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Interferon Gamma Release Assays for Detection of Latent Tuberculosis Infection
Abstract & Commentary
By Mary Louise Scully MD
Dr. Scully is Director, Travel and Tropical Medicine Center, Sansum Clinic, Santa Barbara, CA.
Dr. Scully reports no financial relationships relevant to this field of study.
Synopsis: Interferon gamma assays now are commercially available for the diagnosis of latent tuberculosis infection and have an advantage over tuberculin skin tests in being better able to identify persons with true latent tuberculosis infections versus prior Bacille Calmette-Guéron (BCG) vaccination.
Source: Vinton P, Mihrshahi S, Johnson P, et al. Comparison of QuantiFERON-TB Gold In-Tube test and tuberculin skin test for identification of latent Mycobacterium tuberculosis infection in healthcare staff and association between positive test results and known risk factors for infection. Infect Control and Hosp Epidemiol 2009;30:215-221.
In this study, a total of 358 hospital staff members from 5 hospitals in Melbourne, Australia had both a tuberculin skin test (TST) and a QuantiFERON-TB Gold In-Tube test (QFT-in tube test) performed, and the results were compared. In addition, information about demographic variables and tuberculosis risk factors were obtained from participants. There were fewer overall positive QFT-in tube test results compared to positive TST results (6.7% vs 33.0%). The agreement between the QFT-in tube test and TST was poor (71%) when a TST cut-off of 10 mm of induration was used, but this improved to 82% if a TST cutoff of 15 mm of induration was used.
Discordant results, where the TST was positive and the QFT-in tube was negative, were most strongly associated with receipt of BCG vaccination and having an occupation within the hospital that involved patient contact. A positive QFT-in tube test was associated with birth in a country with high tuberculosis (TB) prevalence, increased number of years having lived in a TB-endemic country, and high–risk occupational contact.
This study suggests that in countries with low TB prevalence but high rates of BCG vaccination, the QFT-in tube test may be better able to identify healthcare workers with true latent tuberculosis, who potentially would benefit from treatment, by reducing the number of false-positive results associated with prior BCG vaccination.
For decades, the TST test was the only means of diagnosing latent tuberculosis infection (LTBI). Although inexpensive, the TST requires a return visit from the patient at 48-72 hours as well as some degree of expertise in proper placement and interpretation of the TST result. More recently, interferon-gamma release assays (IGRAs) have emerged and now are commercially available for the diagnosis of LTBI.
IGRAs are in-vitro blood tests that measure interferon gamma (IFN-g) release from sensitized lymphocytes after stimulation by Mycobacterium tuberculosis-specific antigens. These antigens, early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), are absent from most environmental mycobacteria and, most importantly, from all strains of BCG vaccine. Therefore, a positive IGRA result should be secondary to actual Mycobacterium tuberculosis infection and not prior BCG vaccination.
Commercially available IGRAs include the QuantiFERON-TB Gold, an enzyme-linked immunosorbent assay (ELISA) and the T-SPOT.TB, an enzyme-linked immunospot assay. A newer version of the QuantiFERON-TB Gold test is the Quantiferon-TB Gold In-tube test or "third generation" QuantiFERON assay, in which the collection of blood samples is done in tubes pre-filled with antigen, which helps simplify the laboratory procedure. IGRAs have the advantage of needing only a single patient visit, rapid turn-around time for results, and do not require reader interpretation. Disadvantages of the IGRAs are their higher relative cost and the need for an equipped laboratory. On occasion, the QuantiFERON-TB Gold and QuantiFERON-TB Gold In-tube tests give an "indeterminate" result. Indeterminate results are associated with immunosuppression, young age, and older age.1 Despite this issue, a recent study using a hypothetical model for screening and treating nurses within the Veterans Health Administration demonstrated that IGRAs might actually be more cost-effective across a range of variables compared to standard TST-based strategies.2
In 2005, the Centers for Disease Control and Prevention (CDC) stated in its guidelines that IGRAs may be used in all circumstances in which the TST is used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control.3 Other countries are adjusting their national guidelines as more data become available on IGRAs. For example, the recent Canadian guidelines are complex but involve the use of both TST and IGRAs depending upon epidemiological and personal data.4
There are not enough data yet to predict how well IGRAs will perform in select populations such as at the extremes of age, in the malnourished, or during immunosuppression such as HIV infections. In a recent pediatric study, the QuantiFERON-TB Gold test was not as sensitive as TST for the diagnosis of LTBI in children younger than 2 years of age, raising appropriate concern about the use of IGRAs in very young children.5 Some data suggest that the sensitivity of the T-SPOT.TB test may be higher than that of the QuantiFERON tests in populations with immunosuppressive disorders.6
The full spectrum of the usefulness of IGRAs will require longitudinal studies and further studies in select populations such as young children and immunosuppressed patients. However, the data are encouraging and support the use of IGRAs in patients previously immunized with BCG. In this scenario, a BCG-vaccinated patient with a positive TST (but no recent high-risk TB exposure) and a negative IGRA test would not require a treatment course for latent tuberculosis infection that otherwise might have been recommended prior to the advent of IGRAs.