Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Adipokines and the risk of active TB: a nested case-control study.

BACKGROUND: Adipokines are emerging mediators of immune response, and may affect susceptibility to active TB.OBJECTIVE: To examine the associations between adipokines and the risk of active TB.METHODS: In a case-control study nested within a prospective cohort of middle-aged and older adults in Singapore, 280 incident active TB cases who donated blood for research before diagnosis were matched with 280 controls. Serum levels of adiponectin, resistin, leptin and ghrelin were measured. Multivariable logistic regression models were used to compute the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between adipokines and the risk of active TB.RESULTS: Higher levels of leptin and resistin were associated with reduced risk of TB in a dose-dependent manner. Compared to those in the lowest quartile of leptin levels, those in the highest quartile had an OR of 0.46 (95%CI 0.26-0.82; P for trend = 0.009). Similarly, compared to those in the lowest quartile of resistin levels, those in the highest quartile had an OR of 0.46 (95%CI 0.24-0.90; P for trend = 0.03). Adiponectin and ghrelin levels were not associated with TB risk.CONCLUSION: Increased serum levels of leptin and resistin may be associated with reduced susceptibility to active TB infection.

Diabetes and body mass index in relation to risk of active tuberculosis: a prospective population-based cohort.

SETTING: Although diabetes (DM) and low body mass index (BMI) are established risk factors for active tuberculosis (TB), the joint effect of type 2 diabetes (T2D) and BMI is unclear.DESIGN: A prospective cohort of 63,257 adults aged 45-74 years were recruited from 1993 to 1998 in Singapore. Active TB cases were identified via linkage with the National TB Registry up to December 2014. Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relations of T2D and BMI, independently and jointly, with TB risk.RESULTS: T2D was associated with increased TB risk (HR 2.31, 95% CI 1.93-2.78). Conversely, BMI was inversely associated with TB risk: HR for underweight (BMI < 18.5 kg/m²) was 2.87 (95% CI 2.15-3.82) compared to obese (BMI ≥ 27.5 kg/m²) individuals. Compared to obese individuals without T2D, HR for active TB among underweight individuals with T2D was 8.30 (95% CI 4.43-15.54). There was no statistically significant interaction between BMI and T2D on TB risk (Pinteraction = 0.85).CONCLUSION: Underweight and T2D are independent determinants for active TB. This has important public health implications in Asia where prevalence of tuberculous infection is high, and T2D occurs at lower levels of BMI.

The role of chronic viral hepatitis on tuberculosis treatment interruption.

BACKGROUND: Tuberculosis (TB) drug-induced liver injury (TB-DILI) usually occurs within 8 weeks of anti-tuberculosis drug initiation. In Singapore, we suspected that the onset of TB drug-induced transaminitis may be confounded with hepatitis C virus (HCV) and hepatitis B (HBV) virus co-infection. OBJECTIVE: To determine the impact of HCV/HBV co-infection on the course of treatment in patients with TB treatment interrupted due to transaminitis. DESIGN: TB patients with treatment interruption during 2013-2014 were identified through the Singapore national TB registry. Case notes of those with transaminitis were perused. RESULTS: Of 3860 TB patients notified, 140 had suspected TB-DILI. Of these, respectively 20/140 (14.3%) and 16/140 (11.4%) were HCV- or HBV-positive. The median time to treatment interruption/transaminitis was 5 weeks vs. 9.9 weeks and 9.6 weeks for transaminitis patients without chronic liver disease and with HCV/HBV co-infection (P < 0.01). Multivariate logistic regression analysis revealed that having HCV/HBV co-infection was associated with treatment interruption occurring beyond 8 weeks (adjusted OR [aOR] 4.06, 95%CI 1.28-12.85); HCV transaminitis patients were more likely to take 10 months to complete anti-tuberculosis treatment (aOR 5.11, 95%CI 1.21-21.67) than those without chronic liver disease. CONCLUSION: TB treatment interruption due to transaminitis in HCV/HBV co-infected patients occurred later than in those without liver disease. Most had completed 2 months of pyrazinamide-containing intensive phase treatment before the onset of transaminitis.

Latent tuberculosis in patients with diabetes mellitus: prevalence, progression and public health implications.

BACKGROUND: Diabetes mellitus (DM) confers a higher risk for tuberculosis (TB). Yet, TB screening and chemoprophylaxis for latent TB infection (LTBI) in DM remains controversial. We conducted a cross-sectional study to elucidate LTBI prevalence and longitudinal follow-up to ascertain LTBI to active TB progression rate in DM. METHODS: 220 DM patients without previous TB from the outpatient diabetes clinic of the hospital were enrolled. T-Spot TB, tuberculin-skin-test (TST) and chest radiography (CXR) were performed. LTBI was defined by negative CXR with reactive T-Spot TB. Progression to active TB was confirmed by cross-checking against the TB registry. RESULTS: The prevalence of LTBI was 28.2% (62/220) by reactive T-Spot. None progressed to active TB from 2007-2013. Multivariate analysis revealed that any co-morbidity (p=0.016) was positively associated while metformin (p=0.008) was negatively associated with LTBI. CONCLUSIONS: Over a quarter of DM patients harbor LTBI. While the lack of demonstrable progression to active TB within the follow-up time frame up to this point does not unequivocally support a routine TB screening policy or anti-TB chemoprophylaxis for LTBI in a diabetic population for now, this preliminary evidence needs re-evaluation with longer follow-up of this enrolled cohort over the next decade.

Surveillance of tuberculosis treatment outcomes of Singapore citizens and permanent residents, 2002-2011.

SETTING: Singapore, which had a tuberculosis (TB) incidence rate of 41 per 100,000 resident population in 2011. OBJECTIVE: To report the outcomes of Singapore citizens and permanent residents treated for TB from 2002 to 2011. METHODS: A computerised treatment surveillance module (TSM) was launched in 2001 to track the progress and outcome of TB patients nationally. Physicians were required to submit an electronic or paper return for every patient at each clinic visit. Treatment adherence, drugs prescribed, treatment delivery mode and final outcome, specified as 'completed treatment', 'lost to follow-up', 'death', 'transferred out', 'permanent cessation of treatment' and 'still on treatment/no final outcome', were captured. Quarterly cohort outcomes at 12-15 months after starting treatment were combined to generate annual treatment outcomes. RESULTS: Treatment completion rates increased from 73.4% to 82.8%. The proportion of patients lost to follow-up decreased from 3.4% to 1.7%, while that of patients still on treatment or with no final outcome decreased from 10.5% to 4.4%. The death rate ranged between 10.2% and 11.7%; the majority were not attributed to TB. CONCLUSION: TB treatment completion among Singapore citizens and permanent residents has improved since 2002 as the likely result of the TSM and other initiatives introduced over the past decade.

Notified tuberculosis among Singapore residents by ethnicity, 2002-2011.

SETTING: The National Tuberculosis Programme in Singapore where, among resident cases, higher tuberculosis (TB) rates have been reported in ethnic Malays. OBJECTIVE: To describe the socio-demographic and clinical characteristics of resident TB cases by ethnicity, and to assess whether Malays differ from other groups in terms of the above parameters. DESIGN: Cross-sectional review of records from the tuberculosis registry's electronic database. RESULTS: Among 15 622 resident cases notified, 72.2% were Chinese, 18.7% Malay, 5.8% Indian and 2.9% were from other minorities. Compared to other ethnicities, Malays were more likely to be incarcerated at the time of notification (odds ratio [OR] 3.70, 95%CI 3.03-4.52) and clustered at the same residential address (OR 1.65, 95%CI 1.44-1.89), but were less likely to be aged ≥65 years (OR 0.61, 95%CI 0.54-0.70) or to reside in high-cost housing (OR 0.11, 95%CI 0.07-0.17). In terms of disease characteristics, more Malays had diabetes mellitus (OR 1.54, 1.37-1.73), a highly-positive acid-fast bacilli smear (OR 1.64, 95%CI 1.47-1.83) and cavitary disease on chest X-ray (OR 1.41, 95%CI 1.28-1.55). CONCLUSION: Compared to other ethnicities, reported TB cases among Malays were more severe and were likely to be more infectious. Increased vigilance in case management and contact investigations, as well as an improvement in the socio-economic conditions of this community, are required to reduce TB rates in this ethnic group.

Strong purified protein derivative responses are associated with poor mycobacterium inhibition in latent TB.

The tuberculin skin test (TST) using purified protein derivative (PPD) of Mycobacterium tuberculosis is traditionally used to diagnose latent tuberculosis (TB) infection (LTBI). However, LTBI diagnosis by peripheral blood mononuclear cell (PBMC) interferon (IFN)-gamma responses to M. tuberculosis-specific antigens, early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate protein (CFP)-10 has greater specificity. We investigated the difference in antimycobacterium cellular immunity in TB contacts who were strong TST reactors but nonresponsive to the ESAT-6/CFP-10 assay compared with those with concordant results. Healthy TB contacts were tested using the above two assays and mycobacterium survival was measured after co-culture of infected macrophages with their PBMCs. Whether PPD reactivity was tested by TST or by PBMC-specific IFN-gamma responses, strongly PPD-reactive TB contacts without ESAT-6/CFP-10 responsiveness showed significantly better mycobacterium inhibition activity than ESAT-6/CFP-10-responsive TB contacts with the same PPD reactivity. In the former group, stronger PPD reactivity was associated with improved mycobacterium killing, whereas ESAT-6/CFP-10 responders showed the opposite result. PPD-reactive ESAT-6/CFP-10-nonresponsive TB contacts in our population may have had protective immunity related to prior mycobacterium exposure. ESAT-6/CFP10-responsive TB contacts are more likely to have LTBI and, in this group, strong PPD reactivity may paradoxically be associated with poor mycobactericidal activity.

Tuberculosis treatment effect on T-cell interferon-gamma responses to Mycobacterium tuberculosis-specific antigens.

The hypothesis that T-cell interferon-gamma responses to Mycobacterium tuberculosis-specific antigens decline as disease activity diminishes with tuberculosis (TB) treatment has generated interest in the interferon-gamma release assays (IGRAs) as treatment-monitoring tools. We studied the effect of TB treatment on these responses as measured by the QuantiFERON-TB Gold In-tube (QFT-IT) and T-SPOT.TB assays. 275 sputum culture-positive, HIV-uninfected pulmonary TB patients were tested with QFT-IT and T-SPOT.TB at baseline, treatment completion and 6 months thereafter. The QFT-IT was also performed at the end of the intensive phase. The time-treatment effect on the qualitative and quantitative IGRA results was determined. There were significant declines in the positivity rates and quantitative results of both IGRAs with treatment. The QFT-IT positivity rate was significantly lower than the T-SPOT.TB. The test reversion rate was significantly different for the two assays (13.9% for T-SPOT.TB versus 39.2% for QFT-IT). 79% and 46% tested positive with T-SPOT.TB and QFT-IT respectively at 6 months post-treatment completion. The kinetics of the quantitative responses was not significantly different between subjects with and without risk factors for disease relapse. That a substantial proportion of patients remained test-positive after TB treatment would suggest a limited role of IGRAs as treatment monitoring tools.

Use of a T cell interferon-gamma release assay to evaluate tuberculosis risk in newly qualified physicians in Singapore healthcare institutions.

BACKGROUND: Surveillance for latent tuberculosis in high-risk groups such as healthcare workers is limited by the nonspecificity of the tuberculin skin test (TST) in BCG-vaccinated individuals. The Mycobacterium tuberculosis antigen-specific interferon-gamma release assays (IGRAs) show promise for more accurate latent tuberculosis detection in such groups. OBJECTIVE: To compare the utility of an IGRA, the T-SPOT.TB assay, with that of the TST in healthcare workers with a high rate of BCG vaccination. METHODS: Two hundred seven medical students from 2 consecutive cohorts underwent the T-SPOT.TB test and the TST in their final year of study. Subjects with negative baseline test results underwent repeat testing after working for 1 year as junior physicians in Singapore's public hospitals. RESULTS: The baseline TST result was an induration 10 mm or greater in diameter in 177 of the 205 students who returned to have their TST results evaluated (86.3%), while the baseline T-SPOT.TB assay result was positive in 9 (4.3%) of the students. Repeat T-SPOT.TB testing in 182 baseline-negative subjects showed conversion in 9 (4.9%). A repeat TST in 18 subjects with baseline-negative TST results did not reveal any TST result conversion. CONCLUSIONS: The high rate of positive baseline TST results in our BCG-vaccinated healthcare workers renders the TST unsuitable as a surveillance tool in this tuberculosis risk group. Use of an IGRA has enabled the detection and treatment of latent tuberculosis in this group. Our T-SPOT.TB conversion rate highlights the need for greater tuberculosis awareness and improved infection control practices in our healthcare institutions.

Mortality among tuberculosis patients on treatment in Singapore.

OBJECTIVE: To identify the risk factors associated with mortality among tuberculosis (TB) patients on treatment in Singapore. DESIGN: A retrospective cohort study of 7433 TB patients notified and started on TB treatment from 2000 to 2006 was conducted. Cox regression analysis was used to determine independent risk factors for mortality. RESULTS: Of 7433 patients who started TB treatment between 2000 and 2006, there were 884 deaths (11.9%) from any cause. Older age, male sex, being in a long-term care facility, having comorbidity, absence of cough, more than one site of TB, bacteriologically confirmed laboratory results, resistance to at least isoniazid (INH) and rifampicin (RMP) and absence of cavity were strongly associated with all-cause mortality among TB patients. A total of 203 patients (2.7%) died of TB. Risk factors for death due to TB were older age, male sex, Malay ethnicity, being in a long-term care facility, absence of cough, more than one site of TB, bacteriologically confirmed laboratory results and resistance to at least INH and RMP or to at least INH but not RMP. CONCLUSION: It is important to identify TB patients with risk factors related to mortality so that appropriate and timely interventions can be instituted to prevent deaths among TB patients.

Quantitative T-cell interferon-gamma responses to Mycobacterium tuberculosis-specific antigens in active and latent tuberculosis.

The objective was to compare the quantitative T-cell responses measured by the commercial interferon-gamma (IFNgamma) release assays (IGRAs) in active and latent tuberculosis (TB) states. T-cell responses of culture-proven TB cases were compared with those of contacts with positive IGRA results and tuberculin skin tests >or= 15 mm. T-SPOT.TB results in 270 active TB cases and 183 community contacts showed the median spot-forming cells (SFCs) above negative control/2.5 x 10(5) peripheral blood mononuclear cells to be 27 (-1 to 203) vs 10 (-2 to 174) in response to ESAT-6 (p < 0.001); and 37 (0 to 293) vs 13 (0 to 225) to CFP-10 (p < 0.001). The median IFNgamma levels (antigen minus nil control) as measured by QuantiFERON-TB Gold In-tube in 270 cases and 142 contacts in congregate settings was 2.3 IU/ml (-0.58 to 31.44) vs 1.7 IU/ml (0.35 to 26.51, p = 0.98). Quantitative T-cell responses as measured by the T-SPOT.TB may indicate mycobacterial burden and disease activity, but cannot be used to discriminate active from latent TB.

Treatment outcome of Singapore residents with pulmonary tuberculosis in the first year after introduction of a computerised treatment surveillance module.

INTRODUCTION: A key intervention of the Singapore Tuberculosis Elimination Programme (STEP) was the introduction in 2001 of a computerised treatment surveillance module (TSM) for the real-time monitoring of the treatment progress of the country's notified tuberculosis (TB) cases until a final outcome. We report the treatment outcome as at December 31, 2002 for the cohort of Singapore residents with new and relapsed pulmonary TB in whom treatment was commenced in 2001. METHODS: Each TB notification will activate the TSM, which requires a return on the patient's treatment progress, treatment delivery mode and the treating physician's management decision at each clinic visit to the STEP Registry until an outcome is reached. RESULTS: There were 1,354 Singapore residents with new or relapsed pulmonary TB who started treatment in 2001. Of these, 620 (45.8 percent) underwent directly-observed therapy (DOT) at their nearest polyclinic. As at December 31, 2002 , 79 percent of patients completed treatment, nine percent died (two percent from TB), nine percent interrupted treatment (they were either lost to follow-up or refused treatment), 1.8 percent were still on treatment, 0.6 percent left the country, and 0.5 percent had permanent cessation of treatment due to drug reactions. Factors associated with treatment completion were Chinese ethnicity (odds-ratio [OR] 1.5, 95 percent confidence interval [Cl] 1.1-2, p-value is 0.02), age younger than 65 years (OR 1.8, 95 percent Cl 1.3-3.0, p-value is 0.003) and the use of DOT (OR 3.1, 95 percent Cl 2.3-4.1, p-value is less than 0.05). CONCLUSION: The findings from the TSM's first year provide a baseline for future programme evaluation.

Impact of an asthma education programme on patients' knowledge, inhaler technique and compliance to treatment.

INTRODUCTION: We conducted a study to assess the impact of an asthma education programme (AEP) on knowledge of asthma and medication, compliance to treatment and inhaler technique, emergency department visits and hospital re-admissions. METHODS: Patients hospitalised for asthma exacerbation were administered a questionnaire to test their baseline knowledge and beliefs on asthma, its medications and their compliance to treatment. Their inhaler technique was assessed. They then underwent an AEP consisting of two individualised education sessions. Re-testing was performed after three months. Per protocol approach and McNemar's test was used to analyse the statistical significance of the change in the pre- and post-AEP test scores. Hospital administrative data were used to determine the number of ED visits and hospital admissions pre- and post-AEP. RESULTS: Among the 67 patients who completed the two-phase AEP, there was significant improvement in some knowledge aspects (ability to identify rescue medication [p-value is 0.031], that different stimuli can trigger asthma symptoms [p-value is 0.016], that a peak flow meter is used for monitoring asthma [p-value is 0.004], that asthma symptoms are caused by airway swelling/narrowing [p-value is less than 0.001], that steroid inhaler are to be used daily as preventive therapy [p-value is less than 0.001], in self-reported inhaler compliance (number of puffs per administration [p-value is less than 0.001] and per day [p-value is less than 0.001]), and in inhaler technique [p-value is 0.001]. There was also significant reduction in emergency department attendances (p-value is less than 0.001) and hospital admissions (p-value is less than 0.001) among all 97 subjects over a one-year period. CONCLUSION: This study demonstrated the effectiveness of an AEP in patients hospitalised for asthma exacerbation.

Contact screening and latent TB infection treatment in Singapore correctional facilities.

SETTING: Singapore, a city-state with a tuberculosis (TB) incidence rate of 47 per 100000 population in 2000. OBJECTIVES: 1) To report our experience with contact investigation and latent TB infection (LTBI) treatment in high-risk contacts with unknown human immunodeficiency virus (HIV) status in correctional facilities (CFs) (prisons/drug rehabilitation centres); and 2) to compare the yield of contact screening in this setting with that in the community (household/family) setting. METHODS: The tuberculin skin test (TST) readings of 704 CF contacts screened from 1999 to 2001 were compared with those of 2729 household/family contacts who underwent screening in 2000. RESULTS: Respectively eight (1.1%) and 20 (0.7%) active TB cases were detected among the CF and community contacts. A significantly higher proportion of CF contacts had first (non-conversion) TST readings > or =15 mm (39% vs. 22%, OR 2.3; 95%CI 1.9-2.7; P < 0.001), and 10-14 mm (26% vs. 18%, OR 1.6; 95%CI 1.3-2.0; P < 0.001) and TST conversion (43% vs. 20%, OR 2.9; 95%CI 1.7-4.9; P < 0.001). LTBI treatment was started in 65% of the CF contacts screened; 87% completed treatment. CONCLUSION: We found a high LTBI rate among CF contacts, presenting an opportunity for intervention.

Treatment of latent TB infection for close contacts as a complementary TB control strategy in Singapore.

OBJECTIVE: To describe our initial experience with treatment of latent tuberculosis infection (LTBI) for close contacts of infectious TB cases in Singapore, an intermediate TB burden country with mass BCG (re)vaccination since the 1950s. METHODS: Screening of 5699 contacts of 1374 index cases notified in 1998 was carried out at the TB Control Unit. RESULTS: Seventy-five per cent (4239) completed tuberculin skin testing (TST). Fifty-three cases of TB disease were detected (0.9% yield). Twenty-one per cent (895/4239) of the TST-screened contacts were started on LTBI treatment, comprising 92% (810/883) of contacts with TST > or = 15 mm, 5% (64/1195) of those with TST 10-14 mm and 1% (21/2161) of those with TST < 10 mm. The regimen utilized was isoniazid for 6 months in adults and 9 months in children. Eighty-one per cent completed treatment. The incidence of isoniazid-induced hepatitis was 0.45%. Over the ensuing 4 years, one case of active TB was reported among those treated for LTBI, and 10 cases (five without TST readings) were notified among contacts who did not receive treatment. CONCLUSIONS: Where good case-finding and treatment of TB disease exist, and where resources permit, LTBI treatment for close contacts is feasible as a complementary TB control strategy in an intermediate TB burden country with a BCG-vaccinated population.