Key Point

The tuberculin skin test for latent TB infection is obsolete, and immune-based rapid blood tests may soon replace it. Proper use of these tests could make the elimination of TB feasible in countries with low prevalence of the disease.

MODENA, ITALY—Is it finally time to retire the oldest diagnostic test currently in use: the tuberculin skin test for latent tuberculosis infection (LTBI)?

The skin test’s limitations "constitute the weakest element in the strategy of targeted testing of LTBI," recently observed Luca Richeldi, MD, PhD, Associate Professor in the Department of Oncology, Hematology, and Respiratory Disease at the University of Modena in Italy.¹ "The high-risk groups that are targeted for preventive therapy are also those in which the [tuberculin skin test] most often fails to detect LTBI," he pointed out.

The sensitivity of the tuberculin skin test is also poor in cases of suspected active TB. The test has relatively low specificity, too.

As a response to these drawbacks, new immune-based rapid blood tests are being created to replace the century-old tuberculin skin test. One of these is the whole-blood ELISA-based QuantiFERON-TB Gold assay recently approved by the FDA for in vitro diagnostics. Another promising LTBI test is the T-SPOT.TB, which is based on an overnight enzyme-linked immunospot assay first introduced almost 10 years ago. T-SPOT.TB has been approved for in vitro diagnostics in Europe and is being evaluated by the FDA.

Like the tuberculin skin test, QuantiFERON-TB Gold and T-SPOT.TB were not meant to detect active TB. However, their accuracy has been studied in TB patients with active disease, and these findings can be extrapolated to LTBI, according to Dr. Richeldi.

In five studies with a total of 266 TB patients, the sensitivity of T-SPOT.TB was 83% to 97%, versus 70% to 89% for QuantiFERON-TB Gold in another five studies with a combined 330 TB patients. "When these results are pooled, the sensitivity of T-SPOT.TB seems to be significantly higher compared with QuantiFERON-TB Gold in patients with active TB," Dr. Richeldi reported.

Furthermore, in a study directly comparing the two tests, QuantiFERON-TB Gold was associated with significantly more indeterminate results in patients younger than 5. A greater incidence of indeterminate results in children tested for TB with QuantiFERON-TB Gold has been reported by other investigators as well, suggesting that this test could actually be less sensitive for LTBI than the tuberculin skin test.

T-SPOT.TB and QuantiFERON-TB Gold are both clearly more specific than the skin test, though. T-SPOT.TB also appears to be more sensitive in immunocompetent individuals with LTBI and in patients with active TB—including those with impaired cellular immunity who are at high risk of false-negative tuberculin skin test results, Dr. Richeldi said.

OPERATIONAL ADVANTAGES AND DISADVANTAGES

"In addition to their improved diagnostic accuracy, the blood tests have operational advantages over [the tuberculin skin test]," he related. These advantages include a lack of interindividual variability during administration, a more objective read-out, and next-day availability of results. Because they do not affect the subsequent results, T-SPOT.TB and QuantiFERON-TB can be used for repeated screening of health care workers and other groups at recurrent risk of TB exposure.

An important drawback of these tests is the need to process them within six hours of venipuncture. "Reliability of results declines after this time point," Dr. Richeldi explained. Future test designs may overcome this limitation, however.

Several reports of the use of T-SPOT.TB and QuantiFERON-TB Gold in diagnostic microbiology laboratories and clinical practices in the United States and Europe suggest that immune-based rapid blood tests for LTBI could be routinely applied in these settings. "These technologies also seem to be feasible in relatively rudimentary laboratories in developing countries, including South Africa, Zambia, and India," asserted Dr. Richeldi.

Direct implementation and full replacement of the tuberculin skin test with immune-based rapid blood tests would be the simplest, most accurate strategy and one that has been suggested by the CDC, Dr. Richeldi said. Nevertheless, he acknowledged that more data on the effectiveness of these tests in HIV-infected patients, young children, and other vulnerable groups are needed before such a change can be undertaken.

"The improved diagnostic accuracy for the diagnosis of LTBI coupled with the advantageous operational characteristics of the new blood tests should improve the effectiveness of TB control programs and will be a key factor in making TB elimination feasible in low-prevalence countries," he concluded. "However, achieving these goals depends on the successful deployment of the new tests under routine program conditions."

—Timothy Begany

Reference
1. Richeldi L. An update on the diagnosis of tuberculosis infection. Am J Respir Crit Care Med. 2006;174: 736-742.

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