Abstract & Commentary

Interferon-γ Release Assays: Utility and Limitations

By Lin H. Chen, MD, Assistant Clinical Professor, Harvard Medical School; Director, Travel Medicine Center, Mt. Auburn Hospital, Cambridge, MA

Dr. Chen has received research grants from the Centers for Disease Control and Prevention and Xcellerex. This article originally appeared in the August 2011 issue of Travel Medicine Advisor. At that time it was peer reviewed by Philip R. Fischer, MD, DTM&H, Professor of Pediatrics, Department of Pediatric & Adolescent Medicine, Mayo Clinic, Rochester, MN. Dr. Fischer reports no financial relationship to this field of study.

Synopsis: Interferon-g release assays are recommended in the screening for latent tuberculosis infection, but issues with discordance and reproducibility, lack of prognostic value, and low efficacy in children require further refinement to achieve proper interpretation.

Sources: Herrera V, et al. Clinical application and limitations of interferon-gamma release assays for the diagnosis of latent tuberculosis infection. Clin Infect Dis 2011;52:1031-1037.

Herrera and colleagues reviewed the use of interferon-γ release assays (IGRAs) for the diagnosis of latent tuberculosis infection (LTBI). Interferon-g is released by CD4 cells when infected with Mycobacterium tuberculosis (MTB), and IGRAs measure interferon-γ response in blood. The FDA approved the first IGRA, QuantiFERON-TB test (QFT), in 2001, followed by QuantiFERON-TB Gold test (QFT-G) in 2005. More recently, the FDA approved QuantiFERON-TB Gold-In-Tube test (QFT-GIT) in 2007 and T-Spot in 2008.

QFT-G uses an enzyme-linked immunosorbent assay [ELISA] to measure the interferon-γ released when whole blood is incubated with MTB antigens. The GIT simplified the procedure by collecting blood directly into pre-coated tubes for incubation. T-Spot uses an enzyme-linked immunospot assay to count the cells that produce interferon-γ on pre-coated plates. The two newer tests, QFT-GIT and T-Spot, use specific MTB antigens (early-secreted antigen 6 [ESAT6] and culture filtrate protein 10 [CFP10]) that are not present in other strains of mycobacteria or the BCG vaccine strain; therefore, these tests have increased specificity compared to the tuberculin skin test (TST).

In the United States, TB screening primarily targets persons that may have been infected recently and persons with health conditions that increase their susceptibility for reactivation of LTBI. The ideal timing of screening test is considered to be 8-10 weeks after the possible exposure, prior to which the test may be falsely negative.

Herrera et al note that the QFT-GIT, T-Spot, and TST vary in performance depending on the test population, study type, study definitions/parameters, and that there are very few direct comparisons. Nevertheless, the pooled sensitivity was 83%, 90%, and 89%, respectively, and pooled specificity was 99%, 88%, and 85%, respectively. The IGRAs are superior to TST in its specificity in BCG-vaccinated populations.

The limitations highlighted in this paper include:

  • IGRAs are not sufficiently sensitive to detect a very recent TB exposure.
  • IGRAs have shown discordance with TST.
  • A negative IGRA result does not rule out the diagnosis of LTBI.
  • The quantitative results from IGRAs have not yet demonstrated prognostic value regarding progression to active TB.
  • IGRAs cannot differentiate between active TB, LTBI, treated infection, or recent vs. remote infection.
  • Reproducibility of IGRAs has been variable and serial tests have found conversions and reversions in the range of 12%-50%.
  • Efficacy in children is low and a negative IGRA test does not exclude infection.

The authors recommend some practical approaches to interpreting IGRA and TST results. First of all, conversion from a negative to a positive result could mean a false-positive test in a low-risk person, and possibly could be associated with concurrent illness, laboratory determinants, and nonspecific boosting of interferon-γ. Reversion from a positive to a negative result may be influenced by similar factors. Treatment can lead to reversion, or more likely to a decline in the quantitative result. Because delays in incubation and sample processing can lower interferon-γ responses, quantitative results aid in predicting reversion or conversion when the interferon-γ result is near the test cutoff point.

Regarding discordant IGRA and TST results in a low-risk person, a negative IGRA is more reliable than a positive TST in BCG-vaccinated individuals. On the other hand, a negative TST and a positive IGRA in a high-risk individual should not preclude further evaluation for TB.

Commentary

A total of 11,181 TB cases were reported in the United States in 2010, corresponding to a rate of 3.6 cases per 100,000 population.1 TB cases in foreign-born individuals comprised 60.5% of all cases in those with known country of origin, at a case rate of 18.1 cases per 100,000 population, and has remained in the range of 7,000-8,000 cases per year since 1993.1 Foreign-born persons younger than 18 years of age also have a disproportionately high TB case rate, at 11.4 per 100,000 population or almost 20 times higher than that of their U.S.-born counterparts.2 The burden of disease among foreign-born individuals suggests that screening these populations for LTBI should be a highly effective strategy for TB control and prevention in the United States.3

Similar to foreign-born persons, previous studies have also established that travel destinations determine the TB exposure risk and long-term travelers have risks that resemble the local incidence.4,5 Additionally, health care work overseas was associated with increased risk, and travelers who are visiting friends and relatives (VFR) also have an increased risk.4,6 For example, travelers who participate in health care work overseas had a TST conversion rate of 7.9 per 1,000 person-months of travel, whereas non-health care workers had a rate of 2.8 per 1,000 person-months.4 Travelers whose trips include such activities should be prioritized for screening.

Since the FDA approval of IGRAs, the CDC has published guidelines for using these tests to detect MTB infection.1 All indications focus on their use for TB screening, as an alternative or a complement to TST. Their major advantages over the long-standing TST are: 1) the convenience of a single visit; 2) the omission of trained staff to read and interpret the reaction; and 3) the higher specificity in BCG-vaccinated persons. However, a blood sample is required to perform IGRAs, and Herrera et al have pointed out some significant limitations.

In the U.S. population, IGRAs are more specific, but less sensitive, than TST for predicting future disease. Horsburgh recently summarized the sensitivity of IGRAs for predicting progression to active TB within several years after exposure to be 80%-90% with specificity of 56%-83%, or a positive predictive value of 4%-8%, and negative predictive value of 99%-100%.3 At the same time, a positive TST of 5 mm has a sensitivity of 90%-100% to predict progression to active TB and a specificity of 29%-39%, or a positive predictive value of 2.7%-3.1%, and a negative predictive value of 99%-100%.3

An additional issue noted by Herrera and other authors is the establishment of cutoff points. Whereas TST conversion is defined as an increased induration of 10 mm or more, cutoffs for IGRA conversions are not fully defined.3 Interestingly, screening guidelines using IGRAs vary among countries.3,7 However, most experts agree that IGRAs are valuable when screening BCG-vaccinated individuals, and also better when there is high prevalence of recent TB infection, including recently arrived foreign-born individuals and likely international travelers.1,3

IGRAs can be especially useful in screening BCG-vaccinated travelers, VFR travelers, long-term travelers, and health care travelers. Travel medicine practitioners should be aware of the limitations articulated by Herrera et al. Finally, we need more data to assess the efficacy of IGRAs in screening the specific population of travelers and to establish proper IGRA cutoff values and interpretation for this population.

References

  1. Centers for Disease Control and Prevention. Trends in tuberculosis — United States, 2010. MMWR Morb Mortal Wkly Rep 2011;60:333-337.
  2. Menzies HJ, et al. Epidemiology of tuberculosis among US- and foreign-born children and adolescents in the United States, 1994-2007. Am J Public Health 2010;100:1724-1729.
  3. Horsburgh CR, Rubin EJ. Latent tuberculosis infection in the United States. N Engl J Med 2011;364:1441-1448.
  4. Cobelens F, et al. Risk of infection with Myco-bacterium tuberculosis in travellers to areas of high tuberculosis endemicity. Lancet 2000;356:461-465.
  5. Jung P, Banks RH. Tuberculosis risk in US Peace Corps Volunteers, 1996 to 2005. J Travel Med 2008;15:87-94.
  6. Leder K, et al. Illness in travelers visiting friends and relatives: A review of the GeoSentinel Surveillance Network. Clin Infect Dis 2006;43:1185-1193.
  7. Apers L, et al. The use of interferon-gamma release assays for tuberculosis screening in international travelers. Curr Infect Dis Rep 2011;13:229-235; doi: 10.1007/s11908-011-0173-0.