluate factors associated with recurrent TB disease in Singapore citizens and permanent residents with culture-positive TB from 2006 to 2013 and who developed a second episode of culture-positive TB up to 2016 using multivariable logistic regression analyses. RESULTS: Ninety-one cases with culture-positive first and recurrent TB disease episodes were identified. Recurrent TB was associated with age ≥60 years (adjusted odds ratio [aOR], 1.98 [95% confidence interval {CI}, 1.09-3.61), male sex (aOR, 2.29 [95% CI, 1.22-4.51]), having concomitant pulmonary and extrapulmonary TB (aOR, 3.10 [95% CI, 1.59-6.10]) and extrapulmonary TB alone (aOR, 3.82 [95% CI, 1.12-13.31]), and was less likely in non-Malays (aOR, 0.52 [95% CI, .27-.99]). DNA fingerprinting results for both episodes in 49 cases differentiated these into 28 relapsed and 21 reinfection cases. Relapse was associated with having concomitant pulmonary and extrapulmonary TB (aOR, 9.24 [95% CI, 2.50-42.42]) and positive sputum acid-fast bacilli smear (aOR, 3.95 [95% CI, 1.36-13.10]). CONCLUSIONS: Relapse and reinfection contributed to 57% and 43%, respectively, of recurrent TB in Singapore. Our study highlights the underappreciated association of concomitant pulmonary and extrapulmonary TB as a significant risk factor for disease relapse.

Asthma, Sinonasal Disease, and the Risk of Active Tuberculosis.

BACKGROUND: Although asthma is associated with impaired lung immunity, it is unclear whether asthma affects the risk of active tuberculosis (TB). Because the upper and lower airways are immunologically related, sinonasal disease may also modify susceptibility to TB disease. OBJECTIVES: To evaluate whether asthma and sinonasal disease prospectively modulate the risk of active TB in the Singapore Chinese Health Study. METHODS: In this population-based prospective cohort, we recruited 63,257 Chinese adults aged 45 to 74 years from 1993 to 1998 in Singapore, and conducted follow-up I interviews among 52,325 surviving participants from 1999 to 2004. Data on self-reported history of physician-diagnosed sinonasal disease were collected at baseline, and data on asthma and chronic bronchitis were collected at follow-up I interviews. Active TB cases were identified by linkage with the National TB Notification Registry through December 2014. Multivariable Cox proportional hazards regression models were used to estimate the risk of active TB. RESULTS: During a mean follow-up of 17 years from recruitment, there were 1249 cases of active TB, and among them, 678 cases were diagnosed in the 12-year period from follow-up I interviews. We observed reduced risk of active TB in those with a history of asthma at follow-up I (hazard ratio [HR], 0.55; 95% CI, 0.32-0.93) or sinonasal disease at baseline (HR, 0.59; 95% CI, 0.36-0.95). Conversely, history of chronic bronchitis was not associated with risk of TB (HR, 0.95; 95% CI, 0.68-1.31). CONCLUSIONS: Asthma or sinonasal disease may modulate immunological response to reduce the incidence of active TB in the adult population.

Comparison of sensitivities of two commercial gamma interferon release assays for pulmonary tuberculosis.

There are few head-to-head comparisons of the commercial gamma interferon release assays (GIRAs). We compared the performance of the T-SPOT.TB and QuantiFERON-TB Gold In-Tube (QFT-IT) assays in patients with culture-proven pulmonary tuberculosis. Blood was drawn for both assays within 14 days of starting antituberculosis treatment. The QFT-IT indeterminate rate was 3.5%; the T-SPOT.TB failure rate was 1.4%. There was poor agreement between the GIRAs (kappa = 0.257) among the 270 patients with valid results for both tests. The sensitivities of the T-SPOT.TB and QFT-IT assays were 94.1 and 83.0%, respectively, with a significant difference in the performance of the assays (P = 0.001 [McNemar test]). Factors independently associated with indeterminate QFT-IT results were an age of >or=60 years (odds ratio [OR] 11.18, 95% confidence interval [CI] = 1.841 to 67.823, P = 0.009), female sex (OR = 7.47, 95% CI = 1.517 to 36.733, P = 0.013) and non-Chinese (i.e., Indian or Malay) race (OR = 7.89, 95% CI = 1.585 to 39.267, P = 0.012). The QFT-IT assay was significantly less sensitive in patients >or=60 years old (OR = 0.41, 95% CI = 0.181 to 0.918, P = 0.030) and in Indian compared to Chinese patients (OR = 0.27, 95% CI = 0.073 to 0.990, P = 0.048). The T-SPOT.TB assay was significantly less sensitive in Malay (OR = 0.23, 95% CI = 0.063 to 0.815, P = 0.023) and Indian patients (OR = 0.09, 95% CI = 0.017 to 0.429, P = 0.003) compared to Chinese patients. The performance of both assays was not significantly altered in diabetics. The diminished sensitivity of the GIRAs in persons of Malay and Indian race merits further study.

Randomized controlled trial of nutritional supplementation in patients with newly diagnosed tuberculosis and wasting.

BACKGROUND: Nutritional support is often recommended as part of the treatment of tuberculosis, but it has never been properly tested. OBJECTIVE: We assessed the effects of early nutritional intervention on lean mass and physical function in patients with tuberculosis and wasting. DESIGN: Patients who started antituberculous therapy within the previous 2 wk were randomly assigned to receive standard nutritional counseling (control group) or nutritional counseling to increase their intake through diet and high-energy supplements (nutritional supplement group) for 6 wk. Body composition was measured by dual-energy X-ray absorptiometry, and physical function was assessed by maximum grip strength. RESULTS: Patients in the nutritional supplement group (n = 19) had a significantly greater increase in body weight (2.57 +/- 1.78 compared with 0.84 +/- 0.89 kg, P = 0.001), total lean mass (1.17 +/- 0.93 compared with 0.04 +/- 1.26 kg, P = 0.006), and grip strength (2.79 +/- 3.11 compared with -0.65 +/- 4.48 kg, P = 0.016) than did the control subjects (n = 17) at week 6. During subsequent follow-up, the increase in body weight remained greater in the nutritional supplement group, but this increase was due mainly to a greater gain in fat mass in the nutritional supplement group than in the control group. CONCLUSIONS: Early intervention to increase nutritional intake increases lean mass and physical function. This adjunct to tuberculosis therapy could confer socioeconomic and survival benefits that deserve investigation in large-scale trials. Nutritional intervention after the initial phase of treatment could be less beneficial because it mainly increases fat.