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Should Individuals Who Are Tuberculin Skin Test Negative and Positive to RD1–IFN- Assay Receive Preventive Therapy?

Latent tuberculosis infection (LTBI) is not a disease; rather, it is defined by a specific immune response to Mycobacterium tuberculosis associated with a lifelong risk of active tuberculosis. Risk estimates are derived from the results of large prospective trials in which the tuberculin skin test (TST) has been used to define LTBI, although both sensitivity and specificity of this test are suboptimal (1). Longitudinal studies also showed that the TST may both convert to positive and revert to negative over time (2). The new IFN-–based diagnostic assays for LTBI are now entering clinical practice: obviously, data from longitudinal studies are still scarce. One such study shows that, after exposure to an active tuberculosis case, some TST-negative contacts have a transient antigen-specific immune response in the blood, as detected by RD1-ELISpot (3).

In their letter, Girardi and colleagues, quoting a compelling paper by Lord and coworkers (4), ask whether such transiently ELISpot-positive individuals should be treated with isoniazid, given that their risk for future disease is presumably low. According to Nardell and Wallis (5), we cannot answer this question, mainly because a diagnostic gold standard for LTBI is lacking. Unfortunately, randomized placebo-controlled trials with the new tests (similar to those performed in the past with the TST) appear unethical, and it doesn't make sense to consider the TST, an imperfect test, as the reference for the new assays. Therefore, we aren't sure of what a positive (or first positive and then negative) blood test in the context of a negative skin test means in terms of future disease risk. Anyway, the risk of the healthy, young students with a potential "acute tuberculosis infection" detected by RD1-ELISpot was presumably low: long-term follow-up in this setting was a successful strategy.

On the other hand, Lord and coworkers also state that accuracy studies may suffice if a new test is more specific than, but of similar sensitivity to, an old assay (4) and we already know that IFN-–based tests are more specific than the skin test (6). Since LTBI is not a disease per se, the management of infected subjects will always rely on the best assessment of the individual risk/benefit ratio. At least for now, the use of the new tests for LTBI should not change the principles of targeted testing: this means that the "human factor" (hopefully assisted by more accurate diagnostic tools) will always play the crucial role in the strategies for tuberculosis control.

Luca Richeldi

University of Modena and Reggio Emilia, Modena, Italy

FOOTNOTES

Conflict of Interest Statement: L.R. received 1,900 in 2005 for serving on an advisory board for Oxford Immunotec Ltd, manufacturer of T-SPOT.TB. His institution received an unrestricted grant (a6,000) from A.D.A., Sr, representative of Cellestis Ltd in Italy, for the Quantiferon TB Gold Test.

REFERENCES

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3. Ewer K, Millington KA, Deeks JJ, Alvarez L, Bryant G, Lalvani A. Dynamic antigen-specific T-cell responses after point-source exposure to Mycobacterium tuberculosis. Am J Respir Crit Care Med 2006;174:831–839.[Abstract/Free Full Text]
4. Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials? Ann Intern Med 2006;144:850–855.[Abstract/Free Full Text]
5. Nardell EA, Wallis RS. Here today—gone tomorrow: the case for transient acute tuberculosis infection. Am J Respir Crit Care Med 2006;174:734–735.[Free Full Text]
6. Richeldi L. An update on the diagnosis of tuberculosis infection. Am J Respir Crit Care Med 2006;174:736–742.[Abstract/Free Full Text]

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