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Weighing Gold or Counting Spots

Which Is More Sensitive to Diagnose Latent Tuberculosis Infection?

Center for Pulmonary and Infectious Disease Control, University of Texas Health Center, Tyler, Texas

In this issue of the Journal (pp. 736–742), Richeldi summarizes a rapidly progressing area of research: the use of the IFN-–based blood tests, T-SPOT.TB and QuantiFERON-TB Gold, to diagnose latent tuberculosis infection (LTBI) (1). Both tests detect IFN- produced by memory T cells that recognize Mycobacterium tuberculosis proteins that are absent in M. bovis bacille Calmette-Guérin (BCG). Vaccination with BCG does not yield false-positive results, and this improved specificity over the tuberculin skin test has been confirmed by multiple studies, summarized by Richeldi (1). However, the relative sensitivity of the IFN-–based tests and the tuberculin skin test remains controversial.

To gain perspective on this issue, it is useful to compare the factors necessary to yield a positive test result. The T-SPOT.TB test detects individual memory T cells that produce IFN- in response to M. tuberculosis antigens, using the enzyme-linked immunospot technique. The QuantiFERON-TB Gold test measures IFN- in the supernatant of antigen-stimulated cells by enzyme-linked immunoassay. In other experimental systems, the enzyme-linked immunospot is more sensitive than the enzyme-linked immunoassay for detecting cytokines (2, 3). The tuberculin skin test measures the delayed-type hypersensitivity response, and a positive test requires that memory T cells travel to the skin test site, recognize the mycobacterial antigens, and, together with other cells, mount an inflammatory response that yields induration.

IMMUNOSUPPRESSED PATIENTS

Based on the above information, the T-SPOT.TB test should be more sensitive than the QuantiFERON-TB Gold test, particularly in persons with defects in memory T-cell number or function. Similarly, in the presence of defects in lymphocyte homing or in generation of local inflammation, the IFN-–based tests should be more sensitive than the tuberculin skin test. Defects in memory T cells and delayed-type hypersensitivity responses are observed in many immunosuppressive conditions, including HIV infection, cancer chemotherapy, and the extremes of age (4–6). Diagnosis of LTBI in these patients is important because they are at increased risk for progression of LTBI to tuberculosis. Because there is no gold standard for LTBI, investigators have studied the sensitivity of IFN-–based tests in patients with active tuberculosis, who have reduced capacity to produced IFN- (7). These studies, summarized by Richeldi (1), show that the IFN-–based tests are more sensitive than the tuberculin skin test. In three reports comparing both IFN-–based tests in a total of 134 patients, sensitivity of the T-SPOT.TB test was 83 to 95%, compared with 74 to 83% for the QuantiFERON-TB Gold test (8–10), and this difference was statistically significant in the largest study (8). If these results in patients with tuberculosis can be extrapolated to immunosuppressed patients with LTBI, this suggests that the T-SPOT.TB test is more sensitive than the QuantiFERON-TB Gold test in this population.

Another important issue in evaluating patients with depressed immune function for LTBI is the frequency of indeterminate results. Two studies show that indeterminate IFN-–based test results are more common in immunosuppressed patients than in immunocompetent persons (9, 11). Indeterminate results were significantly more common with the QuantiFERON-TB Gold test than with the T-SPOT.TB test (9). Therefore, current published data indicate that the T-SPOT.TB test yields more evaluable results and is probably more sensitive for the diagnosis of LTBI in immunosuppressed patients than the QuantiFERON-TB Gold test. One caveat to the increased sensitivity of the T-SPOT.TB test is that it may identify persons who clear a transient infection with M. tuberculosis. Some immunocompetent contacts of patients with tuberculosis with negative tuberculin skin tests have positive T-SPOT.TB tests that later become negative, suggesting that the T-SPOT.TB test detects an immune response to M. tuberculosis infection that does not become established (12). However, even if this is the case, in the setting of immunocompromised patients at increased risk for progression of LTBI to tuberculosis, the risk–benefit ratio favors treatment of those with positive T-SPOT.TB tests.

Although current data suggest that the T-SPOT.TB test is superior to the QuantiFERON-TB Gold test in immunosuppressed patients, the number of studies comparing the two tests is limited. Additional comparative studies in patients with conditions that may depress cell-mediated immunity, such as diabetes and renal insufficiency, will be important to further delineate the role of these IFN-–based tests.

IMMUNOCOMPETENT PATIENTS

In contrast to findings in immunosuppressed patients, the IFN-–based tests and the tuberculin skin test may have comparable sensitivity in immunocompetent individuals with good memory T-cell and delayed-type hypersensitivity responses. Richeldi concludes that the T-SPOT.TB test is more sensitive than the QuantiFERON-TB Gold and the tuberculin skin test for diagnosis of LTBI in immunocompetent persons, primarily because T.SPOT-TB test results correlate more strongly than tuberculin skin test results with extent of exposure to tuberculosis (13, 14). However, superior correlation can be due to increased sensitivity, increased specificity, or both. Because the T-SPOT.TB test is clearly more specific than the tuberculin skin test, it is unclear if the T-SPOT.TB test also has increased sensitivity. Given current knowledge, I would consider the IFN-–based tests and the tuberculin skin test to be equally sensitive in healthy individuals. Nevertheless, the IFN-–based tests are superior to the tuberculin skin test because of their increased specificity and more favorable operational characteristics, as summarized by Richeldi (1).

RECOMMENDATIONS

In the United States, the Food and Drug Administration has approved the QuantiFERON-TB Gold test for diagnosis of LTBI and is evaluating the T-SPOT.TB test. The Centers for Disease Control and Prevention have recommended that the QuantiFERON-TB Gold test can generally be substituted for the tuberculin skin test (15). I agree with this recommendation, except that I favor continued use of the tuberculin skin test in populations with depressed cell-mediated immune responses. In Europe, where both IFN-–based tests are available, I believe that the T-SPOT.TB test should be used for persons in whom cell-mediated immunity may be depressed. For immunocompetent persons, either IFN-–based test can be used. Clinical laboratories are likely to prefer the QuantiFERON-TB Gold test because it is simpler to perform than the T-SPOT.TB test.

The past decade has witnessed development of the first improved methods to diagnose LTBI in a century. Additional studies should continue to improve our ability to use the IFN-–based tests to diagnose LTBI and prevent development of tuberculosis.

Acknowledgments

Supported in part by the Cain Foundation for Infectious Disease Research. Peter F. Barnes holds the Margaret E. Byers Cain Chair for Tuberculosis Research.

FOOTNOTES

Conflict of Interest Statement: P.F.B. owns 4,000 shares of Cellestis, which markets the QuantiFERON-TB test.

REFERENCES

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