Delayed diagnosis of tuberculosis: risk factors and effect on mortality among older adults in Hong Kong.

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.

Integrated pharmacokinetic, pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys.

QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb-ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates.

Immigrants and tuberculosis in Hong Kong.

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.

Tuberculosis is associated with increased lung cancer mortality.

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.

Obstructive lung disease does not increase lung cancer mortality among female never-smokers in Hong Kong.

SETTING: High lung cancer mortality is observed among female never-smokers in Hong Kong. OBJECTIVE: To examine the relationship between obstructive lung disease (chronic obstructive pulmonary disease and/or asthma) and lung cancer mortality by sex and smoking status. DESIGN: A cohort of elderly clients (aged ≥65 years) in a health maintenance programme were followed prospectively through linkage with the territory-wide death registry for causes of death, using identity card number as the unique identifier. RESULTS: After 516,055 person-years of follow-up, respectively 1297, 872 and 1908 deaths were caused by lung cancer, other tobacco-related malignancies and non-tobacco-related malignancies. In the overall analysis, obstructive lung disease was independently associated with mortality due to lung cancer (aHR 1.86, P < 0.001) after adjustment for potential confounders. However, no association was detected among female never-smokers (HR 0.97, P = 0.909), in sharp contrast with female ever-smokers, male never-smokers and male ever-smokers (HR 1.98, 2.34 and 2.09, respectively, P from 0.047 to <0.001). Consistent results were observed after exclusion of all deaths in the initial 3 years. CONCLUSION: Obstructive lung disease exerted differential effects on lung cancer mortality across different sex and smoking subgroups in this Asian population, with a conspicuous absence of effect among female never-smokers.

Risk factors for multidrug-resistant tuberculosis in Hong Kong.

SETTING: Previous anti-tuberculosis treatment is a widely reported risk factor for multidrug-resistant tuberculosis (MDR-TB), whereas other risk factors are less well described. In Hong Kong, the clinical characteristics of MDR-TB have not been systematically evaluated. OBJECTIVE: To explore the risk factors for MDR-TB in Hong Kong. DESIGN: MDR-TB patients treated between 1999 and 2003 were compared with non-MDR-TB patients by stratification of previous anti-tuberculosis treatment. RESULTS: One hundred and fifty-six MDR-TB patients, including 93 with and 63 without a previous history of anti-tuberculosis treatment, were identified. Among the 322 non-MDR-TB controls, respectively 192 and 130 patients did and did not have a previous history of anti-tuberculosis treatment. Using logistic regression analysis, non-permanent residents (OR 6.85, 95%CI 1.38-34.09), frequent travel (OR 2.48, 95%CI 1.07-5.74) and younger age were found to be independent predictors of MDR-TB in previously treated patients, whereas living on financial assistance just failed to reach statistical significance (OR 2.75, 95%CI 0.98-7.68, P=0.05). In the treatment-naïve group, despite significant differences in baseline characteristics among MDR-TB and non-MDR-TB patients, no independent predictor variables could be identified. CONCLUSION: In Hong Kong, non-permanent residents, frequent travel and young age were independent predictors of MDR-TB among previously treated patients.

Peak plasma rifampicin level in tuberculosis patients with slow culture conversion.

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.

Comparison of T-Spot.TB and tuberculin skin test among silicotic patients.

In the present study, T-Spot.TB and the tuberculin skin test (TST) were compared in the screening of latent tuberculosis infection among silicotic patients. A conditional probability model was used to compare the potential clinical utilities of T-Spot.TB and TST performed on 134 silicotic subjects from December 1, 2004 to January 31, 2007. Data from a historical cohort were also reanalysed for further comparison. Agreement with T-Spot.TB was best using a TST cut-off of 10 mm. Age >or=65 yrs independently predicted a tuberculin reaction <10 mm (odds ratio = 3), but not a negative T-Spot.TB response. Lower measures of agreement were observed among current smokers and those aged >or=65 yrs. Tuberculin reaction size was well correlated with both early secretary antigenic target 6 and culture filtrate protein 10 spot counts, except among current smokers. Within the current estimates of sensitivity (88-95%) and specificity (86-99%) for T-Spot.TB, the positive likelihood ratio for T-Spot.TB test would be substantially higher (6.29-95.0 versus 1.65-1.94) and negative likelihood ratio substantially lower (0.05-0.14 versus 0.32-0.41) than the corresponding ratios for the tuberculin test. A low tuberculosis risk differential was similarly observed between tuberculin-negative and untreated tuberculin-positive subjects in the historical cohort. T-Spot.TB is likely to perform better than tuberculin test in the screening of latent tuberculosis infection among silicotic subjects.

Smoking and tuberculosis among silicotic patients.

The aim of the present study was to investigate the relationship between smoking and tuberculosis (TB) among high-risk silicotic patients in Hong Kong. A cohort of 435 silicotic patients tuberculin tested from 1995-2002 was prospectively followed-up until the end of 2005. Baseline characteristics were analysed with respect to positive tuberculin reaction (> or =10 mm) at baseline and subsequent development of TB. Smoking, alcohol use and body mass index were independent predictors of positive tuberculin reaction at baseline in multiple logistic regression analysis. Total cigarette pack-yrs did not demonstrate any significant effect. The annual incidences of TB were 1,841, 2,294 and 4,181 per 100,000 for never-, ex- and current smokers, respectively. On Cox proportional hazard analysis, current smokers have a significantly higher risk of TB than other silicotic patients (adjusted hazard ratio (95% confidence interval (CI)): 1.96 (1.14-3.35)) after controlling for age, alcohol use, tuberculin status, treatment for latent TB infection and other relevant background/disease factors. A significant dose-response relationship was also observed with the daily number of cigarettes currently smoked. Smoking cessation may reduce 32.4% (95% CI: 6.5-54.0) of the risk. Smoking increases the risk of both tuberculosis infection and subsequent development of the disease among silicotic patients.

Tuberculin response in BCG vaccinated schoolchildren and the estimation of annual risk of infection in Hong Kong.

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.

Socio-economic factors and tuberculosis: a district-based ecological analysis in Hong Kong.

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.

Smoking and tuberculosis 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.

An unusual case of double tuberculous broncho-oesophageal fistulas in an adult.

Broncho-oesophageal fistula associated with tuberculosis is rarely reported in the literature and has not been reported in Hong Kong. We describe a 30-year-old Chinese human immunodeficiency virus (HIV)-negative man with double tuberculous broncho-oesophageal fistulas proven by histology. Constitutional symptoms of active tuberculosis were absent and chest radiograph did not show an obvious lung lesion. Our case shows that broncho-oesophageal fistula can be the sole manifestation of active tuberculosis and that the diagnosis should be suspected in patients who are seen with chronic respiratory symptoms in areas where the prevalence of tuberculosis is high.

Repeated fed-batch operations for microbial detoxification of mercury using wild-type and recombinant mercury-resistant bacteria.

A wild-type mercury-resistant strain Pseudomonas aeruginosa PU21 (Rip64), and an Escherichia coli PWS1 strain genetically engineered to harbor mercury resistance were examined for their capacity to detoxify soluble mercuric ions with repeated fed-batch operations. The specific mercury detoxification activity for the two strains at different initial mercury concentrations was determined by resting-cell experiments. The fed-batch operations were conducted with different initial culture volumes (Vo), inoculum sizes (Xo), and different mercury feeding rates (FHg) to investigate the effects of those operation parameters on the performance of mercury detoxification. The results showed that the wild-type and the recombinant strains had an optimal specific activity of 5 x 10(-7) and 8 x 10(-8) micrograms cell-1 h-1, respectively. In fed-batch operation for P. aeruginosa PU21, under the conditions of Vo = 400 ml and Xo = 4.5-4.8 x 10(9) cells ml-1 the overall mercury detoxification efficiency (eta) for FHg = 16.9 mg Hg h-1 was 5.26 mg Hg l-1 h-1, nearly 35% higher than that for a lower FHg (11.7 mg Hg h-1). Among the three initial culture volumes examined in this study, the highest eta (5.60 mg Hg l-1 h-1) was obtained when Vo = 1200 ml and FHg = 16.9 mg Hg h-1. It was also found that an inoculum size higher than 4.0 x 10(9) cells ml-1 enabled a stable fed-batch operation, while as the inoculum was reduced to around 1.6 x 10(9) cells ml-1, the mercury feeding caused severe cell death, leading to an unsuccessful fed-batch operation. In the fed-batch operation for E. coli PWS1 strain with Vo = 1200 ml and FHg = 16.9 mg Hg h-1, the mercury detoxification efficiency was 3.07 mg Hg l-1 h-1, only 54% of that for the wild-type P. aeruginosa PU21 strain under the same operating conditions. It was also noticed that the operation with E. coli PWS1 became less efficient at the second fed-batch cycle due to plasmid instability of the recombinant strain.

Development of microbial mercury detoxification processes using mercury-hyperresistant strain of Pseudomonas aeruginosa PU21.

A mercury-hyperresistant strain of Pseudomonas aeruginosa PU21 harboring plasmid Rip64 was utilized to develop bioprocesses able to detoxify and recover soluble mercuric ions in aquatic systems. The kinetics of mercury detoxification was investigated to determine the parameters needed for the design of the bioprocesses. Batch, fed-batch, and continuous bioreactors were utilized to evaluate the efficiency and feasibility of each mode of operation. The results showed that the specific mercury detoxification rate was dependent on cell growth phases, as well as the initial mercury concentrations. Cells at the lag growth phase exhibited the best specific detoxification rate of approximately 1.1 x 10(-6) microg Hg/cell/h, and the rate was optimal at an initial mercury concentration of 8 mg/L. In batch operations with initial mercuric ions ranging from 2 to 10 mg/L, the mercuric ions added were rapidly volatilized from the media in less than 2-3 h. With periodic feeding of 3 or 5 mg Hg/L at fixed time intervals, the fed-batch processes had mercury removal efficiencies of 2.9 and 3.3 mg Hg/h/L, respectively. For continuous operations, the effluent cell concentration (Xe) was essentially invariant at 527 and 523 mg/L with the dilution rates (D) of 0.18 and 0.325 h-1, respectively. The increase in mercury feeding concentrations (Hgf) from 1.0 to 6.15 mg Hg2+/L did not affect the steady-state cell concentration (Xe) but forced the effluent mercury concentration (Hge) to increase. The decrease in the dilution rate, however, resulted in lower Hge values. It was also found that sequential mercury vapor absorption columns recovered over 80% of the Hg degrees released from the bioreactor while the residual mercury vapor was subsequently immobilized by an activated carbon trap in the down stream of the absorption column.