Interferon assay for latent TB may be more specific than skin test

Oct 12, 2001 (CIDRAP News) – Comparison of an interferon-gamma (IFN-gamma) assay for latent tuberculosis infection (LTBI) with the standard tuberculin skin test (TST) suggests that the interferon assay is less likely to produce false-positive results in people with prior BCG vaccination or reactivity to nontuberculous mycobacteria, according to a report in the Journal of the American Medical Association.

The INF-gamma assay "was comparable with the TST in its ability to detect LTBI, was less affected by BCG vaccination, discriminated responses due to nontuberculous mycobacteria [from those due to Mycobacterium tuberculosis], and avoided variability and subjectivity associated with placing and reading the TST," states the report by Gerald H. Mazurek, MD, of the Centers for Disease Control and Prevention (CDC), and colleagues from five major centers.

The study compared the QuantiFERON-TB test (Cellestis Limited, St Kilda, Australia) with the TST. The assay measures the amount of interferon-gamma that is produced by lymphocytes in whole blood when it is incubated overnight with purified protein derivative (PPD) from M tuberculosis and control antigens. The control antigens include saline solution, PPD from Mycobacterium avium, and phytohemagglutinin (mitogen).

The researchers recruited 1,226 adult participants at five university medical schools over a 16-month period. They included (1) 98 people requesting a preemployement or pre–school enrollment TST, (2) 947 people receiving a TST because they were considered to have a high risk of LTBI, (3) 94 people in whom TB was clinically suspected and who had had less than 6 weeks of TB treatment, and (4) 87 people who had completed treatment for active TB within the previous 2 years.

Of the 1,226 participants, 390 (31.8%) had a positive TST result, and 349 (28.5%) had a positive IFN-gamma assay result. Overall agreement between the two tests was 83.1%; the kappa coefficient was 0.60, where values of 0.40 to 0.75 represent fair to good agreement beyond chance, values greater than 0.75 represent excellent agreement, and values less than 0.40 represent poor agreement beyond chance.

When the analysis was confined to the participants for whom the IFN-gamma assay is intended—those being screened for LTBI (groups 1 and 2)—agreement between the two tests was 84.7% (kappa=0.55). In this analysis, agreement was 88.1% (kappa=0.50) for people without BCG vaccination and 70.1% (kappa=0.41) for those with BCG vaccination. Seven of the 33 unvaccinated people (21.2%) who had positive TST and negative IFN-gamma assay results showed immune reactivity to M avium by IFN-gamma assay. A multivariate analysis of the findings for the people being screened for LTBI showed that factors statistically associated with a positive TST result and negative IFN-gamma result included BCG vaccination, M avium reactivity, Asian race, and site of study enrollment.

Because there is no "gold standard" test for LTBI, comparisons cannot show which test is better, the authors note. "Our results suggest that the IFN-gamma assay may be less affected than TST by prior BCG vaccination," but one previous study showed that the IFN test is also affected by BCG, they add. The results in this study suggest that reactivity to nontuberculous mycobacteria may have been the cause of a positive TST in a fifth of the subjects who had positive TSTs but negative IFN-gamma results, the authors state. "Thus, the IFN-gamma assay offers a potentially significant improvement in specificity with the consequent benefit of avoiding LTBI treatment for persons not infected with M tuberculosis."

The article notes that the IFN-gamma assay, unlike the TST, requires only one patient visit and can be completed in less than 24 hours. The authors also say the specificity of the assay will probably improve in the future with the inclusion of antigens that are found in M tuberculosis but not in nontuberculous mycobacteria or BCG. One author of the study is an employee of Cellestis Limited, but the study was funded by the CDC.

Mazurek GH, LoBue PA, Daley CL, et al. Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 2001;286(14):1740-7
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