In the JournalsPerspective

Study confirms poor ability of tests to predict active TB infection

A prospective study examining the ability of tests to predict the development of active tuberculosis found a similarly low positive predictive value in high-burden settings of interferon-gamma release assays, or IGRAs, and tuberculin skin tests, or TSTs, researchers reported in The Lancet Infectious Diseases. The negative predictive value of the tests was high in all settings.

“Between a quarter and a third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis, a state in which viable bacteria persist under immune control without clinically active tuberculosis,” Ibrahim Abubakar, PhD, professor of infectious disease epidemiology at the University College London Institute for Global Health, and colleagues wrote. “Latent tuberculosis infection forms a reservoir from which active tuberculosis will continue to emerge, therefore presenting a major challenge to the global effort to end the tuberculosis epidemic.”

To determine the effectiveness of the tests, Abubakar and colleagues compared the prognostic value of two IGRAs and the TST among high-risk individuals who were not undergoing preventive treatment. The study cohort included 9,610 eligible participants from 54 United Kingdom National Health Service centers and community settings recruited between May 4, 2010, and June 1, 2015. All participants were aged 16 years or older and at high risk for latent TB infection, with 4,861 having had recent contact with an active TB case and 4,749 being migrants who had arrived in the U.K. in the past 5 years from a country with a high burden of TB.

According to the study, each participant received three tests: QuantiFERON-TB Gold-In Tube, T-SPOT.TB and a Mantoux TST.

To identify the most suitable screening test, Abubakar said they used three criteria: a high proportion of tested individuals should be classified as test negative and require no further monitoring; a low rate of progression to TB in those who tested a negative; and increased likelihood of progression in those who test as positive.

Participants were followed up from recruitment to development of TB or censoring for a median of 2.9 years. Through the test results, Abubakar and colleagues said they estimated the prognostic value of IGRAs compared with TST by assessing the incidence rate ratios and predictive values for TB development.

“A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in [Bacillus Calmette-Guérin (BCG)]-naive or 15 mm in BCG-vaccinated (TST-15) participants,” they wrote.

According to the results, 97 participants developed active TB, including 77 of the 6,380 who had results for all three tests. Researchers noted that in all tests, the annual incidence of TB was very low in those who tested negatively. The annual incidence in participants who tested positively was highest for T-SPOT.TB. Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5, Abubakar and colleagues reported. However, they said TST-5 identified a higher proportion of participants who progressed to active TB than all other tests and TST thresholds.

According to Abubakar, there was little between-test variation in TB incidence in participants who tested negative, but the proportion of participants who were classified as test negative, and considered unlikely to progress, varied considerably, especially by TST threshold. TST-5 classified the lowest proportion of participants as negative, followed by TST-10 and TST-15, the researchers reported.

“Our data provide evidence that TST stratified by BCG-vaccination status yields similar predictive values to the two commonly used IGRAs,” they concluded. “IGRA or TST-15 strategies gave a high proportion of negative test results, with low progression among these individuals, and correctly identified a high risk of progression in participants who had positive test results, supporting their use in screening programs. TST-5 will identify most individuals who will benefit from treatment in high-risk groups at the cost of increasing the number of patients classified as more likely to progress to tuberculosis.

“Country-specific cost-effectiveness analyses, stratification of progression risk in sub-populations, and treatment uptake of preventive therapies should inform screening strategies.” – by Caitlyn Stulpin

Disclosure: Abubakar reports being funded by the U.K. National Institute for Health Research, Medical Research Council, U.K. Department of Health and the Wellcome Trust. Please see the study for all other authors’ relevant financial disclosures.

Editor’s note: This story has been updated to indicate that the analysis was a prospective study. The editors regret the error.

A prospective study examining the ability of tests to predict the development of active tuberculosis found a similarly low positive predictive value in high-burden settings of interferon-gamma release assays, or IGRAs, and tuberculin skin tests, or TSTs, researchers reported in The Lancet Infectious Diseases. The negative predictive value of the tests was high in all settings.

“Between a quarter and a third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis, a state in which viable bacteria persist under immune control without clinically active tuberculosis,” Ibrahim Abubakar, PhD, professor of infectious disease epidemiology at the University College London Institute for Global Health, and colleagues wrote. “Latent tuberculosis infection forms a reservoir from which active tuberculosis will continue to emerge, therefore presenting a major challenge to the global effort to end the tuberculosis epidemic.”

To determine the effectiveness of the tests, Abubakar and colleagues compared the prognostic value of two IGRAs and the TST among high-risk individuals who were not undergoing preventive treatment. The study cohort included 9,610 eligible participants from 54 United Kingdom National Health Service centers and community settings recruited between May 4, 2010, and June 1, 2015. All participants were aged 16 years or older and at high risk for latent TB infection, with 4,861 having had recent contact with an active TB case and 4,749 being migrants who had arrived in the U.K. in the past 5 years from a country with a high burden of TB.

According to the study, each participant received three tests: QuantiFERON-TB Gold-In Tube, T-SPOT.TB and a Mantoux TST.

To identify the most suitable screening test, Abubakar said they used three criteria: a high proportion of tested individuals should be classified as test negative and require no further monitoring; a low rate of progression to TB in those who tested a negative; and increased likelihood of progression in those who test as positive.

Participants were followed up from recruitment to development of TB or censoring for a median of 2.9 years. Through the test results, Abubakar and colleagues said they estimated the prognostic value of IGRAs compared with TST by assessing the incidence rate ratios and predictive values for TB development.

“A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in [Bacillus Calmette-Guérin (BCG)]-naive or 15 mm in BCG-vaccinated (TST-15) participants,” they wrote.

According to the results, 97 participants developed active TB, including 77 of the 6,380 who had results for all three tests. Researchers noted that in all tests, the annual incidence of TB was very low in those who tested negatively. The annual incidence in participants who tested positively was highest for T-SPOT.TB. Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5, Abubakar and colleagues reported. However, they said TST-5 identified a higher proportion of participants who progressed to active TB than all other tests and TST thresholds.

According to Abubakar, there was little between-test variation in TB incidence in participants who tested negative, but the proportion of participants who were classified as test negative, and considered unlikely to progress, varied considerably, especially by TST threshold. TST-5 classified the lowest proportion of participants as negative, followed by TST-10 and TST-15, the researchers reported.

“Our data provide evidence that TST stratified by BCG-vaccination status yields similar predictive values to the two commonly used IGRAs,” they concluded. “IGRA or TST-15 strategies gave a high proportion of negative test results, with low progression among these individuals, and correctly identified a high risk of progression in participants who had positive test results, supporting their use in screening programs. TST-5 will identify most individuals who will benefit from treatment in high-risk groups at the cost of increasing the number of patients classified as more likely to progress to tuberculosis.

“Country-specific cost-effectiveness analyses, stratification of progression risk in sub-populations, and treatment uptake of preventive therapies should inform screening strategies.” – by Caitlyn Stulpin

Disclosure: Abubakar reports being funded by the U.K. National Institute for Health Research, Medical Research Council, U.K. Department of Health and the Wellcome Trust. Please see the study for all other authors’ relevant financial disclosures.

Editor’s note: This story has been updated to indicate that the analysis was a prospective study. The editors regret the error.

    Perspective

    Extensive research suggests that both tuberculin skin test (TST) and interferon-gamma release assays (IGRA) represent indirect markers of M. tuberculosis exposure and indicates a cellular immune response to M. tuberculosis. Neither test is perfect. Neither test can accurately differentiate between latent and active TB. Both TST and IGRA have low sensitivity in a variety of immunocompromised populations.

    Cohort studies have shown that both TST and IGRA have low predictive value for progression from infection to active TB. The UK PREDICT TB study by Abubakar and colleagues confirm this.

    Their study showed that greater than 95% of patients with positive TST, T-SPOT or QFT results did not develop active TB during follow-up.

    None of the existing tests have high predictive value for identifying those who are most likely to progress to active disease. We need basic research to develop more predictive tests, and a target product profile for such a test has been published.

    Madhukar Pai, MD, PhD, FCAHS

    Canada research chair, translational epidemiology and global health
    Director, McGill Global Health Programs and McGill International TB Centre
    McGill University
    Montreal

    Disclosure: Pai reports no relevant financial disclosures.