New Tests for the Diagnosis of Latent Tuberculosis Infection

IN RESPONSE:

We agree with Drs. Kunst and Khan that the lack of a proper gold standard is a fundamental problem of all cross-sectional studies of diagnostic tests for latent tuberculosis infection. We state this problem explicitly several times in our paper. We believe that longitudinal studies following cohorts of persons with positive or negative test results will be most valuable, because the later development of active tuberculosis is the only certain indicator of the presence of latent tuberculosis infection. Because treatment reduces incidence of disease, ideally, such cohorts of individuals would be untreated, which poses serious ethical issues. However, as we have pointed out elsewhere (1), individuals with discordant test results could be left untreated, as there is equipoise regarding their management, and prognosis of discordant results is the most critical issue for understanding the predictive value of interferon-γ release assays. Several prospective studies are currently being conducted in different settings (2, 3); we await these results with interest.

With regard to gradients of exposure, we reviewed all available studies (see our Table 3). However, the measurement and categorization of exposure, and disease in the source cases, were too heterogeneous to allow their integration for a proper meta-analysis.

Systematic reviews and meta-analysis must take advantage of published literature to be informative. Hence, we assessed sensitivity and specificity, but pointed out clearly in the paper that these were surrogate measures with significant limitations. If we had only included published studies with the correct gold standard for latent tuberculosis infection (as above), there would have been no papers on which to base our estimates. A considerable amount of published literature is currently available, which has compared 2 or even all 3 currently available tests for latent tuberculosis infection. Both interferon-γ release assays reviewed are currently licensed in many countries and are actively marketed in North America and Europe. Therefore, their relative performance in different patient populations and clinical situations is of considerable interest. We feel strongly that ignoring this large body of information, because of certain limitations, would do a disservice to public health and clinical practitioners who are faced with making choices and managing patients now.