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The Singapore Tuberculosis Elimination Programme (STEP) was launched in 1997 because the incidence of the disease had remained between 49 and 56 per 100,000 resident population for the preceding 10 years. STEP involves the following key interventions: directly observed therapy (DOT) in public primary health care clinics; monitoring of treatment progress and outcome for all cases by means of a National Treatment Surveillance Registry; and preventive therapy for recently infected close contacts of infectious tuberculosis cases. Among other activities are the revamping of the National Tuberculosis Notification Registry, the discontinuation of BCG revaccination for schoolchildren, the tightening up of defaulter tracing, and the education of the medical community and the public. Future plans include an outreach programme for specific groups of patients who are unable to attend their nearest public primary care clinics for DOT, the detention of infectious recalcitrant defaulters for treatment under the Infectious Diseases Act, the molecular fingerprinting of tuberculosis isolates, and targeted screening of high-risk groups. The incidence of tuberculosis fell from 57 per 100,000 population in 1998 to 48 per 100,000 in 1999 and continued to decline to 44 per 100,000 in 2001. With political will and commitment and the support of the medical community and the public it is hoped that STEP will achieve further progress towards the elimination of tuberculosis in Singapore. [ABSTRACT FROM AUTHOR]

BACKGROUNDMatrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODSThirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTSWhole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov NCT02774993.FUNDINGSingapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.

Objectives: WHO recommends that low burden countries consider systematic screening and treatment of latent tuberculosis infection (LTBI) in migrants from high incidence countries. We aimed to determine LTBI prevalence and risk factors and evaluate cost-effectiveness of screening and treating LTBI in migrants to Singapore from a government payer perspective., Design: Cross-sectional study and cost-effectiveness analysis., Setting: Migrants in Singapore., Participants: 3618 migrants who were between 20 and 50 years old, have not worked in Singapore previously and stayed in Singapore for less than a year were recruited., Primary and Secondary Outcome Measures: Costs, quality-adjusted life-years (QALYs), threshold length of stay, incremental cost-effectiveness ratios (ICERs), cost per active TB case averted., Results: Of 3584 migrants surveyed, 20.4% had positive interferon-gamma release assay (IGRA) results, with the highest positivity in Filipinos (33.2%). Higher LTBI prevalence was significantly associated with age, marital status and past TB exposure. The cost-effectiveness model projected an ICER of S$57 116 per QALY and S$12 422 per active TB case averted for screening and treating LTBI with 3 months once weekly isoniazid and rifapentine combination regimen treatment compared with no screening over a 50-year time horizon. ICER was most sensitive to the cohort's length of stay in Singapore, yearly disease progression rates from LTBI to active TB, followed by the cost of IGRA testing., Conclusions: For LTBI screening and treatment of migrants to be cost-effective, migrants from high burden countries would have to stay in Singapore for ~50 years. Risk-stratified approaches based on projected length of stay and country of origin and/or age group can be considered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Singapore is a high-income country in a region with a high prevalence of tuberculosis. The Singapore Tuberculosis (TB) Elimination Program (STEP) was set up in 1997, and the better surveillance and clinical management practices initiated under STEP led to a decade-long decline in the incidence levels. However, incidence rates started to rise again since 2008. The reasons for this rise are unclear. This study involved a spatial analysis of the epidemiology of TB among Singapore residents. More than 30 000 cases reported during 1995-2011 and their residential addresses were analysed for spatial risk and spatial clustering, using spatial point pattern methodology. The principal factor responsible for the increasing resident TB incidence in Singapore is the changing age profile of the population. In particular the burgeoning population aged above 65 years accounts for the increase in reported cases. Singapore's population has one of the world's lowest fertility and mortality rates, and the elderly population is projected to grow substantially over the next few decades. Tuberculosis rates may therefore continue to rise even with static or improving case management and surveillance.

Background: Experimental studies suggest that cholesterol enhances the intracellular survival of Mycobacterium tuberculosis, whereas marine ω-3 (n-3) and ω-6 (n-6) fatty acids (FAs) may modulate responses to M. tuberculosis in macrophage and animal models. However, there are no epidemiologic data from prospective studies of the relation between dietary cholesterol and FAs and the risk of developing active tuberculosis., Objective: We aimed to investigate the relation between dietary intake of cholesterol and FAs and the risk of active tuberculosis in a prospective cohort in Singapore., Methods: We analyzed data from the Singapore Chinese Health Study, a cohort of 63,257 Chinese men and women aged 45-74 y recruited between 1993 and 1998. Dietary intake of cholesterol and FAs was determined with the use of a validated food-frequency questionnaire. Incident cases of active tuberculosis were identified via linkage with the nationwide tuberculosis registry. Analysis was performed with the use of Cox proportional hazards models., Results: As of 31 December 2013, 1136 incident cases of active tuberculosis were identified. Dietary cholesterol was positively associated with an increased risk of active tuberculosis in a dose-dependent manner. Compared with the lowest intake quartile, the HR was 1.22 (95% CI: 1.00, 1.47) for the highest quartile (P-trend = 0.04). Conversely, dietary marine n-3 and n-6 FAs were associated with a reduced risk of active tuberculosis in a dose-dependent manner. Compared with the lowest quartile, the HR for the highest intake quartile was 0.77 (95% CI: 0.62, 0.95) for marine n-3 FAs (P-trend = 0.01) and 0.82 (95% CI: 0.68, 0.98) for n-6 FAs (P-trend = 0.03). There was no association with saturated, monounsaturated, or plant-based n-3 FA intake., Conclusion: Dietary intake of cholesterol may increase the risk of active tuberculosis, whereas marine n-3 and n-6 FAs may reduce the risk of active tuberculosis in the Chinese population., (© 2016 American Society for Nutrition.)

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone., (Copyright ©ERS 2015.)

Drug-resistant tuberculosis (TB) continues to pose a threat to global control of TB: 3.5% of new and 20.5% of previously treated TB cases were estimated to have multidrug-resistant (MDR)-TB in 2013. Approximately 9% of patients with MDR-TB had extensively drug-resistant (XDR)-TB. A 30-year-old Vietnamese woman previously treated for TB in her home country presented with 5 months of cough and shortness of breath 1 year after migrating to Singapore. Xpert MTB/Rif testing showed rpoB gene mutation. Phenotypic drug susceptibility testing revealed XDR-TB. Second and third-line TB drugs were commenced. To strengthen the efficacy of her treatment regimen, the novel anti-TB drug bedaquiline was obtained for the patient on compassionate grounds. We report the first use in Singapore of bedaquiline for the treatment of XDR-TB., (2015 BMJ Publishing Group Ltd.)

The tuberculin skin test (TST) and interferon gamma (IFN-γ) release assays (IGRAs) are used as adjunctive tests for the evaluation of suspected cases of active tuberculosis (TB). However, a positive test does not differentiate latent from active TB. We investigated whether flow cytometric measurement of novel combinations of intracellular cytokines and surface makers on CD4 T cells could differentiate between active and latent TB after stimulation with Mycobacterium tuberculosis-specific proteins. Blood samples from 60 patients referred to the Singapore Tuberculosis Control Unit for evaluation for active TB or as TB contacts were stimulated with purified protein derivative (PPD), ESAT-6 and CFP-10, or heparin-binding hemagglutinin (HBHA). The CD4 T cell cytokine response (IFN-γ, interleukin-2 [IL-2], interleukin-17A [IL-17A], interleukin-22 [IL-22], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor alpha [TNF-α]) and surface marker expression (CD27, CXCR3, and CD154) were then measured. We found that the proportion of PPD-specific CD4 T cells, defined as CD154(+) TNF-α(+) cells that were negative for CD27 and positive for GM-CSF, gave the strongest discrimination between subjects with latent and those with active TB (area under the receiver operator characteristic [ROC] curve of 0.9277; P < 0.0001). Also, the proportions and absolute numbers of HBHA-specific CD4 T cells were significantly higher in those with latent TB infection, particularly CD154(+) TNF-α(+) IFN-γ(+) IL-2(+) and CD154(+) TNF-α(+) CXCR3(+). Finally, we found that the ratio of ESAT-6- and CFP-10-responding to HBHA-responding CD4 T cells was significantly different between the two study populations. In conclusion, we found novel markers of M. tuberculosis-specific CD4 cells which differentiate between active and latent TB., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Singapore is an intermediate tuberculosis (TB) incidence country, with a recent rise in TB incidence from 2008, after a fall in incidence since 1998. This study identified population characteristics that were associated with the recent increase in TB cases, and built a predictive model of TB risk in Singapore., Methods: Retrospective time series analysis was used to study TB notification data collected from 1995 to 2011 from the Singapore Tuberculosis Elimination Program (STEP) registry. A predictive model was developed based on the data collected from 1995 to 2010 and validated using the data collected in 2011., Results: There was a significant difference in demographic characteristics between resident and non-resident TB cases. TB risk was higher in non-residents than in residents throughout the period. We found no significant association between demographic and macro-economic factors and annual incidence of TB with or without adjusting for the population-at-risk. Despite growing non-resident population, there was a significant decrease in the non-resident TB risk (p < 0.0001). However, there was no evidence of trend in the resident TB risk over this time period, though differences between different demographic groups were apparent with ethnic minorities experiencing higher incidence rates., Conclusion: The study found that despite an increasing size of non-resident population, TB risk among non-residents was decreasing at a rate of about 3% per year. There was an apparent seasonality in the TB reporting.

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., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

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.

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.

Background: Tuberculosis remains common in Singapore, increasing in incidence since 2008. We attempted to determine the molecular epidemiology of Mycobacterium tuberculosis complex (MTC) isolates locally, identifying major circulating genotypes and obtaining a glimpse of transmission dynamics., Methodology: Non-duplicate MTC isolates archived between 2006 and 2012 at the larger clinical tuberculosis laboratory in Singapore were sampled for spoligotyping and MIRU-VNTR typing, with case data obtained from the Singapore Tuberculosis Elimination Program registry database. Isolates between 2008 and 2012 were selected because of either multidrug-resistance or potential epidemiological linkage, whereas earlier isolates were randomly selected. Separate analyses were performed for the early (2006-2007) and later (2008-2012) study phases in view of potential selection bias., Principal Findings: A total of 1,612 MTC isolates were typed, constituting 13.1% of all culture-positive tuberculosis cases during this period. Multidrug-resistance was present in 91 (5.6%) isolates - higher than the national prevalence in view of selection bias. The majority of isolates belonged to the Beijing (45.8%) and EAI (22.8%) lineages. There were 347 (30.7%) and 133 (27.5%) cases clustered by combined spoligotyping and MIRU-VNTR typing from the earlier and later phases respectively. Patients within these clusters tended to be of Chinese ethnicity, Singapore resident, and have isolates belonging to the Beijing lineage. A review of prior contact investigation results for all patients with clustered isolates failed to reveal epidemiological links for the majority, suggesting either unknown transmission networks or inadequate specificity of the molecular typing methods in a country with a moderate incidence of tuberculosis., Conclusion: Our work demonstrates that Singapore has a large and heterogeneous distribution of MTC strains, and with possible cross-transmission over the past few years based on our molecular typing results. A universal MTC typing program coupled with enhanced contact investigations may be useful in further understanding the transmission dynamics of tuberculosis locally.

In clinical practice, latent infection with Mycobacterium tuberculosis is defined by the presence of an M. tuberculosis-specific immune response in the absence of active tuberculosis. Targeted testing of individuals from risk groups with the tuberculin skin test or an interferon-γ release assay is currently the best method to identify those with the highest risk for progression to tuberculosis. Positive predictive values of the immunodiagnostic tests are substantially influenced by the type of test, the age of the person who is tested, the prevalence of tuberculosis in the society and the risk group to which the person belongs. As a general rule, testing should only be offered when preventive chemotherapy will be accepted in the case of a positive test result. Preventive chemotherapy can effectively protect individuals at risk from the development of tuberculosis, although at least 3 months of combination therapy or up to 9 months of monotherapy are required, and overall acceptance rate is low. Improvements of the current generation of immunodiagnostic tests could substantially lower the number of individuals that need to be treated to prevent a case of tuberculosis. If shorter treatment regimens were equally effective than those currently recommended, acceptance of preventive chemotherapy could be much improved., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

Singapore has experienced a rise in the tuberculosis (TB) incidence rate among her local population since 2008, which we believe, is contributed in no small part to a recent increase in community transmission due to delayed diagnosis of infectious pulmonary TB cases. Data from the TB notification registry showed an increase from 2004 to 2008 in the number and proportion of sputum acid-fast bacilli smear-positive pulmonary TB cases with prolonged cough. Two surveys at the TB Control Unit showed that healthcare system delays exceeded patient delay in seeking medical consultation. There is thus an urgent need to heighten TB awareness among the public and the medical community in order to reduce the time taken to diagnose infectious TB cases in Singapore.

Infection caused by Mycobacterium avium is common in AIDS patients who do not receive treatment with highly active antiretroviral therapy (HAART) or who develop resistance to anti-HIV therapy. Mefloquine, a racemic mixture used for malaria prophylaxis and treatment, is bactericidal against M. avium in mice. MICs of (+)-erythro-, (-)-erythro-, (+)-threo-, and (-)-threo-mefloquine were 32 μg/ml, 32 μg/ml, 64 μg/ml, and 64 μg/ml, respectively. The postantibiotic effect for (+)-erythro-mefloquine was 36 h (MIC) and 41 h for a concentration of 4× MIC. The mefloquine postantibiotic effect was 25 h (MIC and 4× MIC). After baseline infection was established (7 days), the (+)- and (-)-isomers of the diastereomeric threo- and erythro-α-(2-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol were individually used to orally treat C57BL/6 bg(+)/bg(+) beige mice that were infected intravenously with M. avium. Mice were also treated with commercial mefloquine and diluent as controls. After 4 weeks of treatment, the mice were harvested, and the number of bacteria in spleen and liver was determined. Mice receiving (+)- or (-)-threo-mefloquine or (-)-erythro-mefloquine had numbers of bacterial load in tissues similar to those of untreated control mice at 4 weeks. Commercial mefloquine had a bactericidal effect. However, mice given the (+)-erythro-enantiomer for 4 weeks had a significantly greater reduction of bacterial load than those given mefloquine. Thus, (+)-erythro-mefloquine is the active enantiomer of mefloquine against M. avium and perhaps other mycobacteria.

The total number of new tuberculosis (TB) cases notified in Singapore among citizens, permanent residents and foreigners rose by 46% from 2004 to 2010. During this period, the proportion of foreigners increased from 29% to 47% of the total case burden. In 2008, the TB incidence rate among Singapore citizens and permanent residents increased for the first time in ten years, despite the on-going efforts of the Singapore TB Elimination Programme. Additional measures and resources are clearly needed to curb this rising trend. Pivotal to this is to address TB among foreigners. The political will to battle TB in Singapore must result in action to remove barriers to diagnosis, to enable all TB patients to undergo treatment under directly observed therapy (DOT), and to ensure that all healthcare providers who manage TB patients are responsible and accountable to the public health system.

The global emergence of multidrugresistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR)-TB threatens to derail the efforts of TB control programmes worldwide. From 2000 to 2010, 161 pulmonary MDR-TB cases (including six XDR-TB cases) were reported in Singapore, and of these, 80% occurred among the foreign-born, with an increasing trend seen after 2004. Among new pulmonary TB cases, the highest incidence of MDR-TB occurred among patients from Myanmar (8%), followed by Vietnam (4.4%) and China (2.3%), while among those previously treated, the highest incidence was found in patients from Vietnam (50%), followed by Indonesia (33%) and Bangladesh (33%). Although the proportion of Singapore-born pulmonary TB cases with MDR-TB has remained comparatively low (0.2% and 1.3% in new and previously treated cases, respectively), there is no room for complacency. Top priority must be accorded toward the proper treatment of drug-susceptible TB cases under strict programme conditions so as to prevent the development of MDR-TB in the first place.

Introduction: Extensively drug-resistant tuberculosis (XDR-TB) is an emerging global health risk. We present the first case report of XDR-TB in Singapore., Clinical Picture: A 41-year-old Indonesian lady with previously treated pulmonary tuberculosis presented with chronic cough. Her sputum was strongly acid-fast bacilli positive and grew Mycobacterium tuberculosis complex resistant to first and second-line TB medications., Treatment: She received 5 months of intensive multidrug treatment without sputum smear conversion. She then underwent resection of the diseased lung. The total cost incurred amounted to over S$100,000., Outcome: She achieved sputum smear/culture conversion post-surgery, but will require further medical therapy for at least 18 months., Conclusion: XDRTB is poorly responsive to therapy and extremely expensive to manage. Its prevention by strict compliance to therapy is paramount.

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.

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.

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.

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.

Context: Suicide risk assessment in the emergency department is a challenging task for psychiatrists and is further complicated when patients are admitted involuntarily., Objective: To evaluate the quality of suicide risk assessments in the psychiatric emergency setting by reviewing physician documentation of process indicators., Methods: A retrospective review of medical records for patients who were admitted involuntarily to the Kern Medical Center Psychiatric Emergency Service in Bakersfield, Calif. All patients were deemed a "danger to self" as defined by California Law and were admitted for evaluation in June 2006. Medical records were reviewed for 19 process indicators, which were identified from risk factors and treatment guidelines described in the literature. Documentation that a process indicator was not met by a patient was included in the data. Patients were then separated into two study groups: those who were admitted to the inpatient psychiatric unit, and those who were released. Data were analyzed using t tests for continuous variables and chi(2) tests for categorical variables., Results: The medical records of 145 patients were reviewed. None of the suicide risk assessments documented all 19 process indicators. The three most commonly documented process indicators were access to firearms (75.9%), recent stressful life events (75.2%), and "contract for safety" (74.5%). According to medical records, patients admitted to the inpatient unit were more likely than patients released to home care to have been assessed for command auditory hallucinations (P=.02) or prior psychiatric diagnoses (P=.001). Discharged patients were more likely to have been assessed for a family history of suicide (P=.001) or symptoms of major depressive disorder (P=.02)., Conclusion: Many important risk factors for suicide were not documented in emergency department assessments, suggesting that overall quality of psychiatric risk assessments was not optimal. This lack of documentation has important implications from a treatment and medicolegal perspective.

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.

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.

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.

Rationale: There is currently no available test for monitoring the effect of treatment of latent tuberculosis infection (LTBI) to indicate cure or predict risk of subsequent progression to disease., Objective: We used the T-SPOT.TB assay, which measures T-cell interferon-gamma responses to the Mycobacterium tuberculosis-specific peptides early secretory antigenic target 6-kD protein (ESAT-6) and culture filtrate protein 10 (CFP-10), to determine the effect of LTBI treatment on these responses., Methods: A total of 226 tuberculosis contacts with positive T-SPOT.TB results underwent repeat testing on LTBI treatment completion. The majority (96%) received 6 months of isoniazid. The pre- and post-treatment T-SPOT.TB results were analyzed according to the combined and separate responses to ESAT-6 and CFP-10 antigens., Results: The T-SPOT.TB reverted to negative in 85 (37.6%) contacts at treatment completion. Treatment had a significant effect on the response to CFP-10 (p < 0.001; reversion rate, 48.6%), but not on the response to ESAT-6 (p = 0.081; reversion rate, 21.6%). The median number of spot-forming cells (SFCs)/2.5 x 10(5) peripheral blood mononuclear cells (PBMCs) pre- and post-treatment was 6 versus 4.5 for ESAT-6 (p = 0.116) and 11 versus 4 for CFP-10 (p < 0.001). There was a significant difference between the change (fall) in the pre- and post-treatment responses to CFP-10 (6 SFCs/2.5 x 10(5) PBMCs) and ESAT-6 (0 SFCs/2.5 x 10(5) PBMCs; p < 0.001). Significantly different age-related T-cell responses to the two antigens were found., Conclusion: LTBI treatment had a differential effect on T-cell responses to ESAT-6 and CFP-10 as measured by the T-SPOT.TB. The quantitative response to CFP-10 may be a useful LTBI treatment-monitoring tool.

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.

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.

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.

Objective: The aim of this study was to identify patient and disease characteristics associated with delayed diagnosis of infectious pulmonary tuberculosis (TB)., Methodology: A retrospective analysis of 375 adult patients with culture-positive pulmonary TB and cough, treated at the Singapore Tuberculosis Control Unit (TBCU) in 2000, was carried out using data extracted from the TB notification registry and clinical records of the TBCU. Demographic, social, clinical and disease characteristics of patients with reported cough of duration less than, and exceeding, the median duration for the study population were compared., Results: The median duration of cough reported at TB notification was 4 weeks (range, 1-156 weeks). By multivariate analysis, patients with cough > 4 weeks were more likely to be < 65 years old (adjusted odds ratio (OR), 1.8; 95% CI, 1.1-2.9; P = 0.02), of Chinese ethnicity (adjusted OR, 2.0; 95% CI, 1.2-3; P = 0.004), more likely to be sputum acid-fast bacilli smear-positive (adjusted OR, 1.7; 95% CI, 1.1-2.7; P = 0.016), and to have weight loss (adjusted OR, 2.6; 95% CI, 1.7-4; P < 0.01)., Conclusion: Further studies are needed to identify the possible reasons for delayed diagnosis of TB among those < 65 years old, in the Chinese population in Singapore.

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.

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.