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Comparison Between Tuberculin Skin Testing and Interferon-γ Release Assays in Predicting TB
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
Elimination of tuberculosis (TB) disease in the US hinges on the ability of tests to detect individual risk of developing disease to inform prevention. The relative performance of 3 available TB tests-the tuberculin skin test (TST) and 2 interferon-γ release assays (IGRAs; QuantiFERON-TB Gold In-Tube [QFT-GIT] and SPOT.TB [TSPOT])-in predicting TB disease development in the US remains unknown.
OBJECTIVE
To compare the performance of the TST with the QFT-GIT and TSPOT IGRAs in predicting TB disease in high-risk populations.
DESIGN, SETTING, AND PARTICIPANTS
This prospective diagnostic study included participants at high risk of TB infection (TBI) or progression to TB disease at 10 US sites between 2012 and 2020. Participants of any age who had close contact with a case patient with infectious TB, were born in a country with medium or high TB incidence, had traveled recently to a high-incidence country, were living with HIV infection, or were from a population with a high local prevalence were enrolled from July 12, 2012, through May 5, 2017. Participants were assessed for 2 years after enrollment and through registry matches until the study end date (November 15, 2020). Data analysis was performed in June 2023.
EXPOSURES
At enrollment, participants were concurrently tested with 2 IGRAs (QFT-GIT from Qiagen and TSPOT from Oxford Immunotec) and the TST. Participants were classified as case patients with incident TB disease when diagnosed more than 30 days from enrollment.
MAIN OUTCOMES AND MEASURES
Estimated positive predictive value (PPV) ratios from generalized estimating equation models were used to compare test performance in predicting incident TB. Incremental changes in PPV were estimated to determine whether predictive performance significantly improved with the addition of a second test. Case patients with prevalent TB were examined in sensitivity analysis.
RESULTS
A total of 22 020 eligible participants were included in this study. Their median age was 32 (range, 0-102) years, more than half (51.2%) were male, and the median follow-up was 6.4 (range, 0.2-8.3) years. Most participants (82.0%) were born outside the US, and 9.6% were close contacts. Tuberculosis disease was identified in 129 case patients (0.6%): 42 (0.2%) had incident TB and 87 (0.4%) had prevalent TB. The TSPOT and QFT-GIT assays performed significantly better than the TST (PPV ratio, 1.65 [95% CI, 1.35-2.02] and 1.47 [95% CI, 1.22-1.77], respectively). The incremental gain in PPV, given a positive TST result, was statistically significant for positive QFT-GIT and TSPOT results (1.64 [95% CI, 1.40-1.93] and 1.94 [95% CI, 1.65-2.27], respectively).
CONCLUSIONS AND RELEVANCE
In this diagnostic study assessing predictive value, IGRAs demonstrated superior performance for predicting incident TB compared with the TST. Interferon-γ release assays provided a statistically significant incremental improvement in PPV when a positive TST result was known. These findings suggest that IGRA performance may enhance decisions to treat TBI and prevent TB.
Additional Info
Comparison of Tuberculin Skin Testing and Interferon-γ Release Assays in Predicting Tuberculosis Disease
JAMA Netw Open 2024 Apr 01;7(4)e244769, T Ayers, AN Hill, J Raykin, S Mohanty, RW Belknap, R Brostrom, R Khurana, M Lauzardo, TL Miller, M Narita, AC Pettit, A Pyan, KL Salcedo, A Polony, J FloodFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The authors are to be commended for performing a large study1 involving 22,020 individuals at high risk for developing tuberculosis and for performing a tuberculin skin test (TST), QuantiFERON-TB Gold (QFT), and T-SPOT simultaneously so that they can be compared directly in their ability to predict the development of active tuberculosis. In their excellent analysis, the authors showed that QFT and T-SPOT were better predictors than TST for the future development of tuberculosis, and that gamma interferon tests incrementally improved the predictive value of a known TST.
The utility of quantiferon in predicting the development of active tuberculosis was shown first in a small data by Diel,2 where the QFT was more accurate than the skin test in predicting who would develop tuberculosis. This was later addressed in the UK PREDICT TB study by Abubaker et al,3 similar to this one, in 9610 migrants or close contacts in the UK. In that study, the T-SPOT was the best predictor at 1.32 cases/1000py, followed by a TST of 15 mm at 1.11 cases/1000py and the QFT at 1.01 cases/1000py. A TST of 5 mm was the most sensitive predictor, and a TST approach stratified by BCG showed that the TST was equivalent to the IGRA overall. In the present study, TSTs were considered positive based on standard criteria, so we do not have the breakdown by induration size.
Another issue worth mentioning when considering these results regards "false-negative" gamma interferon tests in the setting of a simultaneous 15-mm response to a skin test in a person at high risk for infection. In an early study by the CDC4 on QFT, 79% of a small group of individuals who were close contacts and had a 15-mm skin test had a negative quantiferon. In a different study5 of high-risk close contacts with a 15-mm TST, 47% had both a negative QFT and a negative T-SPOT. Thus, there are studies that agree with the superiority of the TST and those that do not. If true, though, a 15-mm skin test in a close contact almost certainly represents infection, and one would not want to miss such individuals by using a gamma interferon test. It would be interesting to know whether there were sufficient data to address this if a reanalysis of this study was performed.
All told, this is an excellent study that shows the utility of gamma interferon assays, but some issues in previous studies still need to be addressed. It should be noted that this study and the others mentioned did not use the current version of the QFT test.
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