F.D.A. approves first blood test for screening for latent tuberculosis.

The QuantiFERON-TB blood test, produced by Cellestis Limited, Australia, was approved by the U.S. F.D.A. in October 2001. It is not yet actually available in the U.S., but it is anticipated that it should be very soon. This is a blood test that could potentially take the place of the tuberculin skin test (TST), with the obvious advantages that it does not require a return visit by the patient for test reading and does not rely on skilled nursing staff to administer since a simple blood draw is all that is required. In addition, it may be better than the tuberculin skin test at distinguishing a reaction due to TB infection from a reaction due to BCG vaccination or non-tuberculous mycobacteria. The test involves drawing a heparinized whole blood sample from the patient, incubating the sample overnight with a test tuberculosis antigen and control antigens, then drawing off the plasma and measuring the amount of interferon-gamma (IFN-γ) which has been produced by the patient’s lymphocytes in cell-mediated immune response to the antigens.

One difficulty in evaluating the new test has been the lack of a reliable comparison "gold standard" for detection of latent TB. The TST is the only test currently available for latent TB. While the TST is considered to be fairly sensitive, its specificity may be low in some populations, especially those with history of BCG vaccination or those with exposure to non-tuberculous mycobacteria (such as may be present in the environment).

There have been many clinical trials of the QuantiFERON-TB test. One study reported 98% specificity and 90% sensitivity for detection of latent TB compared to TST results (IJTLD 1996, 2(6):443-450). This same study found that 83% of those with proven active disease and 59% of those with previously treated disease had a positive response. The low QuantiFERON positivity rate for those with previously treated disease is thought to be due to prolonged suppression of this aspect of the cell-mediated response by TB disease. QuantiFERON response may not return to normal until up to 3 years after TB treatment while TST response usually recovers within a couple of weeks after starting treatment. A more recent study (JAMA Oct 10, 2001, 286(14):1740-1747) reported that while the overall agreement between the TST and the IFN-γ assay was 83.1%, those who had been previously BCG-vaccinated were 7 times more likely to have a positive TST and a negative IFN-γ test than an unvaccinated person. Among unvaccinated persons with a positive TST and a negative IFN-γ test, 21.2% showed an IFN-γ response to non-tuberculous mycobacteria.

According to information from the manufacturer, the test is anticipated to be moderately priced at about $10 per test ($440 for a lab kit that will do 44 tests). One possible practical drawback is that blood must be incubated with the test antigens within 12 hours of drawing. We will be obtaining more information from the manufacturer in coming weeks and will keep you informed about feasibility and availability. The Centers for Disease Control and Prevention has not yet issued any guidelines regarding this test, but a statement is anticipated soon.

When is a culture-positive TB case not TB?

When the culture is positive due to cross-contamination in the laboratory. Alas, this may occasionally happen even in the best of labs. A recent journal article (IJTLD Sept 2001, 5(9):861-867) estimated that in the U.S., 0.4% to 3.5% of all positive TB cultures are due to lab contamination. Lab results should always be interpreted with one eye on the patient. Circumstances which might raise a suspicion for a false positive culture due to lab contamination include: 1) the patient’s clinical condition is not consistent with TB, 2) only one culture among many specimens sent is positive and all smears are negative for acid-fast bacilli, 3) the reported growth on the culture is scant (only a few colonies or growth only in broth) or the time until growth is detected is long (>30 days), 4) the specimen was processed in the lab at the same time as another known-positive specimen, including lab controls [MMWR 2000; 49(19)]. When cross-contamination is suspected, it can often be confirmed by sending the specimens in question for restriction fragment length polymorphism (RFLP) DNA fingerprinting. If you should ever suspect a positive TB culture may be due to lab cross-contamination, please call me, Cheryl McRill, M.D., State TB Controller, at 602-230-5820.

Pyrazinamide added to routine drug susceptibility testing for TB cultures done at Arizona State Lab.

All M. tuberculosis specimens sent to Arizona State Laboratory for drug susceptibility testing are now being tested for susceptibility to pyrazinamide in addition to the usual panel of drugs. The Bactec method is being used, so results will be reported only as "susceptible," "resistant," or "intermediate." Confirmatory testing is available for "intermediate" specimens. Pyrazinamide is an important first-line anti-TB drug whose use during the induction phase of treatment is necessary for standard short-course (6 months) treatment.

New recommendations for treatment of TB in patients with advanced HIV disease. 

MMWR (vol. 51, no. 10), March 15, 2002, reports that HIV-infected TB patients with CD4 cell counts of <65/mm³ are more likely to develop rifamycin-resistant TB if treated with a "highly intermittent" treatment regimen (less than 3 doses per week). In a clinical trial of 151 HIV-positive TB patients, 5 who failed or relapsed after TB treatment had acquired rifamycin resistance during treatment. All 5 had CD4 cell counts <65/ mm³, and all 5 had been treated with a twice weekly dosing regimen. Similar occurrences have been observed in two previous clinical trials involving treatment of HIV-TB with rifabutin and rifapentine. Therefore, the CDC recommends that persons with HIV-associated TB and with CD4 cell counts <100/mm³ should not be treated with highly intermittent (once or twice weekly) regimens. These patients should receive daily therapy during the intensive phase and daily or 3 doses per week during the continuation phase. The use of directly observed therapy is advised.