Cynthia Bin Eng Chee

Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries

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. Guidelines on LTBI for low TB incidence countries – essential element of the @WHO #EndTB strategy and TB elimination http://ow.ly/RW8xn

Comparison of Sensitivities of Two Commercial Gamma Interferon Release Assays for Pulmonary Tuberculosis

ABSTRACT 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 (κ = 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 ≥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 ≥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.

Persistent air-leak in spontaneous pneumothorax — clinical course and outcome

Persistent air-leak in patients with spontaneous pneumothorax (SP) is not uncommon and may present a management dilemma in those who are unfit or unwilling for surgery. Video-assisted thoracoscopic surgery (VATS) has been advocated in the management of patients with broncho-pleural fistulae (air-leak persisting beyond 7 days): however the optimum time for surgical intervention remains unclear. We reviewed the records of 130 episodes of SP in 115 patients over a 2-year period to determine clinical course and outcome, particularly with respect to duration of air-leak. There were 90 first episodes and 40 recurrent episodes. Eighty-one episodes (62%) occurred in patients with underlying lung disease (secondary pneumothorax). Initial management consisted of chest-tube drainage in 104 episodes (80%) occurring in 90 patients, percutaneous needle aspiration in five patients (4%) and observation in 21 episodes (16%) in 20 patients. In the group treated with chest-tube drainage, there was spontaneous resolution of air leak and lung re-expansion in 90 episodes (87%). The overall incidence of broncho-pleural fistula was 34.6%. In the primary SP group. 75% of air-leaks ceased by 7 days and 100% by 15 days. In the secondary SP group, 61% of air-leaks resolved by 7 days and 79% by 14 days, after which time resolution of air-leak proceeded at a much slower rate. Five patients underwent surgery while nine patients were discharged with residual pneumothoraces. There were no major complications or mortality. Based on our findings, we advocate surgery for patients with air-leak persisting beyond 14 days, while favouring a conservative approach before this time, as the majority of air-leaks (especially in patients with primary pneumothorax) would resolve by 14 days.

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

The hypothesis that T-cell interferon-&ggr; responses to Mycobacterium tuberculosis-specific antigens decline as disease activity diminishes with tuberculosis (TB) treatment has generated interest in the interferon-&ggr; 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.

Diagnosis and treatment of latent infection with Mycobacterium tuberculosis.

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.

The Singapore Tuberculosis Elimination Programme: the first five years

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.

Use of a T Cell Interferon‐γ Release Assay to Evaluate Tuberculosis Risk in Newly Qualified Physicians in Singapore Healthcare Institutions

BACKGROUND Surveillance for latent tuberculosis in high-risk groups such as healthcare workers is limited by the nonspecificity of the tuberculin skin test (TST) in BCG-vaccinated individuals. The Mycobacterium tuberculosis antigen-specific interferon-gamma release assays (IGRAs) show promise for more accurate latent tuberculosis detection in such groups. OBJECTIVE To compare the utility of an IGRA, the T-SPOT.TB assay, with that of the TST in healthcare workers with a high rate of BCG vaccination. METHODS Two hundred seven medical students from 2 consecutive cohorts underwent the T-SPOT.TB test and the TST in their final year of study. Subjects with negative baseline test results underwent repeat testing after working for 1 year as junior physicians in Singapores 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.

A new asthma severity index: a predictor of near-fatal asthma?

Bronchial hyperresponsiveness (BHR), measured as the provocative dose of inhaled histamine or methacholine required to produce a 20% fall in forced expiratory volume in one second (FEV1) (PD20), is widely used as one of the indices of asthma severity. Excessive bronchoconstriction, reflected by the maximal percentage fall in forced vital capacity (FVC) at PD20 (deltaFVC %) during BHR testing, is considered to be the most important pathophysiological determinant in fatal asthma. The present study hypothesized that an index which combines both the ease of airway narrowing and excessive bronchoconstriction, deltaFVC %/log(PD20), may be better in assessing asthma severity, especially in those at risk of near-fatal attacks. The dose-response curves of 46 asthmatics who underwent methacholine challenge testing were studied. Group 1 (n=14) patients had mild disease, Group 2 (n=21) had moderate disease and Group 3 (n=11) had severe disease, as classified according to the Global Initiative for Asthma. Nine patients had prior intubation for near-fatal asthma. deltaFVC %/log (PD20) was better than deltaFVC % and PD20 in categorizing patients into the three severity groups (p<0.0001), but more importantly, it was able to discriminate patients with previous intubation from those without (p=0.04). It also correlated better with FEV1 (% predicted), frequency of symptoms and inhaled steroid requirement than either index alone. It is concluded that the percentage fall in forced vital capacity/log of the provocative dose causing a 20% fall in forced expiratory volume in one second combines information on the ease and excessive degrees of airway narrowing in asthma. This new index may be better at assessing asthma severity and in discriminating those at risk of near-fatal attacks.

Characteristics of patients with delayed diagnosis of infectious pulmonary tuberculosis.

Objective:  The aim of this study was to identify patient and disease characteristics associated with delayed diagnosis of infectious pulmonary tuberculosis (TB).

Interferon-γ responses to Mycobacterium tuberculosis-specific antigens in diabetes mellitus

To the Editor: Although diabetes mellitus has long been recognised as a risk factor for tuberculosis, it was only recently that strong evidence for this emerged [1]. Persons with diabetes mellitus have a two or three times higher risk of developing tuberculosis disease than nondiabetics; those with tuberculosis and diabetes mellitus have a four times higher risk of death during tuberculosis treatment and a higher risk of tuberculosis relapse [2, 3]. Diabetics therefore constitute a target group in whom the identification of latent tuberculosis infection (LTBI) and its treatment may potentially be an important strategy for tuberculosis elimination [4, 5]. Interferon-γ release assays (IGRAs) are immunodiagnostic tests for identification of LTBI. These tests have shown superior specificity and positive predictive value for progression to active disease over the tuberculin skin test [6–9]. Although the IGRAs do not distinguish active from latent tuberculosis [10, 11], they are often done as part of the work-up for active tuberculosis in cases where diagnostic uncertainty exists. To date, there is scant information in the literature regarding the performance of these assays in diabetics. In a previous report in which we evaluated the T-SPOT. TB (Oxford Immunotec, Abingdon, UK) and QuantiFERON In-Tube (QFT-IT) (Cellestis, Melbourne, Australia) assays in a head-to-head manner in 270 culture-confirmed pulmonary tuberculosis patients, we had found undiminished sensitivity of these assays in the presence of diabetes mellitus [12]. Walsh et al. [13] have also reported that diabetes did not affect the performance of the second-generation QuantiFERON TB Gold (QFT-G) and T-SPOT. TB …