Quantiferon guidelines call for using TST as a back-up test

But only to check positive results

New guidelines for Quantiferon, the newly approved diagnostic test for latent TB infection, will probably suggest using the tuberculin skin test (TST) to confirm positive Quantiferon results.

"In essence, we’ll use Quantiferon as a screening test for the TST, at least for now," says Gerald Mazurek, MD, the epidemiologist at the Centers for Disease Control and Prevention’s Division of Tuberculosis Elimination (DTBE) who has overseen years of trials of the new diagnostic aid in the United States. Using a TST to confirm positive results won’t drive up costs appreciably, because most tests will be negative anyway, Mazurek adds.

The decision to retain the skin test as a backup is mostly aimed at raising users’ comfort level, Mazurek adds. But it’s also an acknowledgement that no one has ever followed subjects who tested positive to see what happens.

"There’s simply not a big cohort of people who’ve been tested and followed through their lifetimes," says Elsa Villarino, MD, MPH, chief of the therapeutics and diagnostics section at the DTBE. "Nor will there be, since if you consider someone infected, you’re obliged to treat them."

Still, that doesn’t mean the new test isn’t trustworthy, say Villarino and Mazurek. Autopsy studies of cattle tested with Quantiferon provide a gold standard the TST is lacking and confirm a tight correlation between Quantiferon results and the presence of TB infection. "Personally, I’m more comfortable with Quantiferon than the tuberculin skin test, and I think that based on the data, it’s a more sensitive test and a better test," says Mazurek. "But the world doesn’t have that much experience with Quantiferon, so I think it’s reasonable for our first step to be a small one."

If the test performs as expected, revised guidelines that would recommend dropping the TST and using Quantiferon results as the sole basis for deciding whether to offer treatment for latent TB infection might be issued at some point, Mazurek adds. The first set of Quantiferon guidelines should be out sometime later this summer and will be included in a Morbidity & Mortality Weekly Report article that will also address issues related to skin-testing.

Two risk categories, two cut-points

The guidelines are expected to lay out two broad categories of risk — "low" and "other" — with a different cut-point assigned to each. With Quantiferon, the two cut-points will correspond not to millimeters of induration, as with the TST, but to two percentages of "optical density," which indicate the percentage in a blood sample of lymphocytes that are sensitized to test antigens.

Thus, a blood sample sensitized to the tuberculin purified protein derivative (PPD) antigen will produce between 15% and 30% more gamma interferon than the mitogen, the test’s control antigen. Subjects judged to be "low risk" must score at least 30% before they can be considered positive; those in the other, higher-risk category need score only 15%. Results can be read visually, but the test also comes with computer software to interpret results, Mazurek notes.

Unlike the tuberculin skin-test, there’s nothing subjective about the test’s reading, says Villarino. What is subjective, however, is the determination of the risk category in which to place a subject. In some instances — health care workers come to mind — there is an ongoing debate about how to make the decision, she concedes. "To me, that’s not an issue," she adds. "I say, look at who the health care worker is and what they’ve been doing."

The draft guidelines were scheduled to be presented before audiences at the American Thoracic Society’s annual meeting in Atlanta in May, and also at the National TB Controllers Association meeting in June. "We don’t expect to get more data; we simply want to formally solicit their input," says Villarino.

The test was originally developed by an Australian veterinarian to detect TB in cattle. It measures the level of gamma interferon (INF-G) produced by lymphocytes sensitized to a specific antigen. The test contains normal saline, used as a negative control; a mitogen, used as a positive control; tuberculin PPD; and Mycobacterium avium PPD. Lymphocytes in blood samples produce INF-G in proportion to the degree to which they have been sensitized. Thus, the test can distinguish whether someone has been sensitized to TB or to M. avium, an atypical mycobacterium that may cause a cross-reaction with the TST.

Because the test uses a one-step blood draw, it doesn’t require subjects to return two to three days later for a reading, as does the TST.

Quantiferon was approved recently by the Food and Drug Administration for use in the United States.