Using Tests for Latent Tuberculous Infection to Diagnose Active Tuberculosis: Can We Eat Our Cake and Have It Too?

Rapid diagnosis of active tuberculosis is challenging. The only rapid test for active tuberculosis is smear microscopy, which has poor sensitivity for both extrapulmonary and less extensive pulmonary forms of tuberculosis (1). Nucleic acid amplification tests have somewhat better but still suboptimal sensitivity (2), whereas mycobacterial cultures are sensitive but require several weeks before results are available (1). The tuberculin skin test (TST) and the new interferon-γ release assays (3, 4) detect a cellular immune response to tuberculosis antigens. On the basis of numerous longitudinal studies (5), the TST is considered to have good sensitivity for the detection of latent tuberculous infection. The interferon-γ release assays appear to have similar sensitivity but improved specificity for latent infection (4, 6). Use of these tests for the diagnosis of active tuberculosis is based on the logic that one must have tuberculous infection in order to have tuberculosis disease.

However, these tests have 2 fundamental problems when used to diagnose active tuberculosis. First, they measure the host immune response to tuberculosis, not the presence of the microorganisms themselves (3, 4). Because reactivation of latent tuberculous infection reflects an impaired immune response, at least temporarily, these tests may be falsely negative at the time of development of disease (3). In a recent meta-analysis, the sensitivity of both TST and the commercially available interferon-γ release assays ranged from 73% to 88% for the diagnosis of active disease (6), implying a substantial proportion of false-negative results. The greater problem with using TST or interferon-γ release assays to diagnose active tuberculosis is their poor specificity for disease, because these tests cannot distinguish an immune response to reactivated tuberculosis from a response to tuberculous infection that remains latent. The prevalence of latent tuberculosis exceeds …