Suzanne Verver

Proportion of tuberculosis transmission that takes place in households in a high-incidence area

The prevalence of infection among household contacts of people with tuberculosis is high. This information frequently guides active case finding. We analysed DNA fingerprints of Mycobacterium tuberculosis from 765 tuberculosis patients in Ravensmead and Uitsig, adjacent suburbs of Cape Town, South Africa. In 129 households in which DNA fingerprints were available for more than one patient, we identified 313 patients, of whom 145 (46%) had a fingerprint pattern matching that of another member of the household. The proportion of transmission in the community that took place in the household was 19%, and therefore, in this high-incidence area, tuberculosis transmission occurs mainly outside the household.

A blood RNA signature for tuberculosis disease risk: a prospective cohort study

BACKGROUND Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease. METHODS In this prospective cohort study, we followed up healthy, South African adolescents aged 12-18 years from the adolescent cohort study (ACS) who were infected with M tuberculosis for 2 years. We collected blood samples from study participants every 6 months and monitored the adolescents for progression to tuberculosis disease. A prospective signature of risk was derived from whole blood RNA sequencing data by comparing participants who developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex quantitative real-time PCR (qRT-PCR), the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. Participants of the independent cohorts were household contacts of adults with active pulmonary tuberculosis disease. FINDINGS Between July 6, 2005, and April 23, 2007, we enrolled 6363 participants from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% CI 63·2-68·9) and a specificity of 80·6% (79·2-82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA sequencing and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6-64·3) and a specificity of 82·8% (76·7-86) in the 12 months preceding tuberculosis. INTERPRETATION The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. FUNDING Bill & Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union, and the South African Medical Research Council.Background Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; blood was collected every 6 months. A prospective signature of risk was derived from whole blood RNA-Sequencing data by comparing participants who ultimately developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. The latter participants were household contacts of adults with active pulmonary tuberculosis disease. Findings Of 6,363 adolescents screened, 46 progressors and 107 matched controls were identified. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% confidence interval, 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA-Seq and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation The whole blood tuberculosis risk signature prospectively identified persons at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. Funding Bill and Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union and the South African Medical Research Council (detail at end of text).

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.

Association between smoking and tuberculosis infection: a population survey in a high tuberculosis incidence area

Background: Associations between smoking and tuberculosis disease including death from tuberculosis have been reported, but there are few reports on the influence of smoking on the risk of developing Mycobacterium tuberculosis infection. The aim of this study was to determine the association between smoking and M tuberculosis infection. Methods: In a cross sectional population survey, data on smoking and tuberculin skin test (TST) results of 2401 adults aged ⩾15 years were compared. Results: A total of 1832 (76%) subjects had a positive TST (⩾10 mm induration). Of 1309 current smokers or ex-smokers, 1070 (82%) had a positive TST. This was significantly higher than for never smokers (unadjusted OR 1.99, 95% confidence interval (CI) 1.62 to 2.45). A positive relationship with pack-years was observed, with those smoking more than 15 pack-years having the highest risk (adjusted OR 1.90, 95% CI 1.28 to 2.81). Conclusion: Smoking may increase the risk of M tuberculosis infection.

No decrease in annual risk of tuberculosis infection in endemic area in Cape Town, South Africa

Objective  To estimate the change in annual risk of tuberculosis infection (ARTI) in two neighbouring urban communities of Cape Town, South Africa with an HIV prevalence of approximately 2%, and to compare ARTI with notification rates and treatment outcomes in the tuberculosis (TB) programme.

The tuberculin skin test versus QuantiFERON TB Gold® in predicting tuberculosis disease in an adolescent cohort study in South Africa.

Setting This study was conducted in a high tuberculosis (TB) burden area in Worcester, South Africa, with a notified all TB incidence rate of 1,400/100,000. Main Objective To compare the predictive value of a baseline tuberculin skin test (TST) with that of the QuantiFERON TB Gold (In-tube) assay (QFT) for subsequent microbiologically confirmed TB disease among adolescents. Methods Adolescents aged 12–18 years were recruited from high schools in the study area. At baseline, blood was drawn for QFT and a TST administered. Participants were followed up for up to 3.8 years for incident TB disease (median 2.4 years). Results After exclusions, 5244 (82.4%) of 6,363 adolescents enrolled, were analysed. The TB incidence rate was 0.60 cases per 100 person years (pyrs) (95% CI 0.43–0.82) for baseline TST positive (≥5 mm) participants and 0.64 cases per 100 pyrs (95% CI 0.45–0.87) for baseline QFT positive participants. TB incidence rates were 0.22 per 100 pyrs (0.11–0.39) and 0.22 per 100 pyrs (0.12–0.38) among those with a negative baseline TST and QFT respectively. Sensitivity for incident TB disease was 76.9% for TST and 75.0% for QFT (p = 0.81). Positive predictive value was 1.4% for TST and 1.5% for QFT. Conclusion Positive TST and QFT tests were moderately sensitive predictors of progression to microbiologically confirmed TB disease. There was no significant difference in the predictive ability of these tests for TB disease amongst adolescents in this high burden setting. Therefore, these findings do not support use of QFT in preference to TST to predict the risk of TB disease in this study population.

High Prevalence of Tuberculosis in Previously Treated Patients, Cape Town, South Africa

More than half of smear-positive case-patients had previously undergone treatment.

Association between passive smoking and infection with Mycobacterium tuberculosis in children

OBJECTIVE. Tuberculosis and smoking are both significant public health problems. The association between passive smoking and Mycobacterium tuberculosis infection is not well documented. The objective of this study was to examine the influence of passive smoking on M tuberculosis infection in children. METHODS. A community survey was conducted in 15% of addresses in 2 adjacent low-income suburbs in Cape Town, South Africa. All children (<15 years of age) and their adult household members residing at these addresses were included in the study. Children underwent tuberculin skin testing. An induration of ≥10 mm was considered to define M tuberculosis infection. Passive smoking was defined as living in the household with at least 1 adult who smoked for at least 1 year. Random-effects logistic regression analysis was performed, and odds ratios were adjusted for age, presence of a patient with tuberculosis in the household, average household income, and clustering at the household level. RESULTS. Of 1344 children, 432 (32%) had a positive tuberculin skin test. Passive smoking was significantly associated with M tuberculosis infection in the unadjusted analyses but not in the adjusted analyses. In the 172 households with a patient with tuberculosis, passive smoking was significantly associated with a positive tuberculin skin test (but not in the 492 households without a patient with tuberculosis. CONCLUSIONS. Passive smoking is associated with M tuberculosis infection in children living in a household with a patient with tuberculosis. More studies are needed to confirm this observation, but the possible association is a cause of great concern, considering the high prevalence of smoking and tuberculosis in most developing countries.

Predictive Value of Recent QuantiFERON Conversion for Tuberculosis Disease in Adolescents

RATIONALE Conversions and reversions occur with IFN-γ release assay (IGRA) serial testing, as with the tuberculin skin test (TST). Recent TST conversion is associated with an established risk of developing tuberculosis (TB) disease, but the risk associated with recent IGRA conversions is unknown. OBJECTIVES To compare the incidence rate of TB disease after recent QuantiFERON TB Gold In-Tube (QFT) conversion compared with nonconverters. METHODS Adolescents with converted IGRA status (QFT converters [n = 534]) and randomly chosen adolescents whose IGRA status had remained negative over a period of 2 years (QFT nonconverters [n = 629]) were identified in a cohort study of TB infection and disease. Subsequent TB disease incidence was compared between the two groups. MEASUREMENTS AND MAIN RESULTS For QFT converters, the TB incidence rate (all cases) was 1.46 cases per 100 person-years (95% confidence interval [CI], 0.82-2.39), and the cumulative incidence was 2.8% (95% CI, 1.58-4.59). A significantly lower TB incidence rate (0.17 cases per 100 person-yr [95% CI, 0.02-0.62]) and cumulative incidence (0.32% [95% CI, 0.03-1.14]) was observed for QFT nonconverters. The incidence rate ratio was 8.54 (95% CI, 2.51-29.13) for all cases of TB and 9.1 (95% CI, 1.65-50.36) for protocol-defined TB. CONCLUSIONS Recent QFT conversion was indicative of an approximately eight fold higher risk of progression to TB disease (compared with nonconverters) within 2 years of conversion in a cohort of adolescents in a high-TB burden population.

High incidence of pulmonary tuberculosis persists a decade after immigration, The Netherlands.

Incidence rates of pulmonary tuberculosis among immigrants from high incidence countries remain high for at least a decade after immigration into the Netherlands. Possible explanations are reactivation of old infections and infection transmitted after immigration. Control policies should be determined on the basis of the as-yet unknown main causes of the persistent high incidence.