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Concept: Mantoux test

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The objective of this study was to identify blood-based protein biomarkers of early stage Mycobacterium tuberculosis (Mtb) infection. We utilized plasma and serum specimens from TB patients and their contacts (age≥12) enrolled in a household contact study in Uganda. In the discovery phase cross-sectional samples from 104 HIV-uninfected persons classified as either active TB, latent Mtb infection (LTBI), tuberculin skin test (TST) converters, or persistent TST-negative were analyzed. Two hundred eighty-nine statistically significant (false discovery rate corrected p<0.05) differentially expressed proteins were identified across all comparisons. Proteins associated with cellular immunity and lipid metabolism were induced early after Mtb infection. One hundred and fifty-nine proteins were selected for a targeted mass spectrometry assay. A set of longitudinal samples from 52 TST-negative subjects who converted to TST-positive or remained TST-negative were analyzed, and multivariate logistic regression was used to identify unique protein panels able to predict TST conversion with cross-validated AUC>0.85. Panel performance was confirmed with an independent validation set of longitudinal samples from 16 subjects. These candidate protein biomarkers may allow for the identification of recently Mtb infected individuals at highest risk for developing active TB and most likely to benefit from preventive therapy.

Concepts: Protein, Regression analysis, Metabolism, Virus, Tuberculosis, Mycobacterium, Multiple comparisons, Mantoux test

49

The existing estimate of the global burden of latent TB infection (LTBI) as “one-third” of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI.

Concepts: Mathematics, Demography, Population, Tuberculosis, Life expectancy, Mantoux test, Latent tuberculosis, World population

28

BACKGROUND: Diagnosis and treatment of latent tuberculosis infection (LTBI) is the most effective strategy to control tuberculosis (TB) among patients with HIV infection. The tuberculin skin test (TST) was the only available method to identify LTBI. The aim of the present work was to evaluate the usefulness of the interferon-gamma release assays (IGRAs): QuantiFERONtuberculosis (TB) Gold-In-Tube test (QFG) and T-SPOT.TB for the diagnosis of LTBI in a diverse cohort of HIV-infected patients. METHODS: A prospective study was carried out in consecutive patients cared for in a single institution in Spain from January 2009 to October 2010. IGRAS and tuberculin skin test (TST) were performed simultaneously. TST induration [greater than or equal to] 5 mm was considered positive. RESULTS: QFG, T-SPOT.TB and TST were performed in 373 subjects. Median CD4 cell count was 470/mul with a median nadir of 150/mul. TST, QFG and T-SPOT.TB were positive in 13.3%, 7.5% and 18.5% cases respectively. Among 277 patients with neither past or current TB nor previous treatment for LTBI and who had TST results, a positive TST result was obtained in 20 (7.2%) cases. When adding QFG results to TST, there were a total of 26 (8.6%) diagnoses of LTBI. When the results of both IGRAs were added, the number of diagnoses increased to 54 (17.9%) (incremental difference: 10.7% [95% confidence interval [CI]:5.3-16.2%] [p <0.001]), and when both IGRAs were added, the number of diagnoses reached 56 (18.5%) (incremental difference: 11.3% [95% CI:5.7%-16.9%] [p < 0.001]). Patients with a CD4 cell count greater than 500 cells/mul and prior stay in prison were more likely to have a diagnosis of LTBI by TST and/or QFG and/or T-SPOT.TB (adjusted odds ratio [aOR]: 3.76; 95% CI, 1.4 - 9.89; and aOR: 3.3; 95% CI, 1.3 - 8.3, respectively). CONCLUSIONS: IGRAs were more sensitive than TST for diagnosis of M. tuberculosis infection in HIVinfected patients. Dual sequential testing with TST and IGRAs may be the optimal approach for LTBI screening in this population.

Concepts: AIDS, Immune system, Interferon, Tuberculosis, Mantoux test, Latent tuberculosis, Interferon-gamma, T-SPOT.TB

27

SETTING: Twenty-four districts in India.OBJECTIVES: To evaluate trends in annual risk of tuberculous infection (ARTI) in each of four geographically defined zones in the country.STUDY DESIGN: Two rounds of house-based tuberculin surveys were conducted 8-9 years apart among children aged 1-9 years in statistically selected clusters during 2000-2003 and 2009-2010 (Surveys I and II). Altogether, 184 992 children were tested with 1 tuberculin unit (TU) of purified protein derivative (PPD) RT23 with Tween 80 in Survey I and 69 496 children with 2TU dose of PPD in Survey II. The maximum transverse diameter of induration was measured about 72 h after test administration. ARTI was computed from the prevalence of infection estimated using the mirror-image method.RESULTS: Estimated ARTI rates in different zones varied between 1.1% and 1.9% in Survey I and 0.6% and 1.2% in Survey II. The ARTI declined by respectively 6.1% and 11.7% per year in the north and west zones; no decline was observed in the south and east zones. National level estimates were respectively 1.5% and 1.0%, with a decline of 4.5% per year in the intervening period.CONCLUSION: Although a decline in ARTI was observed in two of the four zones and at national level, the current ARTI of about 1% in three zones suggests that further intensification of TB control activities is required.

Concepts: Statistics, Tuberculosis, Mantoux test, Tuberculin, Decline, Protein purification, Clemens von Pirquet

22

Intradermal injection using a syringe and needle is generally accepted as the most accurate method for the tuberculin skin test (TST). However, the Mantoux technique using a conventional needle is often difficult to perform reliably, affecting testing results and safety.

Concepts: Mantoux test, Hypodermic needle, Injection

18

Canadian tuberculosis (TB) guidelines recommend targeting postlanding screening for and treatment of latent tuberculosis infection (LTBI) in people migrating to Canada who are at increased risk for TB reactivation. Our objectives were to calculate robust longitudinal estimates of TB incidence in a cohort of people migrating to British Columbia, Canada, over a 29-year period, and to identify groups at highest risk of developing TB based on demographic characteristics at time of landing.

Concepts: Cohort study, Epidemiology, Tuberculosis, Provinces and territories of Canada, Canada, Mantoux test, Latent tuberculosis, British Columbia

18

Vaccination for the control of bovine tuberculosis (bTB) in cattle is not currently used within any international control program, and is illegal within the EU. Candidate vaccines, based upon Mycobacterium bovis bacillus Calmette-Guérin (BCG) all interfere with the action of the tuberculin skin test, which is used to determine if animals, herds and countries are officially bTB-free. New diagnostic tests that Differentiate Infected from Vaccinated Animals (DIVA) offer the potential to introduce vaccination within existing eradication programs. We use within-herd transmission models estimated from historical data from Great Britain (GB) to explore the feasibility of such supplemental use of vaccination. The economic impact of bovine Tuberculosis for farmers is dominated by the costs associated with testing, and associated restrictions on animal movements. Farmers' willingness to adopt vaccination will require vaccination to not only reduce the burden of infection, but also the risk of restrictions being imposed. We find that, under the intensive sequence of testing in GB, it is the specificity of the DIVA test, rather than the sensitivity, that is the greatest barrier to see a herd level benefit of vaccination. The potential negative effects of vaccination could be mitigated through relaxation of testing. However, this could potentially increase the hidden burden of infection within Officially TB Free herds. Using our models, we explore the range of the DIVA test characteristics necessary to see a protective herd level benefit of vaccination. We estimate that a DIVA specificity of at least 99.85% and sensitivity of >40% is required to see a protective benefit of vaccination with no increase in the risk of missed infection. Data from experimentally infected animals suggest that this target specificity could be achieved in vaccinates using a cocktail of three DIVA antigens while maintaining a sensitivity of 73.3% (95%CI: 61.9, 82.9%) relative to post-mortem detection.

Concepts: Immune system, Vaccine, Tuberculosis, Mycobacterium, Cattle, Mantoux test, Mycobacterium bovis, Bacillus Calmette-Guérin

11

A 49-year-old man who had recently emigrated from Myanmar presented with a 6-month history of rusty brown sputum with hemoptysis. A tuberculin skin test was positive, but sputum smears were negative for acid-fast bacilli, ova, and parasites.

Concepts: Bacteria, Parasites, Tuberculosis, Mantoux test, Tuberculin, Acid-fast, Acid fast bacilli, Rusty Brown

8

In the spring of 2015, a local health department (LHD) in county A notified the California Department of Public Health (CDPH) about three adults with close ties to one another and a congregate community site who had received diagnoses of tuberculosis (TB) disease within a 3-month period. Subsequent review revealed matching TB genotypes indicating that the cases were likely part of a chain of TB transmission. Only three TB cases in California in the preceding 2 years shared this same genotype. One of those three previous cases occurred in a lung-transplant recipient who had no identified epidemiologic links to the outbreak. CDPH, multiple LHDs, and CDC conducted an investigation and determined that the lung-transplant donor (patient 1) was epidemiologically linked to the three outbreak cases and had a tuberculin skin test (TST) conversion detected in 2012 upon reentry at a local jail. Three other solid organ recipients from this donor were identified; none had developed TB disease. This investigation suggests that review of organ donors' medical records from high-risk environments, such as jails, might reveal additional information about TB risk. The evaluation of TB in organ recipients could include genotyping analysis (1) and coordination among local, state, and national partners to evaluate the potential for donor-derived TB.

Concepts: Public health, Genetics, Epidemiology, Biology, Tuberculosis, Organ donation, Mantoux test, Tuberculin

6

Bovine tuberculosis (bTB) is one of the most serious economic animal health problems affecting the cattle industry in Great Britain (GB), with incidence in cattle herds increasing since the mid-1980s. The single intradermal comparative cervical tuberculin (SICCT) test is the primary screening test in the bTB surveillance and control programme in GB and Ireland. The sensitivity (ability to detect infected cattle) of this test is central to the efficacy of the current testing regime, but most previous studies that have estimated test sensitivity (relative to the number of slaughtered cattle with visible lesions [VL] and/or positive culture results) lacked post-mortem data for SICCT test-negative cattle. The slaughter of entire herds (“whole herd slaughters” or “depopulations”) that are infected by bTB are occasionally conducted in GB as a last-resort control measure to resolve intractable bTB herd breakdowns. These provide additional post-mortem data for SICCT test-negative cattle, allowing a rare opportunity to calculate the animal-level sensitivity of the test relative to the total number of SICCT test-positive and negative VL animals identified post-mortem (rSe). In this study, data were analysed from 16 whole herd slaughters (748 SICCT test-positive and 1031 SICCT test-negative cattle) conducted in GB between 1988 and 2010, using a Bayesian hierarchical model. The overall rSe estimate of the SICCT test at the severe interpretation was 85% (95% credible interval [CI]: 78-91%), and at standard interpretation was 81% (95% CI: 70-89%). These estimates are more robust than those previously reported in GB due to inclusion of post-mortem data from SICCT test-negative cattle.

Concepts: Statistics, Mathematics, Type I and type II errors, Tuberculosis, Cattle, Estimation, Mantoux test, Mark Slaughter