Interferon-gamma-release assays: Better than tuberculin skin testing?

CASE 1: A FOREIGN-BORN HEALTH CARE WORKER WITH A POSITIVE RESULT

A 30-year-old woman, an immigrant from the Philippines, is applying for a position as a registered nurse. On preemployment screening, her QFT-GIT test is positive: 8.1 IU/mL in the tuberculin antigen tube minus 0.6 IU/mL in the nil tube, for a tuberculin response of 7.5 IU/mL. Her medical record shows that previous tuberculin skin tests were positive. Her current screening examination and chest radiograph are normal. She received BCG vaccination as a child.

Comment. This case illustrates how the assays are useful in diagnosing latent tuberculosis in foreign-born health care workers. Whereas this patient’s previous positive skin tests may have been falsely positive because of her childhood BCG vaccination, BCG vaccination does not affect the results of interferon-gamma-release assays, and thus a positive QFT-GIT test is likely to indicate latent tuberculosis.

Case continued

We believe our patient has latent tuberculosis, and we recommend isoniazid therapy. However, she does not want to take isoniazid: she says she underwent a tuberculin skin test 2 days before the QFT-GIT test, and she thinks that may have affected her QFT-GIT test result.

Comment. Can tuberculin skin testing influence the results of interferon-gamma-release assays? The question is important, considering that the UK National Institute for Health and Clinical Excellence recommends a two-step procedure, with tuberculin skin testing first, then an interferon-gamma-release assay if the skin test is positive.¹⁰

Studies have found conflicting results.¹⁴ However, van Zyl-Smit et al¹⁴ obtained blood samples for QFT-GIT and T-SPOT.TB testing in 26 South Africans at 21, 14, and 7 days before tuberculin skin testing, and also on the day of the test and at 3, 7, 28, and 84 days after. They observed higher interferon-gamma responses after tuberculin skin testing, greater than the within-subject variability. This “boosting” effect was evident on day 7 but not on day 3, leading the investigators to conclude that interferon-gamma-release assays should ideally be performed no more than 3 days after a skin test.

The Canadian guidelines¹⁵ recommend an interferon-gamma-release assay on or before the day the skin test is read if both types of tests will be used. It is important to note that interferon-gamma-release assay testing does not boost subsequent test results,⁹ such as when used for serial or periodic testing.

For our patient in this case, isoniazid therapy is still recommended.

CASE 2: A MAN AT LOW RISK WITH A POSITIVE RESULT

A 26-year-old man applying for a position in health data services has a positive QFT-GIT test on preemployment health screening. He was born and raised in the United States, and has no known contacts with tuberculosis. He has never had a tuberculin skin test. A chest radiograph shows no evidence of tuberculosis, and he has no symptoms. His quantitative result (ie, the interferon-gamma level in his blood incubated with tuberculin antigens, minus the interferon-gamma level in his blood cultured without antigens) is 0.37 IU/mL.

Comment. QFT-GIT results are considered positive if the tuberculin response (tuberculin antigen tube minus nil tube) is 0.35 IU/mL or higher, and at least 25% higher than in the nil sample (Table 1), so this man’s result is just above the cutoff. T-cell responses can vary from time to time in the same person and from person to person, and this variation is reflected in the 15% variance accepted by the FDA.¹⁶ Given the applicant’s history, he is unlikely to have latent tuberculosis or to need isoniazid treatment.

This case shows the importance of having the actual quantitative interferon-gamma value when evaluating a patient with a positive interferon-gamma-release assay, particularly a patient at low risk of tuberculosis.

CASE 3: SEROCONVERSION

A 59-year-old woman, born and raised in the United States and working in the hospital environmental services department, has a positive QFT-GIT result on routine annual screening. Previous tuberculin skin tests were negative, and her first QFT-GIT test result on annual screening was negative. Her chest radiograph is negative, and she has no symptoms. One year ago her QFT-GIT value (tuberculin antigen tube minus nil tube) was 0.09 IU/mL; now it is 0.61 IU/mL. A tuberculin skin test is placed and is negative.

Comment. This case illustrates “QFT-GIT conversion,” ie, a positive test result in a person who previously had negative results.¹⁷ However, as with the man in case 2, 0.61 IU/mL can also be considered a weakly positive result. If the QFT-GIT result is weakly positive and the skin test is negative, results must be interpreted with caution. Nonspecific variations can occur with serial testing, and weakly positive responses may fluctuate over time.¹⁸

Veerapathran et al¹⁸ studied the shortterm reproducibility of the QFT-GIT test in 14 health care workers who underwent serial testing; discordance was mostly noted in those who had interferon-gamma values around the cutoff point. They suggested that a QFT-GIT conversion should be defined as a change from a negative to a positive result and at least a 30% increase in the baseline interferon-gamma response.¹⁷

Also, a small prospective series in a highrisk US immigrant population showed that the QFT-GIT test had inconsistent results in 13% of those tested, particularly in those with low positive responses (< 0.69 IU/mL).¹⁹

For clinicians, the question remains whether we need to use another cutoff to distinguish new infection from nonspecific variations, and whether the cutoff should vary depending on risk of infection.