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Objective: To assess the risk factors and effects of delayed diagnosis on tuberculosis (TB) mortality in Hong Kong., Methods: All consecutive patients with TB notified in 2010 were tracked through their clinical records for treatment outcome until 2012. All TB cases notified or confirmed after death were identified for a mortality survey on the timing and causes of death., Results: Of 5092 TB cases notified, 1061 (20.9%) died within 2 years of notification; 211 (4.1%) patients died before notification, 683 (13.4%) died within the first year, and 167 (3.3%) died within the second year after notification. Among the 211 cases with TB notified after death, only 30 were certified to have died from TB. However, 52 (24.6%) died from unspecified pneumonia/sepsis possibly related to pulmonary TB. If these cases are counted, the total TB-related deaths increases from 191 to 243. In 82 (33.7%) of these, TB was notified after death. Over 60% of cases in which TB diagnosed after death involved patients aged ≥80 years and a similar proportion had an advance care directive against resuscitation or investigation. Independent factors for TB notified after death included female sex, living in an old age home, drug abuse, malignancy other than lung cancer, sputum TB smear negative, sputum TB culture positive, and chest X-ray not done., Conclusions: High mortality was observed among patients with TB aged ≥80 years. Increased vigilance is warranted to avoid delayed diagnosis and reduce the transmission risk, especially among elderly patients with co-morbidities living in old age homes.

Introduction: Pleural fluid adenosine deaminase level can be applied to rapidly detect tuberculous pleural effusion. We aimed to establish a local diagnostic cut-off value for pleural fluid adenosine deaminase to identify patients with tuberculous pleural effusion, and optimise its utility., Methods: We retrospectively reviewed the medical records of consecutive adults with pleural fluid adenosine deaminase level measured by the Diazyme commercial kit (Diazyme Laboratories, San Diego [CA], United States) during 1 January to 31 December 2011 in a cluster of public hospitals in Hong Kong. We considered its level alongside early (within 2 weeks) findings in pleural fluid and pleural biopsy, with and without applying Light's criteria in multiple scenarios. For each scenario, we used the receiver operating characteristic curve to identify a diagnostic cut-off value for pleural fluid adenosine deaminase, and estimated its positive and negative predictive values., Results: A total of 860 medical records were reviewed. Pleural effusion was caused by congestive heart failure, chronic renal failure, or hypoalbuminaemia caused by liver or kidney diseases in 246 (28.6%) patients, malignancy in 198 (23.0%), non-tuberculous infection in 168 (19.5%), tuberculous pleural effusion in 157 (18.3%), and miscellaneous causes in 91 (10.6%). All those with tuberculous pleural effusion had a pleural fluid adenosine deaminase level of ≤100 U/L. When analysis was restricted to 689 patients with pleural fluid adenosine deaminase level of ≤100 U/L and early negative findings for malignancy and non-tuberculous infection in pleural fluid, the positive predictive value was significantly increased and the negative predictive value non-significantly reduced. Using this approach, neither additionally restricting analysis to exudates by Light's criteria nor adding closed pleural biopsy would further enhance predictive values. As such, the diagnostic cut-off value for pleural fluid adenosine deaminase is 26.5 U/L, with a sensitivity of 87.3%, specificity of 93.2%, positive predictive value of 79.2%, negative predictive value of 96.1%, and accuracy of 91.9%. Sex, age, and co-morbidity did not significantly affect prediction of tuberculous pleural effusion using the cut-off value., Conclusion: We have established a diagnostic cut-off level for pleural fluid adenosine deaminase in the diagnosis of tuberculous pleural effusion by restricting analysis to a level of ≤100 U/L, and considering early pleural fluid findings for malignancy and non-tuberculous infection, but not Light's criteria.

Objective: To examine the impact of immigrant populations on the epidemiology of tuberculosis in Hong Kong., Design: Longitudinal cohort study., Setting: Hong Kong., Participants: Socio-demographic and disease characteristics of all tuberculosis notifications in 2006 were captured from the statutory tuberculosis registry and central tuberculosis reference laboratory. Using 2006 By-census population data, indirect sex- and age-standardised incidence ratios by place of birth were calculated. Treatment outcome at 12 months was ascertained from government tuberculosis programme record forms, and tuberculosis relapse was tracked through the notification registry and death registry up to 30 June 2013., Results: Moderately higher sex- and age-standardised incidence ratios were observed among various immigrant groups: 1.06 (Mainland China), 2.02 (India, Pakistan, Bangladesh), 1.59 (Philippines, Thailand, Indonesia, Nepal), and 3.11 (Vietnam). Recent Mainland migrants had a lower sex- and age-standardised incidence ratio (0.51 vs 1.09) than those who immigrated 7 years ago or earlier. Age younger than 65 years, birth in the Mainland or the above Asian countries, and previous treatment were independently associated with resistance to isoniazid and/or rifampicin. Older age, birth in the above Asian countries, non-permanent residents, previous history of treatment, and resistance to isoniazid and/or rifampicin were independently associated with poor treatment outcome (other than cure/treatment completion) at 1 year. Birth outside Hong Kong was an independent predictor of relapse following successful completion of treatment (adjusted hazard ratio=1.76; 95% confidence interval, 1.07-2.89; P=0.025)., Conclusion: Immigrants carry with them a higher tuberculosis incidence and/or drug resistance rate from their place of origin. The higher drug resistance rate, poorer treatment outcome, and excess relapse risk raise concern over secondary transmission of drug-resistant tuberculosis within the local community.

Setting: Elderly persons living in the community in Hong Kong., Objective: To examine the association between tuberculosis (TB) and lung cancer., Design: Elderly clients enrolled in a health programme from 2000 to 2003 were retrospectively cross-matched with the territory-wide TB notification registry for TB before enrolment. The cohort was followed up prospectively through linkage with the territory-wide death registry for cause of death until 31 December 2011. All subjects with suspected malignancy or recent weight loss (≥5%) at enrolment and deaths within the first 2 years of follow-up were excluded., Results: Of the 61,239 subjects included, 516 had TB before enrolment. After 490,258 person-years of follow-up, respectively 1344, 910 and 2003 deaths were caused by lung cancer, other tobacco-related malignancies and non-tobacco-related malignancies. TB before enrolment was associated with death due to lung cancer (Mantel-Haenszel weighted relative risk 2.61, 95%CI 1.82-3.74, P < 0.001) but not other malignancies after stratification by sex. TB remained an independent predictor of lung cancer death (adjusted hazard ratio 2.01, 95%CI 1.40-2.90; P < 0.001), after adjustment for multiple potential confounders., Conclusions: TB was independently associated with subsequent mortality due to lung cancer. This finding calls for intensification of tobacco control and better targeting of lung cancer screening in high TB burden areas.

IN THIS YEAR-IN-REVIEW ARTICLE, we summarizes 104 articles published on tuberculosis in the International Journal of Tuberculosis and Lung Disease from the January to the August issue in 201, and arbitrarily categorise them according to three subject areas: active TB, latent TB infection (LTBI),and operational research.

Background: In Hong Kong there has been nearly universal neonatal BCG vaccination coverage since 1980., Method: 21 113 schoolchildren aged 6-9 years were skin tested with one unit of tuberculin (PPD RT-23) using the intradermal technique during a routine BCG revaccination programme. Information on sex, date of birth, date of tuberculin testing, and tuberculin reaction size at 72 hours was retrieved. The annual risk of tuberculous infection (ARTI) was estimated by three different approaches., Results: Significantly higher tuberculin positive rates were found in girls and with increasing age at all commonly used cut-off points (5, 10, and 15 mm). Using a cut-off point of > or =10 mm and the formula 1- (1 - tuberculin positive rate)(1/age), the ARTI was estimated to be 1.93% (95% CI 1.84 to 2.03) for girls and 1.41% (95% CI 1.33 to 1.50) for boys. Using the differences in the tuberculin positive rate between the 6-7 year and 8-9 year age groups, the ARTI became 1.90% (95% CI 1.09 to 2.70) and 1.84% (95% CI 1.15 to 2.54) for girls and boys, respectively. When the prevalence of infection was estimated by locating a secondary peak of the tuberculin reaction distribution curve at 15 mm and assuming a symmetrical distribution of reaction sizes among those infected around this peak, the corresponding ARTI was much lower at 0.52% (95% CI 0.46 to 0.59) and 0.43% (95% CI 0.37 to 0.49) for girls and boys, similar to that estimated indirectly from the prevalence of disease., Conclusion: The ARTI as estimated by conventional methods was unexpectedly high among BCG vaccinated children and did not agree with that anticipated from the annual incidence of active disease. Further studies are needed to address the discrepancies, including the possible interaction between BCG and other environmental stimuli.

Background: Relatively little is known about the impact of socio-economic factors on tuberculosis in a metropolitan city with high disease incidence., Method: District-specific tuberculosis notification rates for 1995--1997 and 2000--2002 were indirectly sex- and age-adjusted and compared with the socio-economic characteristics in the 1996 by-census and 2001 census., Results: The differences between the 18 districts persisted after 3-year averaging and indirect standardisation. Only the percentage of population born locally, the percentage of the population widowed or divorced and the percentage of households residing in rooms or bedsits were consistently associated with the standardised notification ratios (SNR) for both periods, the first being negatively so (all P < 0.05). In a combined analysis with a general linear model for both periods, birth in China, residence <7 years, speaking other Asian languages, being married and in a single household were also significantly associated with the SNR (all P < 0.05). Using a backward conditional approach, only local birth, being married, and residing in rooms or bedsits were independent predictors of SNR (all P < 0.05). There was no significant association between SNR and socio-economic indices on education, occupation, unemployment and income., Conclusion: Socio-economic factors other than simple poverty are affecting the district-specific tuberculosis rates in Hong Kong.

Objective: To study the relationship between smoking and tuberculosis in Hong Kong., Method: Indirect sex and age adjustment was used to compare the prevalence of ever smokers between a sample of 851 patients from the 1996 tuberculosis notification registry and the general population. The clinical characteristics of smokers and non-smokers were compared by stratified univariate analysis and multiple logistic regression., Results: Tuberculosis patients were more likely to have smoked than population controls. The respective odds ratios for ever smoking between tuberculosis patients and population controls were 2.44 and 2.08 for males and females aged 16-64 (Mantel-Haenszel weighted OR = 2.40, P < 0.001), and 2.09 and 2.83 for males and females aged > or = 65 (Mantel-Haenszel weighted odds ratio = 2.19, P < 0.001). Male sex, age > or = 65, working at onset of illness, regular alcohol use, drug abuse and absence of contact history were associated with ever smokers (all P < 0.05). Ever smokers were more likely to have cough (OR 1.69), dyspnoea (OR 1.84), upper zone involvement (OR 1.67), cavity (OR 1.76), miliary lung involvement (OR 2.77), positive sputum culture (OR 1.43), but less isolated extrathoracic involvement (OR 0.31), even after controlling for the confounding background variables (all P < 0.05)., Conclusion: There was a consistent association between smoking and tuberculosis. More aggressive lung involvement was also found among ever smokers.

Setting: Revaccination of tuberculin-negative school-children is a regular practice in Hong Kong., Objective: To assess the efficacy of BCG revaccination guided by tuberculin skin testing., Method: A cohort of 303,692 children vaccinated at birth was followed through the tuberculosis notification register for the development of active disease. The percentage of cohort who participated in the BCG revaccination program during primary school was estimated from the vaccination statistics of the Hong Kong Department of Health. The BCG revaccination history of identified cases was ascertained through vaccination cards and clinic records., Results: A total of 85.2% of the cohort participated in the BCG revaccination programme; 79.7% of the participants were tuberculin-negative and revaccinated; 343 developed tuberculosis after the age of 11; 302 were among the participants in the programme while 41 were not. The tuberculosis incidence was 16.5 and 12.9 per 100,000 person-years for participants and non-participants, respectively (RR 1.28, 95%CI 0.92-1.77). Among the participants, tuberculosis incidence was 12.5 and 32.0/100,000 person-years, respectively, for the tuberculin-negative/BCG revaccinated group and the tuberculin-positive/non-revaccinated group (RR 0.39, 95%CI 0.31-0.49)., Conclusion: This study failed to demonstrate any significant difference in the incidence rates of tuberculosis among participants and non-participants in a school BCG revaccination programme. The increased risk for tuberculosis in the tuberculin-positive group does not support the use of the tuberculin testing for detection of immunity conferred by neonatal BCG vaccination.

Setting: Hong Kong silicotic patients are followed regularly at the Pneumoconiosis Clinic., Objective: To quantify the incidence of tuberculosis disease that occurs after the date of diagnosis of silicosis (DOD), and to identify the risk factors for its development., Design: Retrospective analysis of a Hong Kong silicotic cohort with DOD from 1 January 1988 to 31 December 1993., Results: Of 718 subjects whose records were identified, 11 were excluded from the study. The incidence of tuberculosis (TB) after DOD was 3019 patients per 100,000 population, approximately nine times that of the local population matched for age and sex. Twelve factors were subject to univariate analysis followed by logistic regression. Four TB risk factors were identified: 1) no anti-tuberculosis treatment before DOD (relative risk [RR] 4.51, 95% confidence interval [CI] 2.46-8.24), 2) progressive massive fibrosis (PMF) (RR 3.78, 95%CI 2.25-6.36), 3) small opacities exceeding 1.5 mm (RR 2.17, 95%CI 1.38-3.42), and 4) caisson work (RR 1.56, 95%CI 1.01-2.41). Relative risks were calculated for patient subgroups stratified according to TB risk factors., Conclusion: This study has reaffirmed the strong association of tuberculosis and silicosis, and has identified several TB risk factors with a logistic regression model.

The clinical utility of therapeutic drug monitoring in tuberculosis has not been adequately evaluated by controlled clinical trials. To examine the relationship between slow culture conversion and peak plasma rifampicin level (Cmax-rfm) in a case-control study, patients with persistence of positive sputum smear despite at least 8 weeks of directly observed treatment with standard pyrazinamide-containing regimens were enrolled prospectively in government chest clinics from 16 December 2005 to 15 November 2006. Patients with multidrug-resistant tuberculosis, human immunodeficiency virus infection, or poor treatment adherence were excluded. Cases referred to patients with persistence of positive culture whereas controls had negative culture despite positive smear. Blood was checked at 2 and 4 hours post-dosing to capture Cmax-rfm. A cohort of 88 patients was identified. After excluding 16 patients, there were 36 controls and 36 cases. None had symptoms of malabsorption. Cmax-rfm was below 6 mg/l among 47% of controls and 44% of cases. Univariate and multiple logistic regression analyses showed no significant association between slow culture conversion and Cmax-rfm after logarithmic transformation. Thus, there is probably no association between Cmax-rfm and slow culture conversion. [ABSTRACT FROM AUTHOR]

Currently, linezolid is the only oxazolidinone recommended for treating multidrug-resistant tuberculosis (MDR TB), including extensively drug-resistant (XDR) TB [1], even though its prolonged use frequently results in serious adverse reactions, notably bone-marrow suppression and peripheral/optic neuropathy; the risk is significantly higher for daily dosage(s) exceeding 600 mg [2]. Linezolid-based regimens for multidrug-resistant tuberculosis (TB): a systematic review to establish or revise the current recommended dose for TB treatment. 13 S. Wasserman, G. Meintjes, G. Maartens, Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index, Expert Rev Anti Infect Ther, 14, 2016, 901-915 10.1080/14787210.2016.1225498Wasserman S, Meintjes G, Maartens G. Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index. [Extracted from the article]