Poor agreement between diagnostic tests for latent tuberculosis infection among HIV-infected persons in Hong Kong.

BACKGROUND AND OBJECTIVE: The tuberculin skin test (TST), T-Spot.TB (T-Spot) and QuantiFERON-TB Gold-In Tube (QFT) were compared in diagnosing latent tuberculosis infection (LTBI) among human immunodeficiency virus (HIV)-infected persons. METHODS: Human immunodeficiency virus-infected persons without previous history of tuberculosis or LTBI were simultaneously tested by TST, T-Spot and QFT annually and followed up for tuberculosis. RESULTS: Among 110 HIV-infected subjects with 85% previous TST screening coverage, 75% on anti-retroviral therapy, well-preserved median CD4 count (414/µL) and low median viral load (<75/µL), baseline TST, T-Spot and QFT were positive in 5.5%, 5.6% and 4.9%, respectively, with almost complete discordance of positive results. Among 91 (83%), 66 (60%) and 26 (24%) subjects successfully undergoing the first, second and third annual retesting, TST, T-Spot and QFT were, respectively, positive in 11/123 (8.9%), 13/173 (7.5%) and 21/182 (11.5%) on retesting, with similar discordance of positive results. There was no significant association with the concurrent CD4 count or viral load. Conversion occurred in 11/123 (8.9%), 8/160 (5.0%) and 18/168 (10.7%) of TST, T-Spot and QFT, respectively, and none was associated with changes in CD4 count or viral load. More than half of the positive T-SPOT and QFT results reverted to negative on follow-up. None of these tests picked up the single case of culture-confirmed tuberculosis observed after 798 person-years of follow-up. CONCLUSION: Major discordance in positive results, high reversion rates and low tuberculosis incidence among test-positive subjects cast serious doubt on the utility of the currently available LTBI tests in the annual screening of HIV-infected persons in an intermediate tuberculosis burden area.

T-Spot.TB outperforms tuberculin skin test in predicting development of active tuberculosis among household contacts.

BACKGROUND AND OBJECTIVE: In Hong Kong, neonatal Bacillus Calmette-Guerin (BCG) vaccination is practiced with 99% coverage. This study was to compare the performance of T-Spot.TB and tuberculin skin test (TST) in predicting tuberculosis (TB) among household contacts. METHODS: From 1 March 2006 to 31 July 2010, 1049 asymptomatic household contacts of smear-positive patients were simultaneously tested with T-Spot.TB and TST, and then followed for up to 5 years for development of TB. Attending clinicians and subjects were blinded to the results of T-Spot.TB. RESULTS: T-Spot.TB gave a significantly higher positive rate (32.7% vs 22.1%) and better association with exposure time than TST at the 15 mm cut-off. Agreement between T-Spot.TB and TST using cut-offs of 5, 10 and 15 mm were relatively poor (kappa 0.25-0.41) irrespective of presence or absence of BCG scar. Only T-Spot.TB positivity was negatively associated with BCG scar. Both T-Spot.TB (incidence rate ratio between test-positive and test-negative subjects, IRR: 8.2) and TST (IRR: 4.1, 6.1 and 2.8, using cut-offs of 5 mm, 10 mm and 15 mm, respectively) helped to predict TB. Using a TST cut-off of 15 mm, 56% of future TB cases and 62.5% of bacteriologically confirmed cases were missed. Lowering the TST cut-off to 10 mm or 5 mm could achieve sensitivity comparable with that of T-Spot.TB, but at the expense of lower specificities, with more positive tests (thus requiring treatment) per case of TB predicted. CONCLUSIONS: T-Spot.TB outperformed TST in predicting TB among household contacts in a high-income area with widespread BCG vaccination coverage.

WHO group 5 drugs and difficult multidrug-resistant tuberculosis: a systematic review with cohort analysis and meta-analysis.

It is often necessary to include WHO group 5 drugs in the treatment of extensively drug-resistant tuberculosis (XDR-TB) and fluoroquinolone-resistant multidrug-resistant tuberculosis (MDR-TB). As clinical evidence about the use of group 5 drugs is scarce, we conducted a systematic review using published individual patient data. We searched PubMed and OvidSP through 7 April 2013 for publications in English to assemble a cohort with fluoroquinolone-resistant MDR-TB treated with group 5 drugs. Favorable outcome was defined as sputum culture conversion, cure, or treatment completion in the absence of death, default, treatment failure, or relapse. A cohort of 194 patients was assembled from 20 articles involving 12 geographical regions. In descending order of frequency, linezolid was used in treatment of 162 (84%) patients, macrolides in 84 (43%), clofazimine in 65 (34%), amoxicillin with clavulanate in 56 (29%), thioridazine in 18 (9%), carbapenem in 16 (8%), and high-dose isoniazid in 16 (8%). Cohort analysis with robust Poisson regression models and random-effects meta-analysis similarly suggested that linezolid use significantly increased the probability (95% confidence interval) of favorable outcome by 57% (10% to 124%) and 55% (10% to 121%), respectively. Defining significant associations by risk ratios ≥ 1.2 or ≤ 0.9, neither cohort analysis nor meta-analysis demonstrated any significant add-on benefit from the use of other group 5 drugs with respect to outcome for patients treated with linezolid, although selection bias might have led to underestimation of their effects. Our findings substantiated the use of linezolid in the treatment of XDR-TB or fluoroquinolone-resistant MDR-TB and call for further studies to evaluate the roles of other group 5 drugs.

Can intermittent dosing optimize prolonged linezolid treatment of difficult multidrug-resistant tuberculosis?

We evaluated treatment with linezolid, dosed at 800 mg once daily for 1 to 4 months as guided by sputum culture status and tolerance and then at 1,200 mg thrice weekly until ≥ 1 year after culture conversion, in addition to individually optimized regimens among 10 consecutive patients with extensively drug-resistant tuberculosis or fluoroquinolone-resistant multidrug-resistant tuberculosis. All achieved stable cure, with anemia corrected and neuropathy stabilized, ameliorated, or avoided after switching to intermittent dosing. Serum linezolid profiles appeared better optimized.

Association of polymorphisms in the Chr18q11.2 locus with tuberculosis in Chinese population.

A GWAS study has reported that two single nucleotide polymorphisms (SNPs) were associated with predisposition to tuberculosis (TB) in African populations. These two loci represented the long-waited GWAS hits for TB susceptibility. To determine whether these two SNPs are associated with TB in Chinese population, we attempted an replication in a cohort of over one thousand Chinese TB patients and 1,280 healthy controls using melting temperature shift allele-specific genotyping analysis. We found that only SNP rs4331426 was significantly associated with TB in Chinese population (p = 0.011). However, the effect was opposite. The G allele of the SNP in Chinese population is a protective allele (OR = 0.62, 95 % CI 0.44-0.87), while it was the risk allele for African population (OR = 1.19, 95 % CI 1.12-1.26). No significance was found for SNP rs2335704. The results provided an independent support for a role in susceptibility to TB for SNP rs4331426. However, it also indicated that direct predisposition element to TB and the association effects may vary across ethnic groups.

CISH and susceptibility to infectious diseases.

BACKGROUND: The interleukin-2-mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling. METHODS: Using a case-control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections. RESULTS: We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P=3.8x10(-11) for all comparisons), with -292 accounting for most of the association signal (P=4.58x10(-7)). Peripheral-blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production--that is, 25 to 40% less CISH expression. CONCLUSIONS: Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.

Transmission of multidrug-resistant and extensively drug-resistant tuberculosis in a metropolitan city.

Multidrug-resistant (MDR)- tuberculosis (TB) and extensively drug resistant (XDR)-TB reportedly lead to increased household transmission. This is a retrospective cohort study of active TB occurring among household contacts exposed to MDR-TB. Of 704 contacts in 246 households, initial screening identified 12 (1.7%) TB cases (prevalent cases) and 17 (2.4%) contacts that subsequently developed active TB (secondary cases) after a median (range) duration of 17 (5-62.5) months. Eight prevalent cases and three secondary cases had MDR-TB. TB incidence rates per 100,000 person-years were 254.9 overall and 45.0 for MDR-TB. XDR-TB in the index MDR-TB patient significantly increased the odds of identifying a prevalent TB case to 4.8 (95% CI 1.02-22.5), and the hazard of finding a secondary TB case to 4.7 (95% CI 1.7-13.5). Molecular fingerprinting confirmed household transmission of MDR-TB. Of 20 retrievable isolates from 27 XDR-TB index cases, restriction fragment length polymorphism analysis showed clustering among 13 (65%), with 11 (55%) due to recent transmission by n-1 method and an identifiable household source in only three (27.2%) of the 11 cases. XDR-TB relative to MDR-TB significantly increases household transmission of TB, probably reflecting prolonged/higher infectivity, and indicating a need for prolonged household surveillance. XDR-TB may largely transmit outside of the household settings.

Pyrazinamide may improve fluoroquinolone-based treatment of multidrug-resistant tuberculosis.

The role of pyrazinamide in the current treatment of multidrug-resistant (MDR) tuberculosis (TB) is uncertain. From a territory-wide registry of MDR-TB cases diagnosed between 1995 and 2009, we assembled a cohort of 194 patients with MDR pulmonary TB given fluoroquinolone-containing regimens. Stratified by pyrazinamide use and susceptibility, there were 83 users with pyrazinamide-susceptible MDR-TB (subgroup A), 24 users with pyrazinamide-resistant MDR-TB (subgroup B), 40 nonusers with pyrazinamide-susceptible MDR-TB (subgroup C), and 47 nonusers with pyrazinamide-resistant MDR-TB (subgroup D). We estimated the adjusted risk ratio (ARR) of early sputum culture conversion (ARR-culture) that occurred within 90 days posttreatment and that of cure or treatment completion (ARR-success) that occurred by 2 years posttreatment due to pyrazinamide use with susceptibility. In comparison with subgroup B, ARR-culture and ARR-success were 1.38 (95% confidence interval [CI], 0.89 to 2.12) and 1.38 (95% confidence interval [CI], 0.88 to 2.17), respectively. Corresponding findings were 0.99 (95% CI, 0.81 to 1.22) and 0.99 (95% CI, 0.78 to 1.26) in comparison with subgroup C and 1.09 (95% CI, 0.84 to 1.42) and 0.94 (95% CI, 0.74 to 1.20) in comparison with subgroup D. Early culture conversion significantly increased the incidence proportion of cure or treatment completion by 71% (95% CI, 26% to 133%). Selection bias among pyrazinamide nonusers might have underestimated the role of pyrazinamide. Comparison of pyrazinamide users showed that pyrazinamide increased the incidence proportion of early culture conversion and that of cure or treatment completion by a best estimate of 38% for both. This magnitude of change exceeded the 15 to 20% increase in the 2-month culture conversion rate of drug-susceptible TB that results from adding pyrazinamide to isoniazid and rifampin. Pyrazinamide is likely important in fluoroquinolone-based treatment of MDR-TB.

T-Spot.TB outperforms tuberculin skin test in predicting tuberculosis disease.

RATIONALE: Silicosis is a well-recognized risk factor for tuberculosis (TB). OBJECTIVES: To compare T-Spot.TB with tuberculin skin test (TST) in predicting the development of TB. METHODS: Male patients with silicosis without clinical suspicion of active TB, past history of TB, and treatment for latent TB infection (LTBI) were offered both T-Spot.TB and TST in the Pneumoconiosis Clinic of Hong Kong from 2004 to 2008, and followed prospectively until September 30, 2009, for development of TB. MEASUREMENTS AND MAIN RESULTS: Active TB and culture- or histology-confirmed TB developed in 17 (5.5%) and 14 (4.5%) of 308 recruited subjects at an annual rate of 2,247 and 1,851 per 100,000 person-years, respectively. Active TB occurred in 7.4% (15 of 204) and 1.9% (2 of 104) of T-Spot.TB-positive and -negative subjects, respectively, whereas the corresponding figures for TST (cutoff 10 mm) were 6.4% (13 of 203) and 3.9% (4 of 205), respectively. A positive T-Spot.TB test significantly predicted the subsequent development of active TB (relative risk, 4.50; 95% confidence interval, 1.03-19.68) and culture- or histology-confirmed TB (relative risk, 7.80; 95% confidence interval, 1.02-59.63). Consistent results were obtained after exclusion of subjects treated for LTBI and adjustment for potential confounders. TST did not significantly predict the development of active TB or culture- or histology-confirmed TB, irrespective of the cutoff values with or without exclusion of subjects treated for LTBI. Culture filtrate protein 10 spot count, but not early secretary antigenic target 6 spot count, was significantly associated with subsequent TB development. CONCLUSIONS: T-Spot.TB performs better than TST in the targeted screening of LTBI among patients with silicosis.

Choice of spirometric reference values for compensation assessment.

BACKGROUND AND OBJECTIVE: Two sets of local reference values are available for spirometry in Hong Kong, but it is uncertain how well they work in the assessment of occupational lung diseases. This study examined their relative performance in the compensational assessment of silicosis. METHODS: Local reference values published in 1982 and 2006 were compared in two different populations comprising normal construction/quarry workers and silicosis patients. Only men aged 20-74 years were included. RESULTS: The FVC results of 93 normal workers were significantly higher than those predicted by either the 1982 or the 2006 reference values. Compared with the 1982 reference values, the mean FEV(1)% or FVC% was age-dependent and 5.2% higher in the normal workers. Smoking decreased the forced expiratory ratio, but did not show a major effect on FEV(1) or FVC among asymptomatic subjects. Despite their derivation largely from never-smokers, the 2006 reference values better predicted FEV(1) and FVC among all smoking categories. Among the 357 silicosis patients, the 1982 reference values also gave 8.8% higher FEV(1)% and 7.4% higher FVC%. These spirometric values differed by more than 10% in patients aged 60 years or more. Despite the presence of disease, the mean FVC% was still significantly above 100%. CONCLUSIONS: Both the 1982 and 2006 local reference values underestimated the FVC of normal construction and quarry workers, reflecting possible occupational selection factors. The 2006 reference values outperformed the 1982 ones, especially among older subjects. Careful calibration with similar occupational groups in the same laboratory is highly desirable in the choice of spirometric reference values for compensation assessment. Smoking does not appear to affect this choice.

Tuberculin skin test reaction and body mass index in old age home residents in Hong Kong.

OBJECTIVES: To study the relationship between body mass index (BMI) and tuberculin skin test (TST) reaction in predicting the development of active tuberculosis (TB). DESIGN: A follow-up study. SETTING: Old age homes. PARTICIPANTS: Three thousand six hundred five residents who took part in a screening program for TB and had two-step TST using two units of the tuberculin PPD-RT23. MEASUREMENTS: Rate of development of active TB in these residents over an average follow-up period of 2.5+/-1.25 years. RESULTS: After one-step and two-step testing, 46.3% and 69.6% of residents, respectively, had positive TST reactions (> or =10 mm). Thirty-four residents developed active TB (323 per 100,000 person-years) during follow-up. The only significant risk factors associated with development of active TB were positive TST according to one-step testing (adjusted odds ratio (OR)=2.91, 95% confidence interval (CI)=1.26-6.74) and a BMI less than 18.5 (adjusted OR=3.15, 95% CI=1.45-6.86). Residents with a BMI less than 18.5 and a negative TST also had greater risk of active TB than residents with a BMI greater than 18.5 and negative TST (adjusted OR=4.36, 95% CI=1.04-18.3), whereas those with a positive TST had the highest risk (adjusted OR=10.2, 95% CI=2.63-39.4). Two-step testing increased the sensitivity but reduced the specificity of TST in identifying active TB on follow-up. CONCLUSION: In the elderly population, interpretation of TST should take into consideration the BMI of the individual. A positive TST according to one-step but not two-step testing was useful in predicting the development of active TB on follow-up.

Prevalence of tuberculous infection and active tuberculosis in old age homes in Hong Kong.

OBJECTIVES: To assess the prevalence of tuberculous infection and active tuberculosis (TB) in old age homes in Hong Kong and to determine whether there is institutional transmission in these homes. DESIGN: Cross-sectional. SETTING: Old age homes. PARTICIPANTS: Total of 2,243 residents, representing 84.6% of all residents in 15 old age homes; 1,698 were women, and 545 were men, with an average age of 82. MEASUREMENTS: All residents had a questionnaire-based interview, medical record review, two-stage tuberculin testing using two units purified protein derivative-RT23, and a chest x-ray. Those with radiological abnormalities had sputum examined for acid-fast bacilli. RESULTS: The estimated prevalence rate of active TB in this population was 669 per 100,000, significantly higher in men than in women (1,101 per 100,000 vs 530 per 100,000). The proportion with positive tuberculin reactivity (> or =10 mm induration) after two-stage testing was 68.6%, significantly higher in men than in women. There was no evidence of active transmission of disease in these old age homes, with restriction fragment length polymorphism (RFLP) analysis performed on five cases of active pulmonary TB in the home with the highest rate of TB showing unique RFLP patterns. CONCLUSION: The rate of active TB and TB infection in old age homes in Hong Kong is still high. Because treatment for latent TB carries a high risk for liver dysfunction in this population, clinicians and other healthcare workers need a high index of suspicion and to diagnose and treat this disease as early as possible to prevent transmission.

Risk of active tuberculosis among schoolchildren in Hong Kong.

OBJECTIVE: To estimate the risk of active tuberculosis (TB) and its implication on preventive treatment among BCG-vaccinated schoolchildren. DESIGN: Cohort and case-control designs. SETTING: Community settings in a high-prevalence area. PARTICIPANTS: Children in primary school. The main exposure was their tuberculin response. MAIN OUTCOME MEASURES: Of 94,928 primary schoolchildren tuberculin tested during a routine school revaccination program in 1999, 656 with a tuberculin response at 20 mm or more were followed up prospectively through the territory-wide TB registry up to December 31, 2003, for the development of TB. In a separate case-control analysis, the tuberculin responses of children who subsequently had active TB (at the age of 10-15 years) were compared with those of their sex- and age-matched classmates to ascertain the relative risks of TB for different tuberculin reaction categories. The absolute and relative risks were applied to the 1999 cohort for estimating the incidence of TB among different tuberculin reactors. RESULTS: The annual incidence (95% confidence interval) of active TB was estimated to be 13.4 (5.6-40.6) per 100,000 for the entire cohort and 7.5 (2.4-24.5), 7.5 (1.7-32.0), 16.0 (4.4-57.2), 92.6 (26.6-320.2), and 340.6 (163.3-626.4) per 100,000 for children with a tuberculin reaction at 0 to 4, 5 to 9, 10 to 14, 15 to 19, and 20 mm or more, respectively. By using 10 mm as the cutoff, 482 (95% confidence interval, 163-1391) children have to be treated to prevent a single case of active TB within 5 years. Treatment will cover 17.5% of the cohort, but prevent only 54.1% of all active TB cases. CONCLUSION: It is desirable to reexamine the existing screening method for BCG-vaccinated children from high-prevalence countries.

Diagnostic application of genotypic identification of mycobacteria.

This study evaluated conventional methods, GLC and three molecular tests, including 16S rRNA sequencing, for the identification of mycobacteria, and the experiences of the authors with the integration of these methods into a diagnostic clinical laboratory were also recorded. Of 1067 clinical isolates of mycobacteria identified by conventional tests, 365 were tested by Accuprobe hybridization assays and PCRs specific for Mycobacterium tuberculosis (MTB) complex or Mycobacterium avium complex (MAC), 202 were tested by 16S rRNA sequencing, and 142 were tested by GLC. Three runs of all tests were performed on a weekly basis. The identifications for 209 MTB complex and 118 MAC isolates obtained by species-specific PCR were in complete agreement with AccuProbe hybridization and conventional test results. The 16S rRNA sequence-based identification, at a similarity of > or =99 %, for 132 of 142 isolates was concordant with the identifications made by the biochemical methods, and for 134 isolates was concordant with the identifications made by GLC at species, group or complex level. 16S rRNA sequencing resulted in fewer incorrectly identified or unidentified organisms than GLC or conventional tests. For the slowly growing non-tuberculous mycobacteria, the mean turnaround times for identification were 4-5 days for 16S rRNA sequencing, 14-29 days for GLC and 22-23 days for conventional methods. Considering the large proportion of some species among clinical isolates, a strategy of initial screening with species-specific PCR (or AccuProbe assays) for the MTB complex and MAC, followed by direct sequencing of the strains that yield negative results, should make 16S rRNA sequencing more affordable for routine application in diagnostic laboratories.

Seasonal pattern of tuberculosis in Hong Kong.

BACKGROUND: Summer predominance of tuberculosis (TB) was reported previously in temperate regions. No consistent data were available for lower latitudes. METHOD: The monthly TB notification data in Hong Kong from 1991 to 2002 were examined for seasonal fluctuation. A seasonal model was then developed after standardization by period, sex, age, history of TB, form of disease, and bacteriological status. RESULTS: The raw monthly counts showed remarkably consistent seasonal fluctuation across different periods, sexes, and age groups. A sine model was fitted for 82 104 notifications (adjusted R(2) = 0.373, P < 0.001). A summer peak was observed with seasonal fluctuation of 18.4% (P < 0.001), which was substantially higher than that reported previously for temperate regions. The amplitudes of fluctuation were 35.0, 15.0, 19.0, and 20.2% for those aged < or =14, 15-34, 35-64, and >/=65 years, respectively (all P < 0.001). No gender difference was noted (18.2% vs 19.0%, P = 0.790). Seasonal pattern was detected among new cases (18.6%, P < 0.001), but not retreatment cases (5.2%, P = 0.333). Culture-positive cases showed greater fluctuation than culture-negative cases (29.4% vs 6.4%, P < 0.001). No significant difference was found between pulmonary and extrapulmonary cases (16.8% vs 21.6%, P = 0.356). TB cases notified in summer were more likely to be smear-positive [odds ratio (OR) 1.100, 95% confidence interval (CI) 1.045-1.158, P < 0.001] and culture-positive (OR 1.175, 95% CI 1.121-1.232, P < 0.001) than those notified in winter, even after stratification by other key variables. CONCLUSION: A consistent seasonal pattern was found, with variable amplitudes of fluctuation in different subgroups and differing disease characteristics in different seasons. These observations are suggestive of the presence of a seasonal disease-modifying factor.