Role of Interferon Gamma Release Assay (IGRA) in Diagnosing Latent Tuberculosis Infection
Interferon Gamma Release Assays (IGRAs) are recommended as either a replacement for or complement to the tuberculin skin test (TST) for diagnosing latent tuberculosis infection (LTBI), with specific testing strategies varying based on patient risk factors and BCG vaccination status. 1
What are IGRAs?
IGRAs are blood tests that measure the immune response to Mycobacterium tuberculosis antigens. Two commercially available IGRAs are:
- QuantiFERON-TB Gold In-Tube (QFT-GIT)
- T-SPOT.TB
These tests detect interferon-gamma released by T-cells in response to M. tuberculosis-specific antigens that are not present in BCG vaccine or most non-tuberculous mycobacteria, offering improved specificity compared to TST in BCG-vaccinated individuals 2.
Advantages of IGRAs over TST
- Single patient visit (versus two for TST)
- Results available within 24-48 hours
- Not affected by prior BCG vaccination
- No boosting effect with repeated testing
- More objective laboratory-based measurement
- No cross-reactivity with most non-tuberculous mycobacteria 1, 2
Limitations of IGRAs
- Cannot distinguish between LTBI and active TB
- Limited predictive value for progression to active TB
- Reduced sensitivity in immunocompromised patients
- Potential for variability in results (preanalytical, analytical, and immunological factors)
- Higher cost than TST 2, 3
Recommended Testing Approaches
Current guidelines recommend four main approaches for IGRA use 1:
1. Two-Step Approach
- TST first, followed by IGRA if TST positive: Increases specificity in BCG-vaccinated individuals (recommended for immigrant screening)
- TST first, followed by IGRA if TST negative: Increases sensitivity in immunocompromised individuals
2. Either TST or IGRA (but not both)
- Based on availability, cost considerations, and patient factors
3. TST and IGRA Together
- Increases sensitivity for high-risk groups (HIV-infected, TNF-α inhibitor candidates)
4. IGRA Only (replacing TST)
- Particularly in BCG-vaccinated populations
Patient-Specific Recommendations
Immunocompromised Patients (HIV, TNF-α inhibitor candidates)
- Higher risk of progression to active TB if infected
- Either use both tests together to maximize sensitivity, or
- Two-step approach with IGRA following a negative TST 1
- T-SPOT.TB may be less affected by immunosuppression than QFT-GIT 1
Immigrants from TB-Endemic Countries
- TST followed by IGRA if positive (to increase specificity)
- Accounts for high rates of BCG vaccination in TB-endemic countries 1
Healthcare Workers (Serial Testing)
- Caution with IGRAs due to higher false conversion rates in serial testing
- Consider the potential for variability in test results 3
Interpretation and Management
- A positive IGRA result should not be the sole factor in diagnosing LTBI
- Consider epidemiologic and medical history, along with risk factors for TB progression
- Exclude active TB through clinical evaluation, chest radiography, and when indicated, sputum testing
- Negative IGRA results do not definitively exclude infection, especially in high-risk individuals 1
Important Considerations
- Repeat testing may be useful when initial IGRA results are indeterminate, borderline, or invalid
- In low-risk individuals with positive results, consider the possibility of false positives
- In discordant results (IGRA positive/TST negative or vice versa), individualized assessment is needed based on risk factors and test quality 1
IGRAs represent an important advance in LTBI diagnosis, but their optimal use requires understanding their strengths, limitations, and appropriate application in different clinical scenarios.