Definition and Use
- M. tuberculosis infection may present with a range of disease syndromes, including acute infection, active infection, latent infection, and reactivation disease. Patients are evaluated on the basis of clinical presentation, epidemiologic risk assessment, radiographic studies, and evidence of host response by screening tests; diagnosis is established by detection of M. tuberculosis by culture or molecular diagnostic methods.
- In the past, the tuberculin skin test (TST) was used to detect host response, but the recent development of FDA-approved interferon-gamma release assays (IGRAs) has provided an alternative method for detecting immunologic response to M. tuberculosis antigens. IGRAs may be used in the evaluation of patients for latent or active (acute or reactivation) TB.
Method
- Three FDA-approved IGRAs are currently available.
- IGRAs measure immune reactivity of a patients WBCs when challenged with synthetic antigens that are present in all strains of M. tuberculosis but absent in BCG strains. Immune reactivity is measured by the interferon-gamma concentration, or number of interferon-gamma " “producing cells, after exposure of viable WBCs to these antigens.
- Advantages of IGRAs include
- IGRAs require only a single patient visit to conduct the test.
- Results are available within 24 hours, which may facilitate patient evaluation and contact investigation.
- IGRA testing does not boost the immunologic response in subsequent tests.
- Prior BCG vaccination does not cause false-positive reaction in IGRAs.
- The assessment of IGRA test accuracy depends on the populations studied, the comparator method, and other factors. In general, the sensitivity of the IGRAs is high and comparable to TSTs. Studies suggest that the specificity of IGRAs is slightly higher than the specificity of TSTs. IGRAs may be used and considered acceptable medical and public health practice in all situations in which the CDC recommends TST to aid in the diagnosis of TB.
- IGRA assays (and TSTs) are recommended only for patients with a significant prior probability of tuberculosis; routine patient testing is not recommended. If indicated, either TST or IGRA may be used.
- IGRA testing may be recommended after initial TST in special circumstances:
- If the initial, primary test is negative, and
- The risk for poor patient outcome (severe or progressive disease) is high, as for young children or HIV-infected patients.
- The clinical suspicion for TB, based on other criteria, is high.
- A positive result from a second test would be interpreted as increased sensitivity for detection of infection.
- If the initial, primary test is positive, and
- Additional evidence of infection may encourage a patient's acceptance of the diagnosis and compliance with therapy.
- A negative result would establish a false-positive TST result in patients with a low probability of tuberculosis based on other factors.
- Initial TST indeterminate or equivocal test result is seen in patients in whom TB cannot be ruled out by other factors.
Special Collection and Transport Instructions
- Specimens must be collected into tubes specified by the manufacturer.
- Specimens must be collected strictly following the manufacturers instructions.
- Specimens must be inverted or shaken vigorously according to the manufacturer's instructions.
- Transport at room temperature. Specimens should not be refrigerated or frozen during transport.
Interpretation
- Expected results: Negative.
- Positive results: Positive results suggest that infection with M. tuberculosis is likely, but cannot determine the stage of infection. Reactive specimens support a diagnosis of acute, active or, latent infection, or reactivation TB.
- Negative results: Infection with M. tuberculosis is unlikely.
- Indeterminate or borderline: M. tuberculosis infection is not established. Alternative or sequential testing may resolve the diagnosis.
Limitations
- The performance of IGRAs has not been adequately evaluated in certain patient populations, like pregnant women, children, patients with malignancies and other chronic infections, patients treated with medications that affect immune response, and patients with extended therapy with antituberculous agents.
- Negative test results cannot exclude a diagnosis of TB.
- Results, especially negative responses, must be interpreted in the context of the patients state of immunocompetence.
- TSTs are preferred for the evaluation of children, especially those younger than 5 years of age.
- For patients with latent TB, IGRAs cannot be used to predict which patients will progress to reactivation disease.
- The use of IGRAs versus TSTs, as a first-line screening tool, must be determined on the basis of several factors, including cost, patient population served, likely compliance of patients with return visits, prior vaccination with BCG, and access to laboratory processing in a timely manner.
- The effect of recent live-virus vaccination on the performance of IGRAs has not been well studied. IGRAs may be performed prior to or on the same day as live-virus vaccination. Otherwise, the IGRA should be delayed for 4 " “6 weeks after vaccination.
- The effect of lymphopenia on IGRAs is unknown.
- The antigens used in IGRAs (ESAT-6 and CFP-10) are present in Mycobacterium kansasii, M. szulgai, M. marinum, and several other non " “M. tuberculosis species. Infection with other mycobacterial species should be considered, and ruled out as appropriate, in patients with positive IGRA test results.
- Common pitfalls:
- IGRAs (and TSTs) may be submitted for patients at very low risk for infection with M. tuberculosis.
- Delayed transport or improper specimen handling during transport may decrease the viability of lymphocytes and result in false-negative results.
Suggested Reading
1Centers for Disease Control and Prevention. Updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection " ”United States, 2010. MMWR Morbid Mortal Wkly Rep. 2010;59(RR-5).