© 2006 American Thoracic Society doi: 10.1164/rccm.200608-1101ED
Finally, a Perfect Diagnostic Test for Pulmonary Tuberculosis—or Is It?Department of Internal Medicine, University of New Mexico Health Sciences Center School of Medicine, Albuquerque, New Mexico Smear-negative pulmonary tuberculosis raises a particular dilemma for clinicians. Unfortunately, current diagnostic laboratory techniques are either limited in their accuracy or introduce a delay in diagnosis. Newer techniques in immunodiagnosis of this disease are therefore being explored.
The pulmonary immune response to mycobacteria consists of several steps. After inhalation of viable mycobacteria and their local growth, organisms travel to local lymph nodes, where dendritic cells process mycobacterial antigens, and present them to CD4+ lymphocytes. The CD4+ cells are then induced to express a Th1 pattern, migrate to the site of infection, proliferate, secrete IFN- Our ability to use assays of immune response to mycobacteria to diagnose disease depends on several factors. First, we must determine the antigens that are recognized by the immune system. Second, we must devise a test that can detect sensitized Th1-type lymphocytes. Last, and most important from a clinical viewpoint, we must be able to distinguish the response to actively proliferating mycobacteria from the response to the residue of remote mycobacterial infection.
Recent advances in understanding mycobacterial biology have led to the use of antigens that are more sensitive and specific for Mycobacterium tuberculosis (2). The enzyme-linked immunospot (ELISPOT) assay can detect individual lymphocytes secreting IFN-
Most previous reports of mycobacteria-induced IFN- The accuracy of any diagnostic test is determined by its sensitivity, specificity, positive predictive value, and negative predictive value (8). Although sensitivity is the proportion of patients correctly identified as having disease by the diagnostic test under investigation, specificity is the proportion of patients correctly identified as not having disease by the test. Using a diagnostic threshold of 5 antigen-reactive cells per 200,000 BAL mononuclear cells for either of the two Mycobacterium tuberculosis peptides, the diagnostic test examined by Jafari and colleagues demonstrated a 100% sensitivity and specificity, with a narrow 95% confidence interval of 97 to 100%, despite a relatively small sample size. The results of this small study also suggest positive and negative predictive values of 100%. The excellent evaluation parameters of this test, as reported in this study, raise hopes that we may have finally found a perfect test for the rapid and accurate diagnosis of this disease. However, further validation is needed before this test is included into the clinical armamentarium. When evaluating a diagnostic test, we assume that patients can ultimately be categorized as having disease or no disease. This differentiation is made by a reference standard test (8) Unfortunately, there currently exists no single reference standard test to categorize the presence or absence of smear-negative pulmonary tuberculosis. Defining the reference standard, therefore, usually involves a degree of compromise, often a combination of tests, and occasionally a period of follow-up to evaluate response to empiric antituberculosis therapy. In this study, of the 12 patients diagnosed to have pulmonary tuberculosis, eight had microbiological confirmation on culture and four were presumed to have disease based on clinical and radiologic response to empiric antituberculosis therapy on follow-up. The evaluation of the accuracy of this diagnostic test depends largely on the accuracy of the presumptions about the reference standard, which in turn may depend on the level of training of the provider and the prevalence of disease. There are many potential sources of bias and variability in a diagnostic test (9). For instance, lack of blinding (i.e., the diagnostic test being interpreted by someone who knows the result of the reference standard [test review bias], or the reference standard being interpreted by someone who knows the diagnostic test result [diagnostic review bias]) may have introduced bias in this study. In addition, reproducibility, including interobserver variation in test interpretation, has not been adequately reported for this clinical trial. Furthermore, the study and control groups differed markedly with respect to age, and the possible role of age as a confounding factor cannot be ruled out. Future studies would need to evaluate additional covariates, such as clinical presentation of disease (chronicity, stage of illness, comorbid lung conditions, extrapulmonary sites), as well as nutritional, smoking, and HIV infection status (10). Previous work suggests that, in actual clinical settings, test performance may vary from that in specialized research laboratories (9). Future studies performed in various clinical settings are therefore needed, not only to evaluate the real-world variations in test accuracy but also the test's cost-effectiveness, given the increased prevalence of pulmonary tuberculosis in economically disadvantaged communities. Additional practical problems associated with the expense and invasive nature of bronchoalveolar lavage, and the reluctance of physicians to perform bronchoscopies in patients with possible tuberculosis, may limit the usefulness of this test. What message should the clinician derive from this article? We may be at the threshold of an exciting advance in the immunodiagnosis of smear-negative pulmonary tuberculosis. However, we need to validate the findings of this study in larger cohorts, in diverse clinical settings, with varying pretest probabilities; be mindful of the various biases at work; and gain further knowledge of the cost-effectiveness of this diagnostic test. 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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(and many other cytokines), and are believed to be important in the control of mycobacterial infection. If mycobacterial infection recurs, the number of antigen-specific cells increases greatly at the site of infection, due to a combination of local in situ proliferation and migration from other sites (