Frank Cobelens

Rapid Diagnosis of Tuberculosis with the Xpert MTB/RIF Assay in High Burden Countries: A Cost-Effectiveness Analysis

A cost-effectiveness study by Frank Cobelens and colleagues reveals that Xpert MTB/RIF is a cost-effective method of tuberculosis diagnosis that is suitable for use in low- and middle-income settings.

Risk of infection with Mycobacterium tuberculosis in travellers to areas of high tuberculosis endemicity.

BACKGROUND No data exist on risks of infection with Mycobacterium tuberculosis in travellers. We studied incidences of and risk factors for tuberculin skin-test conversion among Dutch long-term travellers to countries of high tuberculosis endemicity. METHODS In a multicentre, prospective cohort study based in travel and tuberculosis clinics in the Netherlands, 1072 BCG-naive immunocompetent travellers to countries with an estimated annual risk of M. tuberculosis infection of at least 1% were skin tested before departure with 1 tuberculin unit purified protein derivative (PPD) of M. tuberculosis in Tween-80. Those with results less than 2 mm were retested 2-4 months after their return with simultaneous testing for cross-sensitivity to environmental mycobacteria (1 tuberculin unit PPD of M. scrofulaceum in Tween-80). M. tuberculosis infection was defined as a post-travel M. tuberculosis tuberculin skin-test result of at least 10 mm that was 3 mm or more larger than the M. scrofulaceum result. FINDINGS Post-travel skin-test results were available for 656 (66%) of 988 individuals who were eligible for follow-up. Among these, 12 M. tuberculosis infections were identified (1.8%). The overall incidence rate was 3.5 per 1000 person-months of travel (95% CI 2.0-6.2), and 2.8 per 1000 person-months of travel (1.2-5.5) after exclusion of health-care workers. Two had active tuberculosis at the time of testing (incidence rate 0.6 per 1000 person-months of travel [0.3-2.3]). Work in patient care abroad was an independent risk factor (adjusted rate ratio 5.34, p=0.015). INTERPRETATION The risk of M. tuberculosis infection in long-term travellers to high-endemicity countries, even if not engaged in health-care work, is substantial and of similar magnitude to the average risk for the local population. BCG vaccination or post-travel tuberculin skin-testing of high-risk travellers should be considered.

Interferon-gamma release assays for tuberculosis screening of healthcare workers: a systematic review

Healthcare workers (HCWs) are at increased risk of exposure to tuberculosis (TB). Traditionally, screening for latent TB infection (LTBI) is done using the tuberculin skin test (TST). Interferon-gamma release assays (IGRAs) are now increasingly being used for diagnosis of LTBI, but their role in HCW screening is unclear. A systematic review was conducted of all IGRA studies in HCWs to summarise their performance in cross-sectional and serial testing settings. By searching four electronic databases and other sources, all available studies using any one of the commercial IGRA assays in HCWs were retrieved and screened. 50 unique studies were identified which met the inclusion criteria including five from high TB incidence settings. Among 24 cross-sectional studies in low TB incidence settings, the pooled prevalence of positive IGRA using either test was significantly lower than for a positive TST. However, in high-incidence settings (n=2) there were no consistent differences in the prevalence of positive tests. IGRAs showed good correlation with occupational risk factors for TB exposure in low-incidence settings. Only 10 studies assessed use of IGRA for serial testing and all showed large variation in the rates of conversions and reversions, with no data suggesting that IGRAs are better at identifying the incidence of new TB infection than the TST. The use of IGRAs instead of TST for one-time screening may result in a lower prevalence of positive tests and fewer HCWs who require LTBI treatment, particularly in low TB incidence settings. However, the use of IGRAs for serial testing is complicated by lack of data on optimum cut-offs for serial testing and unclear interpretation and prognosis of conversions and reversions. Further longitudinal research will be required to inform guidelines on serial testing using IGRAs.

Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-γ release assays (IGRAs), QuantiFERON-TB® Gold In-tube (QFT-GIT) and T-SPOT.TB®, and the tuberculin skin test (TST) in immigrants contacts. Immigrant close contacts of sputum smear-positive TB patients were included when aged ≥16 yrs and their TST result was ≥5 mm 0 or 3 months after diagnosis of the index patient. Contacts were followed for the next 2 yrs for development of TB disease. Of 339 immigrant contacts with TST ≥5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB®, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB®. The PPV for progression to TB during this period was 9/288 = 3.1% (95% CI 1.3–5.0%) for TST ≥10 mm, 7/184 = 3.8% (95% CI 1.7–5.9%) for TST ≥15 mm, 5/178 = 2.8% (95% CI 1.0–4.6%) for QFT-GIT and 6/181 = 3.3% (95% CI 1.3–5.3%) for T-SPOT.TB®. Sensitivity was 100%, 88%, 63% and 75%, respectively. The predictive values of QFT-GIT, T-SPOT.TB® and TST for progression to TB disease among immigrant close contacts were comparable.

Incidence and risk factors of probable dengue virus infection among Dutch travellers to Asia

We studied the incidence of dengue virus (DEN) infections in a cohort of Dutch short‐term travellers to endemic areas in Asia during 1991–92. Sera were collected before and after travel. All post‐travel sera were tested for DEN immunoglobulin M (IgM) [IgM capture (MAC)‐enzyme‐linked immunosorbent assay (ELISA)] and IgG (indirect ELISA). Probable DEN infection was defined as IgM seroconversion or a fourfold rise in IgG ratio in the absence of cross‐reaction with antibody to Japanese encephalitis virus (JEV). Infections were considered clinically apparent in case of febrile illness (> 24 H) with headache, myalgia, arthralgia or rash. Probable DEN infection was found in 13 of 447 travellers (incidence rate 30/1000 person‐months, 95% CI 17.4–51.6). One infection was considered secondary; no haemorrhagic fever occurred. The clinical‐to‐subclinical infection rate was 1 : 3.3. The risk of infection showed marked seasonal variation. DEN infections are frequent in travellers to endemic areas in Asia; most remain subclinical.

Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment.

BACKGROUND Severe liver injury has been attributed to preventive treatment of latent tuberculosis infection with a 2-month course of rifampin-pyrazinamide. METHODS A retrospective cohort study in The Netherlands compared the hepatotoxicity of preventive treatment with rifampin-pyrazinamide with that of preventive treatment with isoniazid, and also with that of treatment for active tuberculosis containing at least isoniazid, rifampin, and pyrazinamide. RESULTS Preventive treatment with rifampin-pyrazinamide caused severe hepatotoxicity more often than did preventive treatment with isoniazid (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.26-5.39; P=.012), especially in patients <25 years old. It also caused severe hepatotoxicity more often than triple- or quadruple-drug tuberculosis treatment (OR, 2.61; 95% CI, 1.21-5.59; P=.016), especially if the pyrazinamide dose was > or =30 mg/kg. Preventive treatment with rifampin-pyrazinamide was more hepatotoxic even when the advised pyrazinamide dose of up to 20 mg/kg for preventive treatment was compared with the pyrazinamide dose of 30 mg/kg for tuberculosis treatment. CONCLUSIONS Preventive treatment with rifampin-pyrazinamide causes severe hepatotoxicity more often than does preventive treatment with isoniazid or curative treatment for tuberculosis.

National survey of tuberculosis prevalence in Viet Nam.

OBJECTIVE To estimate the prevalence of tuberculosis in Viet Nam with data from a population-based survey, compare it with the prevalence estimated by the World Health Organization, and identify major demographic determinants of tuberculosis prevalence. METHODS A cross-sectional survey with multistage cluster sampling, stratified by urban, rural and remote areas, was done in 2006-2007 in 70 communes. All inhabitants aged > or = 15 years were invited for cough and chest X-ray examination. Participants with findings suggestive of tuberculosis provided sputum specimens for smear examination and culture. Point prevalence estimates, 95% confidence intervals and design effects were calculated. Confidence intervals and P-values were adjusted for the cluster design. FINDINGS Of 114,389 adult inhabitants, 94 179 (82.3%) were screened. Of 87,314 (92.7%) screened by both questionnaire and chest X-ray, 3522 (4.0%) had productive cough, 518 (0.6%) had a recent history of tuberculosis and 2972 (3.4%) had chest X-ray abnormalities suggestive of tuberculosis. Sputum tests were done for 7648 participants. Sputum test, bacterial culture or both confirmed 269 tuberculosis cases, 174 of which were smear-positive. The prevalence rate of smear-positive tuberculosis was 145 per 100,000 (95% confidence interval: 110-180) assuming no tuberculosis in persons aged < 15 years. Prevalence was 5.1 times as high in men as in women, increased with age, was higher in rural than in urban or remote areas and showed a north-to-south gradient. CONCLUSION In Viet Nam, the tuberculosis prevalence rate based on positive sputum smear tests was 1.6 times as high as previously estimated. Age and sex patterns were consistent with notification data. Tuberculosis control should remain a high priority in Viet Nam.

Combined Species Identification, Genotyping, and Drug Resistance Detection of Mycobacterium tuberculosis Cultures by MLPA on a Bead-Based Array

The population structure of Mycobacterium tuberculosis is typically clonal therefore genotypic lineages can be unequivocally identified by characteristic markers such as mutations or genomic deletions. In addition, drug resistance is mainly mediated by mutations. These issues make multiplexed detection of selected mutations potentially a very powerful tool to characterise Mycobacterium tuberculosis. We used Multiplex Ligation-dependent Probe Amplification (MLPA) to screen for dispersed mutations, which can be successfully applied to Mycobacterium tuberculosis as was previously shown. Here we selected 47 discriminative and informative markers and designed MLPA probes accordingly to allow analysis with a liquid bead array and robust reader (Luminex MAGPIX technology). To validate the bead-based MLPA, we screened a panel of 88 selected strains, previously characterised by other methods with the developed multiplex assay using automated positive and negative calling. In total 3059 characteristics were screened and 3034 (99.2%) were consistent with previous molecular characterizations, of which 2056 (67.2%) were directly supported by other molecular methods, and 978 (32.0%) were consistent with but not directly supported by previous molecular characterizations. Results directly conflicting or inconsistent with previous methods, were obtained for 25 (0.8%) of the characteristics tested. Here we report the validation of the bead-based MLPA and demonstrate its potential to simultaneously identify a range of drug resistance markers, discriminate the species within the Mycobacterium tuberculosis complex, determine the genetic lineage and detect and identify the clinically most relevant non-tuberculous mycobacterial species. The detection of multiple genetic markers in clinically derived Mycobacterium tuberculosis strains with a multiplex assay could reduce the number of TB-dedicated screening methods needed for full characterization. Additionally, as a proportion of the markers screened are specific to certain Mycobacterium tuberculosis lineages each profile can be checked for internal consistency. Strain characterization can allow selection of appropriate treatment and thereby improve treatment outcome and patient management.

Tuberculin Skin Testing in Patients with HIV Infection: Limited Benefit of Reduced Cutoff Values

BACKGROUND When determining eligibility for isoniazid preventive therapy of human immunodeficiency virus (HIV)-infected patients, the cutoff value of the tuberculin skin test (TST) is often reduced from an induration of 10 mm in diameter to one of 5 mm in diameter to compensate for loss of sensitivity. The effectiveness of this reduction depends on the underlying mechanism: a gradual decrease in skin test responsiveness with decreasing immunocompetence or an all-or-nothing switch to complete anergy. No published studies have assessed this directly in patients with tuberculosis. METHODS We performed a cross-sectional study of TST responses and HIV infection among patients with sputum smear-positive pulmonary tuberculosis in 6 hospitals in Tanzania. Skin test anergy was defined as a TST reaction < or =2 mm in diameter. RESULTS Of 991 patients with complete results, 451 (45.5%) had HIV infection. Anergy was observed in 111 (24.6%) of 451 HIV-infected patients and 18 (3.3%) of 540 HIV-uninfected patients (P<.001). The reaction size distributions among nonanergic HIV-infected and uninfected patients showed a limited difference (mean diameter +/- standard deviation, 15.9 +/- 5.0 mm and 16.8 +/- 3.8 mm, respectively; P=.048). The sensitivity of the TST among HIV-uninfected patients was 91.1% at a cutoff value of 10 mm and 95.2% at a cutoff value of 5 mm. The sensitivity of the TST among HIV-infected patients was 64.3% at a cutoff value of 10 mm and 71.2% at a cutoff value of 5 mm; the sensitivity of the TST was 67.6% and 74.5%, respectively, after adjustment for tuberculosis-specific anergy. CONCLUSION In subjects with tuberculosis disease and HIV infection, loss of TST sensitivity is predominantly attributable to anergy (i.e., an all-or-nothing phenomenon). The decrease in the proportion of false-negative TST results obtained by reducing the cutoff value from 10 mm to 5 mm is limited.

Delays in the diagnosis and treatment of tuberculosis patients in Vietnam: a cross-sectional study

BackgroundTreatment delay is an important indicator of access to tuberculosis diagnosis and treatment. Analyses of patient delay (i.e. time interval between onset of symptoms and first consultation of a health care provider) and health care delay (i.e. time interval between first consultation and start of treatment) can inform policies to improve access. This study assesses the patient, health care provider and total delay in diagnosis and treatment of new smear-positive pulmonary tuberculosis patients, and the risk factors for long delay, in Vietnam.MethodsA cross-sectional survey of new patients treated by the National Tuberculosis Control Programme was conducted in 70 randomly selected districts in Vietnam. All consecutively registered patients in one quarter of 2002 were interviewed using a pre-coded structured questionnaire.ResultsMedian (range) delay was 4 weeks (1–48) for total, 3 (1–48) weeks for patient and 1 (0–25) week for health care delay. Patients with long total delay (≥ 12 weeks, 15%) accounted for 49% of the cumulative number of delay-weeks. Independent risk factors (p < 0.05) for long total delay were female sex, middle age, remote setting, residence in the northern or central area, and initial visit to the private sector. For long patient delay (≥ 6 weeks) this was female sex, belonging to an ethnic minority, and living at > 5 km distance from a health facility or in the northern area. For long health care delay (≥ 6 weeks) this was urban setting, residence in the central area and initial visit to a communal health post, TB hospital or the private sector.ConclusionAnalyses of patient and treatment delays can indicate target groups and areas for health education and strengthening of the referral system, in particular between the private sector and the NTP.