© 2007 American Thoracic Society doi: 10.1164/rccm.200701-024ED
The New IGRA and the Old TSTMaking Good Use of DisagreementMcGill University, Montreal, Canada In many high-income countries, the diagnosis and treatment of latent tuberculosis infection (LTBI) are an integral part of tuberculosis (TB) control and plans (hopes) for elimination. However, a major limitation of this strategy has been the diagnosis of LTBI using the tuberculin skin test (TST). The TST suffers from lack of specificity, particularly in populations where bacillus Calmette-Guérin (BCG) vaccination is given after infancy (1). More importantly, the TST cannot discriminate the 90% of persons with LTBI who will never develop active TB from the 10% who will.
Two new interferon- The study by Arend and colleagues in this issue of the Journal (pp. 618–627) has many strengths (4). The authors conducted a three-way head-to-head comparison of the TST with both commercially available IGRAs. This provided clinically relevant results, and allowed direct comparison of test characteristics, plus analysis of discordant test results. A large, well-characterized population was studied, and careful, insightful analysis was performed in which the cutoff points for all tests were varied. This study, as with all other evaluations of IGRAs, used a cross-sectional design—a design fundamentally limited by the lack of a gold standard for LTBI. The only gold standard for LTBI is the later development of active TB. This can be ascertained only through longitudinal cohort studies. As a result of the limitations of the cross-sectional design, the substantial discordance between all three tests (one of the study's major findings) is unexplained. If all three tests were highly concordant, this would mean their sensitivity and specificity were equivalent. In such a situation, the only advantages of IGRAs would be operational; such advantages would have to be weighed against the increased cost and technical complexity of IGRAs. Hence, discordance is expected: TST+/IGRA– if the IGRAs are more specific, and TST–/IGRA+ if IGRAs are more sensitive. In the study by Arend and colleagues (4), both types of discordance were common. Almost half of those with a TST of 15 mm or greater were IGRA negative; this discordance was associated with older age and foreign birth—both indicators of remote exposure (but also risk factors for TB disease). These findings suggest possible lack of sensitivity for IGRAs, as has been reported in several previous studies (5–8). In the past, when exposed contacts had a negative TST, this was taken as evidence that they had avoided primary infection altogether. Prospective studies indicated their risk of active disease was low (reviewed in Reference 9). Yet, Arend and colleagues reported that IGRA+/TST– discordance was associated with indicators of recent exposure, as has been reported in several other studies (8, 10, 11). In two studies, a high proportion of persons with discordant IGRA+/TST– reactions had spontaneous IGRA reversion to negativity (12, 13). This suggests that exposure could lead to infection, which was then cleared (14). It also suggests that IGRAs may provide more quantitative and dynamic measurement of cellular immune response than the TST, which would be important for serial testing studies. The study by Arend and colleagues raises several intriguing questions. What host, biologic, or environmental factors explain the discordance between IGRAs and the TST? Can IGRAs have lower sensitivity for remote LTBI but better sensitivity for recent infection? If this were the case, these assays would be important for outbreak and contact investigations where it is important not to miss recently infected individuals. The key question is whether IGRAs are better than the TST in predicting risk of development of TB disease, and thus identifying persons who will benefit most from LTBI therapy. As reviewed elsewhere (9), there is abundant evidence, from numerous large-scale cohorts and randomized trials, regarding the prognosis of untreated persons with positive TST results; this remains the greatest advantage of the TST. What is urgently needed is similar evidence from longitudinal studies of cohorts who have been tested with an IGRA (ideally both IGRAs) and the TST. However, in almost all low-incidence, high-income countries, it would be ethically impossible not to treat persons with evidence of LTBI. Moreover, in high-incidence countries, where treatment of LTBI is not the current standard of care, it would seem unethical to test for a condition without plans to offer appropriate treatment. However, this should not be a problem. Almost everyone would agree that individuals with concordant positive TST and IGRA are highly likely to have LTBI, and they will never inform the question as to which test predicts active TB better. Thus, such patients can and should be managed appropriately. However, individuals with discordant results (TST+/IGRA– or vice versa) will be informative regarding the risk of development of active disease without treatment. In addition, because the clinical interpretation, and therefore management, is unclear for persons with such discordant results, equipoise exists. Therefore, close observation without treatment is reasonable, and ethical. In most studies, individuals with discordant reactions represent about 10 to 20% of all tested (2, 3). Their identification would therefore require that large numbers of individuals are tested and then followed up. This would be complex, expensive, and require a strong commitment by public health and other government agencies, as well as investigators and funding agencies. Where to find the funding? Extrapolating from a 1991 study (15), more than $120 million is spent annually on screening and preventive therapy for LTBI in the United States. If only a small fraction of these expenditures were used to evaluate IGRAs, this would be more than enough to fund an extensive, comprehensive cohort study. Could this be done? Possibly. Should it be done? Definitely. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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release assays (IGRAs) are now available for the diagnosis of LTBI: the QuantiFERON-TB Gold (Cellestis, Victoria, Australia) and the T-SPOT.TB (Oxford Immunotec, Oxford, UK). IGRAs offer important potential advantages over the TST. They are unaffected by prior BCG vaccination, hence are more specific, and are ex vivo tests, thus reducing the potential risk of adverse events and of boosting (
