Better Tests Help Physicians in Fight against an Old Foe: Tuberculosis

Latent tuberculosis infection (LTBI) in the US remains a considerable problem, with an estimated prevalence of 4.2%, according to NHANES data. That represents approximately 9 million people. "Theoretically, this translates to roughly 450,000 new cases of active TB without secondary transmission or new immigration," said David P Holland, MD, MHS, of Duke University Hospital, during his presentation on the science behind the interferon-gamma release assays (IGRAs) guidelines at the 48th annual IDSA meeting in Vancouver.

"The big catch with LTBI is determining who has it," Holland said. Traditionally, it has been identified using a positive skin test, and no clinical evidence of active TB. The skin test, however, is very operator-dependent. It relies on proper placement and reading technique. "In the average clinical setting the reliability of this test is abysmal," he said. Even in the best setting, using trained observers and the correct technique, the intra- and inter-observer reliability is only fair.

The IGRAs, by comparison, stand to improve the detection of LTBI. Two tests currently commercially available are the T-SPOT TB, which is an Elispot technique, and Elisa. Both measure interferon-y release. The Elisa test is known commercially as the Quantiferon-TB Gold in-Tube (QTF-G-IT) test.

In reviewing the data on the IGRAs, Holland pointed out that their specificity, in all studies done to date, is very high — 93-99%. The estimated sensitivity for QTF-G IT is 70%, compared with 90% for the T-SPOT TB test. "Importantly, there are no differences between BCG-vaccinated and non-BCG vaccinated populations, he said. However, the IGRAs do not reliably exclude TB.

"The big question is how well these tests predict active TB," Holland said. In answering that question, he summarized data from three studies which, taken together appear to indicate that the IGRAs are probably at least as good as the skin test at predicting TB, if not slightly better.

The issue of accurate predictive testing is uniquely important in people with Human Immunodeficiency virus (HIV). "Unfortunately the data are more limited in this population, but there does seem to be an effect of the IGRAs in HIV infected patients with confirmed active TB," Holland said. A small study from Zambia showed 84% sensitivity in HIV-negative patients, and 63% sensitivity in HIV-positive patients. "However, the CD4 count had a major effect on sensitivity," Holland said. "Patients with very low CD4 counts were much less likely to test positive."

With respect to IGRAs in children, there are data to show that children under five years of age do better with T-SPOT compared with the QFT-G. However, there is a high rate of indeterminate results in the studies done to date, usually due to a low mitogen response. Nevertheless, the sensitivity of the IGRAs appears to be similar to that of the TST (67-93%), and the specificity remains high.

"Despite their limitations, these new tests are potentially useful in the detection of TB infection, and their appropriate use is a function of the test characteristics, limitations, and available resources," Holland concluded.